Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:23][CH3:24])[CH:5]=1.ClS([N:30]=[C:31]=[O:32])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]([C:31](=[O:32])[NH2:30])[CH:12]=2)=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C(N)=O)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 30.8 %

Procedure:
To a solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (5.04 grams, 14.80 mmol) in methylene chloride (150 mL) was added chlorosulfonylisocyanate (1.3 mL, 14.80 mmol) and the resulting solution was stirred for 5 days at room temperature. The solution was then concentrated in vacuo, and the crude product dissolved in a 6:1 ratio of acetone:water (180 mL). The pH of this solution was adjusted to approx. 8 by the addition of 2 M sodium hydroxide (aq). The resulting mixture was stirred, at room temperature, for 45 minutes. The reaction was diluted with water (300 mL) and the resulting suspension was stirred for 30 minutes. Filtration, followed by trituration of the solid in methanol gave 4-[1-carbamoyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.75 grams). The filtrate was concentrated, and the crude chromatographed on silica gel (2.5% methanol/methylene chloride) to give additional 4-[1-carbamoyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.36 grams, 37% yield overall).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]([O:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[O:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29](=[O:30])[O:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([N:8]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:10]=[CH:9]3)=[CH:38][CH:39]=2)(=[O:26])=[O:27])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cnc(-c4ccccc4)c3-c3ccccc3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,5-diphenylimidazole and 4-{2-[({[(4-Methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid: MS (ESI) m/z 538 [M+H]+, 536 [M−H]−, 1H-NMR (CDCl3) δ 2.43 (3H, s), 2.84 (2H, t, J=6.6 Hz), 4.22-4.28 (2H, m), 6.86-6.95 (2H, m), 7.03-7.08 (4H, m), 7.21-7.52 (10H, m), 7.73 (1H, s), 7.85-7.90 (2H, m).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.ClCCl.CN(C)C=O.[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=C3)[CH:24]=1)=[O:19])[CH3:16]>C(OCC)(=O)C>[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:25]2[CH:33]=[C:32]3[C:31](=[CH:27][CH:26]=2)[NH:30][CH:29]=[C:2]3[CH:1]=[O:5])[CH:24]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cnn(-c2ccc3[nH]ccc3c2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccc3[nH]cc(C=O)c3c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.56 mL, 6.6 mmol) was added to anhydrous dichloromethane (50 mL), N,N-dimethylformamide (0.51 mL, 6.6 mmol) was added thereto at 0° C., and the mixture was stirred for 30 min at 0° C. To this reaction solution was added a mixture of 1-(1H-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (1.40 g, 5.47 mmol) obtained in Preparation 1 and dichloromethane (50 mL). The mixture was stirred under reflux for 1 h at room temperature, and the solvent was removed. Tetrahydrofuran (100 mL) and 20% aqueous ammonium acetate solution (100 mL) were added, which was then heated for 30 min while being stirred under reflux. After completion of the reaction, the reaction solution was cooled. Ethyl acetate was added and the mixture was washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@@H:9]2C3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4C(O)=C3C[C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)C[C@H](N)[C@@H]1O.C1C(CC(O)=O)=CC(I)=C([O:47]C2C=C(I)C(O)=C(I)C=2)C=1I.[CH2:62]=[O:63]>>[OH:63][C@@H:62]1[O:47][C@H:10]([CH2:9][OH:8])[C@H:11]([OH:37])[C@H:33]([OH:34])[C@H:35]1[OH:36]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: O=C(O)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: C=O
Product: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 24 h

Procedure:
Cells were seeded on 100-mm culture dishes and treated with doxorubicin, tetrac or both for 24 h, after which the cells were subjected to trypsin treatment at 37° C. for 3 min, fixed with 4% formalin in PBS, and washed with PBS. Then they were incubated with 0.1 μg/ml Hoechst 33248 (bisbenzimide, Sigma-Aldrich) and spotted on slides for microscopy. Positive cells are counted and their fractions between non treated and treated populations are compared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.[CH2:23](N(C(C)C)C(C)C)C.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:21])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[N:12]=[C:11]([O:22][CH3:23])[CH2:10][N:9]=1
Reactant: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: CCN(C(C)C)C(C)C
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COC1=Nc2cc(OC)c(F)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 3.0 g (0.0094 mole) of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ia), 11.8 mL of ethyl diisopropyl amine, 4.62 g of 1,2,4-triazole and 45 mL of tetrahydrofuran at 0° C., was added 1.575 mL of phosphorous oxychloride. After 20 minutes, the cooling bath was removed, and the mixture was stirred at room temperature for another 60 minutes. Then, 17 mL of 4.37 M sodium methoxide in methanol solution was added to the reaction mixture. After stirring for 2 hours, another 5 mL of sodium methoxide solution was added, and the mixture stirred overnight. The mixture was then partitioned between ethyl acetate and water. The ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 3.2 g of 5-(2-chlorophenyl)-7-fluoro-2,8-dimethoxy-3H-1,4-benzodiazepine (intermediate Va), which was of sufficient purity to use in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[NH:66]1[CH2:71][CH2:70][CH:69]([N:72]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[NH:74][C:73]2=[O:82])[CH2:68][CH2:67]1>O.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][C:10]([CH2:11][C:12](=[O:13])[N:66]1[CH2:67][CH2:68][CH:69]([N:72]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[NH:74][C:73]2=[O:82])[CH2:70][CH2:71]1)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccc(C)c(C)c1)C(=O)OCC
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc(C)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 10.0 g (29.7 mmol) 4-(3,4-dimethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic acid, 10.5 g (32.7 mmol) TBTU, 4.2 g (30.5 mmol) HOBt, 5.8 mL (32.4 mmol) ethyldiisopropylamine, 270 mL THF and 30 mL water was stirred for 15 min at RT and then combined with 7.6 g (32.9 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one. The reaction mixture was stirred for 5 h at RT and evaporated down under reduced pressure. The residue was stirred with 150 mL saturated NaHCO3 solution, suction filtered, washed with water and dried in the circulating air dryer.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2-c2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1

Procedure:
To a solution of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[12-a]quinoxaline in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine followed by stirring and heating under reflux for 2 hours. The hot reaction mixture is filtered through diatomaceous earth and the filter cake washed with hot chloroform and the filtrate concentrated in vacuo. The residue is triturated with ethyl acetate and the mixture filtered to give the desired product as crystals, m.p. 225°-228° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C@@H:15]([O:28][CH2:29][CH:30]=C)[C@H:14]([CH3:32])[O:13][C:12]1=[O:33])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:36].[Na+].O=[O+][O-].CSC>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:34])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C@@H:15]([O:28][CH2:29][CH:30]=[O:36])[C@H:14]([CH3:32])[O:13][C:12]1=[O:33])[CH2:8][O:9][CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C([O-])O
Reactant: C=CCO[C@@H]1[C@@H](Cc2ccc(F)cc2)CCC[C@H](N(COC)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(F)cc2)[C@@H](OCC=O)[C@H](C)OC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of tert-butyl((3S,7R,8R,9S)-8-(allyloxy)-7-(4-fluorobenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (480 mg, 1.001 mmol), NaHCO3 (8.41 mg, 0.10 mmol) and anhydrous MeOH (0.31 mL) in anhydrous CH2Cl2 (9.7 mL) was treated with ozone at −78° C. until the solution became light blue in color. The mixture was purged with nitrogen until colorless and then quenched by addition of dimethyl sulfide (0.148 mL, 2.00 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h, concentrated, and purified by column chromatography on SiO2 (gradient, hexanes/EtOAc) to provide the title compound as a mixture of rotamers in the form of a white solid (461 mg, 96%): mp 51-53° C.; IR (neat) 2935, 1740, 1701, 1509, 1367, 1297, 1173, 1081 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 7.17-7.06 (m, 2H), 7.00-6.91 (m, 2H), 4.99-4.16 (m, 6H), 3.87-2.97 (m, 4H), 2.46-2.27 (m, 1H), 2.17-2.01 (m, 1H), 1.97-1.75 (m, 1H), 1.74-1.37 (m, 17H), 0.95-0.78 (m, 1H); HRMS-ESI (m/z) ([M]+) calcd for C25H36FNO7, 481.2476; found, 481.2481.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=[N:2][NH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNc1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(NN=Cc2cc(I)ccc2F)c1
Yield: 97.6 %

Procedure:
3-Hydrazinylbenzoic acid (1.52 g, 10 mmol)), 2-fluoro-5-iodobenzaldehyde (2.5 g, 10 mmol) and caesium carbonate (3.26 g, 10 mmol) were stirred in DMF (10 mL) at room temp under argon atmosphere for 2.5 h. Water (40 mL) was added and the clear solution was acidified with aqueous HCl (1.7 M). The beige-orange precipitate that formed was collected by, filtration, washed with water and dried in vacuo to give the title compound (3.75 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[C:4]([CH:8]=[C:9]([S:11]([NH:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:32][C:33]([C:41]1[S:45][C:44]([NH2:46])=[N:43][N:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:17])=[C:4]([CH:8]=[C:9]([S:11]([NH:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH:10]=1)[C:5]([NH:46][C:44]1[S:45][C:41]([C:33]([CH3:34])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:32])=[N:42][N:43]=1)=[O:7]
Reactant: CCNS(=O)(=O)c1cc(Cl)c(F)c(C(=O)O)c1
Reactant: CC(C)(c1ccccc1)c1nnc(N)s1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNS(=O)(=O)c1cc(Cl)c(F)c(C(=O)Nc2nnc(C(C)(C)c3ccccc3)s2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109.2 %

Procedure:
To 3-chloro-5-[(ethylamino)sulfonyl]-2-fluorobenzoic acid (60 mg, 0.213 mmol) in DMF (3 ml) and DCM (3 ml) was added EDC (40.8 mg, 0.213 mmol) and HOBt (32.6 mg, 0.213 mmol). After 10 mins, 5-(1-methyl-1-phenylethyl)-1,3,4-thiadiazol-2-amine (41.6 mg) was added. The reaction mixture was stirred at rt overnight, concentrated and purifed by HPLC to give the title compound (100 mg) LC/MS: m/z 482.8 (M+H), rt 2.05 min.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=4)[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:33]1([NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH2:39].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(#N)C>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:40][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:18]2[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:11][CH:12]=3)[CH:21]=[CH:20][N:19]=2)=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
To a solution of 21 (crude from the previous step) in dry acetonitrile (50 mL) was added 1,2-phenylenediamine (1.83 g, 16.9 mmol) followed by Et3N (2.65 mL, 19.0 mmol), HOBt.H2O (1.03 g, 7.6 mmol) and EDCI.HCl (1.62 g, 8.5 mmol). The mixture was stirred at room temperature for 72 h, filtered to remove salts and filtrate was concentrated to form a residue, which was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98 to 5/95). Trituration of this material with a mixture of EtOAc/CH2Cl2, allowed affording the title compound 22a (696 mg, 1.3 mmol, 31% yield over 2 steps) as a white solid. 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 9.55 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.77 (t, J=6.4 Hz, 1H), 7.44 (d, J=7.2 Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 7.07 (d, J=5.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.92 (td, J=7.6, 1.6 Hz, 1H), 6.73 (dd, J=8.0, 1.6 Hz, 1H), 6.55 (td, J=7.4, 1.2 Hz, 1H), 4.85 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.13 (t, J=5.6 Hz, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.68 (t, J=5.6 Hz, 2H), 2.45 (t, J=4.4 Hz, 4H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH2:13])[C:8]([NH:11][CH3:12])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]([CH3:29])[C:12]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:13][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CNc1ccc(S(C)(=O)=O)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(S(C)(=O)=O)ccc21
Yield: 65.9 %

Procedure:
(5-Methanesulfonyl-1-methyl-1H-benzoimidazol-2-yl)-(6-trifluoromethoxy-benzothiazol-2-yl)-amine (72 mg) was prepared by following General Procedure D starting from 4-methanesulfonyl-N1-methyl-benzene-1,2-diamine (50 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (59 mg), 1,1′-thiocarbonyl-diimidazole (44 mg), and EDC (48 mg). LC/MS: m/z 444.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.C(Br)(Br)(Br)[Br:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: BrC(Br)(Br)Br
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CBr
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
(4-Bromo-2-methylphenyl)methanol (10.4 g, 51.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (18.8 g, 56.8 mmol) added. The reaction mixture is cooled to 0-5° C. and PPh3 (14.9 g, 56.8 mmol) is added. The reaction mixture is stirred overnight then hexane/EtOAc (9:1) (250 mL) is added with vigorous stirring. The triphenylphosphine oxide that forms during the reaction is filtered off and the filtrates are concentrated in vacuo. The resulting oil is purified on a silica gel pad with hexane/EtOAc (8:2). The solvent are removed on a rotary evaporator and the bromoform is removed by vacuum distillation (15 mm Hg, bp: 40-50° C.) to provide the expected product 1-Bromo-4-(bromomethyl)-3-methylbenzene (13.23 g, 97%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.37-7.27 (2H, m), 7.17 (1H, d, J=8.1 Hz), 4.45 (2H, s), 2.39 (3H, s).
Reaction SMILES: [Mg].Br[CH2:3][CH:4]1[CH2:7][CH2:6][CH2:5]1.[C:8](OCC)(=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])[C:8](=[O:14])[CH2:3][CH:4]1[CH2:7][CH2:6][CH2:5]1)[CH3:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: BrCC1CCC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC1CCC1
Temperature: 60 °C
Yield: 35.7 %

Procedure:
To a suspension of 5 mg per mL Rieke® magnesium in THF (37.9 mmol, 40 mL) at room temperature is added bromomethyl cyclobutane (37.9 mmol, 4.25 mL) dropwise. After the addition, the reaction is heated to 60° C. for 1 h. The mixture is transferred via syringe to a −78° C. solution of diethyl oxalate (37.9 mmol, 5.14 g) in THF (20 mL). The reaction is allowed to warm to 0° C. and is quenched with 1N HCl. Diethyl ether is added (20 mL) and the layers are separated. The organic layer is dried (Na2SO4) and adsorbed onto silica and purified using a gradient to 0-10% EtOAc/Hexanes to yield the title compound (2.3 g, 37%). LC-MS: 171.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[I-].[K+].Cl[CH2:17][C:18]1[N:19]=[C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:23]=[C:22]([S:34][CH2:35][CH3:36])[N:21]2[CH:37]=1>CN(C=O)C>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[C:24]1[N:23]=[C:22]([S:34][CH2:35][CH3:36])[N:21]2[CH:37]=[C:18]([CH2:17][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:19]=[C:20]2[CH:25]=1
Reactant: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CCl)cn12
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCOCC3)cn12
Reaction time: 16 h

Procedure:
102 mg (1.17 mmol) of morpholine are introduced into 7 ml of DMF at 0° C., and 236 mg (0.78 mmol) of triethylamine and a catalytic amount of potassium iodide are added. A solution of 290 mg of 2-(chloromethyl)-7-(2,4-dichlorophenyl)-5-(ethylsulphanyl)imidazo[1,2-c]pyrimidine (Example 91A) in DMF is then slowly added dropwise. The mixture is allowed to reach RT and is stirred at this temperature for a further 16 h. Purification of the crude product by preparative HPLC and drying under high vacuum result in 214 mg (43% of theory) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([O-])(=O)C.[NH4+:33]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:33]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(/C=C/C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nc(-c3ccccc3)c[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxo-2-phenylethyl)acrylic acid amide (100 mg) and ammonium acetate (410 mg) in acetic acid (5 mL) was heated under reflux for 10 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=5:1) to obtain 34 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH3:39][C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:45][C:42]3[S:43][CH:44]=[C:40]([CH3:39])[N:41]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: CN1CC[C@H](Oc2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(C(=O)O)c2)C1=O
Reactant: Cc1csc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@H]3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.10 mL, 0.75 mmol) was added to a solution of the 3-[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 6) (265 mg, 0.62 mmol) in DCM (5 mL) and stirred at ambient temperature for 30 minutes, a further aliquot of 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.10 mL) was added and stirring continued for a further 30 minutes. 4-Methyl-1,3-thiazol-2-amine (142 mg, 1.2 mmol) and pyridine (0.10 mL, 1.2 mmol) were added and the reaction stirred for 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and DCM (15 mL), washed with water (2×10 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated under reduced pressure to give the crude product which was purified by flash chromatography on silica, eluting with a gradient of 0-5% methanol in DCM, to afford the product (181 mg, 58%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.26 (m, 4H), 2.38 (quintet, 2H), 2.50-2.63 (m, 1H), 2.93 (s, 3H), 3.33-3.56 (m, 2H), 4.26 (t, 2H), 4.69 (t, 2H), 4.84 (t, 1H), 6.54 (s, 1H), 7.15 (s, 1H), 7.36 (s, 1H), 7.53 (s, 1H), 8.32 (s, 1H), 8.82 (s, 1H), 10.43 (s, 1H); m/z 509 (M+H)+