Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[O:21]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:29][CH:30]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc(Oc2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 4-phenoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 432.27 g/mol.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C.O[Li].O.CS(C)=O>C1COCC1.O>[N:22]([C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([OH:25])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3])=[N+:23]=[N-:24]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1O)[C@@H]2C(=O)O
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII) (845 mg, 2.45 mmol) in THF (21 mL) and H2O (6 mL) was added LiOH.H2O (411 mg, 9.8 mmol) and the mixture was stirred at 23° C. for 18 h. The benzyl alcohol was extracted with ether, the aqueous layer acidified with 1 M KHSO4 -sol., saturated with solid NaCl, extracted with EtOAc (4×50 mL) and dried over MgSO4. After removal of the solvent under vacuum crude (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (XI) (581 mg, quant.) was obtained as white solid, sufficiently pure for further transformations. 1H-NMR (250 MHz, DMSO) □1.75 (1H, t, J=3.5 Hz), 1.84 (1H, m), 1.92-2.07 (2H, m), 2.15 (1H, dd, J=12.5, 7 Hz), 3.87 (1H, btJ=7 Hz); MS[ISN] 226 [(M-H)-]; mp 124-128° C.; □D20 -61.48° (c=0.90, H2O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:23])([F:24])[F:25])[CH2:9][C:10]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C(F)(F)F
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C(F)(F)F)ccn1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-(2-trifluoromethyl-phenyl)-propionamide and 4-bromo-2-methylpyridine was prepared the title compound as a white solid, MS (ESI+): m/z=448.0 ([M+H]+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH2:13][OH:14]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][CH2:13][OH:14])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(Br)cn1CCO
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 5-bromo-2(1H)-pyridone (1000 mg, 5.74 mmol) in dry DMF (10 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 264 mg, 11.5 mmol). After 20 min at 23° C., 2-bromoethyl alcohol (448 μl, 6.32 mmol) was added and the reaction mixture was stirred at 23° C. for 3 days. The reaction was quenched with NH4Cl (sat., 20 mL) and extracted with 9:1 CH2Cl2/iPrOH (50 mL; 25 mL×6). The combined organics were dried over MgSO4, and concentrated to an oil under reduced pressure from toluene. iPrOH (0.5 mL) was added, and the solution was seeded with crystals of the product. The resulting solids were washed with iPrOH (0.5 mL) and ether (2×2 mL). The mother liquor was then purified on silica (12 g) eluting with 0-3% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 217/219. Calc'd exact mass for C7H8BrNO2: 216. 1HNMR (400 MHz, CDCl3): δ 3.34 (br. s., 1H) 3.90-3.94 (m, 2H) 4.02-4.10 (m, 2H) 6.49 (d, J=9.59 Hz, 1H) 7.39 (dd, J=9.68, 2.64 Hz, 1H) 7.49-7.53 (m, 1H). 13C NMR (101 MHz, CDCl3) δ ppm 53.11, 61.04, 98.15, 121.80, 138.62, 143.04, 161.89
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1C=O.[CH3:14][O:15][CH:16](OC)[O:17][CH3:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:14][O:15][CH:16]([O:17][CH3:18])[C:3]1[C:2]([F:1])=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:7][C:6]=1[F:13]
Reactant: COC(OC)OC
Reactant: O=Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(OC)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Yield: 143.4 %

Procedure:
A solution of 2,6-difluoro-3-nitro-benzaldehyde (9.0 g, 48.1 mmol), p-toluenesulfonic acid monohydrate (183 mg, 0.962 mmol), trimethylorthoformate (3.5 ml, 32.4 mmol) and methanol (200 ml) was heated at reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The resultant residue was dissolved in DCM (250 mL) and washed with a mixture of water (200 mL) and saturated NaHCO3 solution (50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to yield the title compound (10.83 g, 97%). 1H NMR (DMSO-d6, 300 MHz): 8.28 (1 H, ddd, J=9.34, 8.48, 5.51 Hz), 7.39 (1 H, td, J=9.34, 1.81 Hz), 5.66 (1 H, s), 3.40 (6 H, s).
Reaction SMILES: [NH2:1][CH:2]=[CH:3][CH2:4][CH2:5][NH2:6].[N:7]1([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([S:23](Cl)(=[O:25])=[O:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][N:14]=[C:13]2[N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:25])=[O:24]
Reactant: NC=CCCN
Reactant: O=S(=O)(Cl)c1ccc2ncnc(N3CCCCC3)c2c1
Solvent: ClC(Cl)Cl
Product: NCCCCNS(=O)(=O)c1ccc2ncnc(N3CCCCC3)c2c1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
In 100 ml of chloroform was dissolved 4.4 g of 1,4-diaminobutene, and to the solution was added dropwise 50 ml of a chloroform solution containing 3.1 g of 4-piperidino-6-quinazolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and the reaction solution was extracted with a 10% aqueous hydrochloric acid solution. The chloroform layer was washed with water and dried with anhydrous potassium carbonate. Then chloroform was distilled from the chloroform layer, and the residue was separated by Prep LC/System 500 (Waters Associates, U.S.A.) [column: Prepack 500/C18 ; solvent: H2O/CH3CN=85/15 (volume ratio); flow rate: 100 ml/minute] to give 2.8 g of N-(4-aminobutyl)-4-piperidino-6-quinazolinesulfonamide [i.e. Compound(31)] as an oily substance in a yield of 77%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([CH3:25])[CH:6]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([CH:6]([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[F:14])[CH:5]([CH3:25])[CH2:4][CH2:3][N:2]([CH3:1])[S:33]([CH3:32])(=[O:35])=[O:34])(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(CCN(C)S(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
To the amine from Step (b) (0.116 g, 0.3 mmol) in dry dichloromethane (5 ml) was added pyridine (0.060 ml, 0.75 mmol), followed by methanesulfonyl chloride (0.035 ml, 0.45 mmol), and the mixture was stirred at room temperature for 48 hours. After dilution with water (20 ml) and extraction with ethyl acetate (3×20 ml), the combined organic fractions were washed with brine, dried (MgSO4 and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 10% to 30% ethyl acetate in iso-hexane to give as a mixture of diastereoisomers the title compound as a colourless oil (35 mg, 25%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3]([NH:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:4].Cl[CH2:14][C@@H:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.CC(C)([O-])C.[Na+].N#N>CN(C=O)C>[CH3:20][C:17]1([CH3:21])[O:16][C@H:15]([CH2:14][N:8]2[CH:9]=[CH:10][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:12])([CH3:11])[CH3:1])=[N:7]2)[CH2:19][O:18]1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: CC(C)(C)C(=O)Nc1cc[nH]n1
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(C)(C)C)n2)O1
Temperature: 100 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide (1.67 g, 10 mmol) was dissolved in DMF (17 ml). (S)-4-Chloromethyl-2,2-dimethyl-[1,3]dioxolane (1.52 g, 10 mmol) was added into the mixture. Finally Sodium tert-butoxide (0.98 g, 10 mmol) was added at room temperature. The mixture was heated to 100° C. with agitation for 23 hours under N2 atmosphere. UPLC indicated that there was 26% 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide remained in the mixture. Additional 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide (0.76 g, 5 mmol) and Sodium tert-butoxide (0.49 g, 5 mmol) was added. The mixture was stirred at 100° C. for another 24 hrs. HPLC indicated 2,2-Dimethyl-N-(1H-pyrazol-3-yl)-propionamide was 9.4% remained, the selectivity of N1/N2 alkylation products was 2.8:1. The DMF was concentrated under reduced pressure. Water (10 ml) was added. The mixture was extracted with DCM (2×12 ml), the organic layer was washed with 10% aqueous NaCl (2×20 ml). The organic layer was dried over Na2SO4, concentrated under reduced pressure to give oil, which is purified by silicon column (hexane/EA=5:1 to hexane/EA=3:1) to give off-white solid (0.84 g), yield: 30%. 1H-NMR (400 MHz, d6-DMSO): δ 9.85 (s, 1H), 7.59 (s, 1H), 6.47 (s, 1H), 4.36-4.39 (m, 1H), 4.08-4.12 (m, 2H), 4.0-4.02 (m, 1H), 3.73-3.75 (m, 1H), 1.33 (s, 3H), 1.26 (s, 3H), 1.19 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[N:12]=[C:11]([C@@H:13]([O:18][C:19]([C@H:21]3[C@@H:23]([CH:24]=[C:25]([Cl:27])[Cl:26])[C:22]3([CH3:29])[CH3:28])=[O:20])[C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.FC1C=CC(OC2N=C([C@H](OC([C@@H]3[C@H](C=C(Cl)Cl)C3(C)C)=O)C(F)(F)F)C=CC=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:12]=[C:11]([CH:13]([O:18][C:19]([C@H:21]3[C@@H:23]([CH:24]=[C:25]([Cl:27])[Cl:26])[C:22]3([CH3:29])[CH3:28])=[O:20])[C:14]([F:16])([F:17])[F:15])[CH:10]=[CH:9][CH:8]=2)=[CH:30][CH:31]=1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O[C@H](c1cccc(Oc2ccc(F)cc2)n1)C(F)(F)F
Agent: CC1(C)[C@H](C(=O)O[C@@H](c2cccc(Oc3ccc(F)cc3)n2)C(F)(F)F)[C@@H]1C=C(Cl)Cl
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(c1cccc(Oc2ccc(F)cc2)n1)C(F)(F)F

Procedure:
[1-[6-(4-Fluorophenoxy)-2-pyridinyl]-(R)-2,2,2-trifluoroethyl]-(1S)-cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate plus [1-[6-(4-fluorophenoxy)-2-pyridinyl]-(S)-2,2,2-trifluoroethyl]-(1R)-cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:14]=1[C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:21]([C:18]1[CH:19]=[CH:20][C:13]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:22]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 106.6 %

Procedure:
To a solution of 3-(trifluoromethyl)phenol (1.435 g, 8.85 mmol) and 2-fluoro-5-formylbenzonitrile (1.2 g, 8.05 mmol) in DMF (25 mL) was added K2CO3 (3.34 g, 24.14 mmol) under argon. The mixture was heated at 90° C. for 0.5 h. After removing the solvent, the residue was diluted with water, extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated. Recrystallization in EA then afforded the title compound (2.5 g, 8.58 mmol, 107% yield). LCMS: rt=3.34 min, [M+H+]=292
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2/[CH:14]=[CH:15]/[C:16]2[S:17][C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:33][C:22]([C:18]1[S:17][C:16](/[CH:15]=[CH:14]/[C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:20][C:19]=1[CH3:21])=[O:23])([CH3:39])[CH3:35]
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 2-{(E)-2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (75 mg, 0.22 mmol) and TBTU (77 mg, 0.24 mmol) in DMF (0.4 mL) was added DIPEA (186 μL, 1.09 mmol). Then isopropylamine (21 μL, 0.24 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 1 to 5% methanol in dichloromethane) afforded the title compound (28 mg, 33%) as an off white solid after recrystallisation from ethylacetate and heptane. MS: m/e=386.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[N:23]=[CH:22][S:21][C:19]4=3)[N:14]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:13]2=[O:29])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:30]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH2:24]([N:14]1[C:15]2[C:20](=[C:19]3[S:21][CH:22]=[N:23][C:18]3=[CH:17][CH:16]=2)[C:12]2([C:3]3=[CH:4][C:5]4[O:10][CH2:9][CH2:8][O:7][C:6]=4[CH:11]=[C:2]3[O:1][CH2:30]2)[C:13]1=[O:29])[CH2:25][CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)CCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c1ccc1ncsc21
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CC(C)CCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c1ccc1ncsc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-isopentyl-6H-thiazolo[5,4-e]indol-7(8H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6′-isopentyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,8′-thiazolo[5,4-e]indol]-7′(6′H)-one was obtained (17%) as a colorless solid: mp 169-171° C.; 1H NMR (300 MHz, CDCl3) δ8.89 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 6.21 (s, 1H), 4.84 (ABq, 2H), 4.30-4.17 (m, 2H), 4.17-4.08 (m, 2H), 4.03-3.89 (m, 1H), 3.90-3.75 (m, 1H), 1.91-1.51 (m, 3H), 1.04 (d, J=6.1 Hz, 6H); MS (ES+) m/z 423.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[C:26]=2[Cl:33])[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[C:26]=4[Cl:33])[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=C(CBr)Nc1nc(-c2ccc(Cl)c(Cl)c2Cl)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(Cl)c(Cl)c3Cl)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-[4-(2,3,4-trichlorophenyl)-1,3-thiazol-2-yl]acetamide (134 mg, 0.334 mmol) in the presence of NaH (10 mg, 0.416 mmol) in dry DMF (5.0 mL) to give 37 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.40 (s, 3H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.70 (s, 1H), 7.77 (s, 2H), 12.74 (br s, 1H). APCI-MS (m/z) 498.14 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([N+:24]([O-])=O)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>O>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:27]
Reactant: O=C(c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1

Procedure:
By reducing N,N-dibenzyl-4-benzyloxy-3-nitrobenzamide (melting point 131°-132° C.) in water-containing methanol with reduced iron powder-hydrochloric acid, 3-amino-N,N-dibenzyl-4-benzyloxybenzamide (melting point 81° C.) was obtained. Then, by reacting 3-amino-N,N-dibenzyl-4-benzyloxybenzamide with ethyl oxalyl chloride in the presence of pyridine in tetrahydrofuran, ethyl 2-benzyloxy-5-(N,N-dibenzylcarbamoyl)oxanilate (melting point 132°-133° C.) was obtained. A solution of 3.6 g of ethyl 2-benzyloxy-5-(N,N-dibenzylcarbamoyl)oxanilate thus obtained in 100 ml of ethanol was catalytically hydrogenated in the presence of 0.8 g of 10% palladium carbon until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide 2.7 g of ethyl 5-(N,N-dibenzylcarbamoyl)-2-hydroxyoxanilate, a gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23]B(O)O.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc(-c2cc(C)cc(C(F)(F)F)c2)co1
Temperature: 100 °C
Yield: 78 %

Procedure:
A stirred solution of methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44, 0.150 g, 0.397 mmol), methylboronic acid (0.071 g, 1.19 mmol), and triethylamine (0.402 g, 3.97 mmol) in DMF (10.0 mL) was degassed and then purged with nitrogen. To this reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.0203 mmol) and the resulting reaction mixture was heated at 100° C. for 6 h. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water and saturated sodium chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 9:1) to provide methyl 3-(4-(3-methyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.097 g, 78%) as a viscous yellow oil.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:20][C:21]([O:23]C)=[O:22].C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:50][CH2:49][CH2:48]3)=[CH:43][CH:42]=2)O1>C1(C)C=CC=CC=1>[C:54]([O:53][C:52]([NH:51][C:47]1([C:44]2[CH:45]=[CH:46][C:41]([C:2]3[N:6]4[C:7]5[CH:19]=[CH:18][CH:17]=[N:16][C:8]=5[NH:9][C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[C:5]4=[N:4][C:3]=3[CH2:20][C:21]([OH:23])=[O:22])=[CH:42][CH:43]=2)[CH2:50][CH2:49][CH2:48]1)=[O:58])([CH3:57])([CH3:55])[CH3:56]
Reactant: COC(=O)Cc1nc2n(c1Br)-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CC(=O)O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a suspension of methyl 2-(3-bromo-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.15 g, 1 eq.) in a mixture of toluene (8 mL), ethanol (8 mL), and saturated sodium bicarbonate (2 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.219 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.045 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (30 mL). The aqueous phase was extracted with dichloromethane (2×30 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (0-100% ethyl acetate in hexanes) gave 2-(3-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetic acid (0.04 g, 19%). LCMS: 538 [M+H].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:22][CH2:23][O:24][C:25]([CH2:27][CH:28]1[C:33](=O)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]>>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:29]3[CH:28]([CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])[CH2:33][CH2:32][CH2:31][C:30]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CC(C)(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(C(C)(C)C)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-tert-butylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[NH:30]N>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:30]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1nccs1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3nccs3)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and thiazol-2-yl-hydrazine according to the method described for example 91. MS: M=400.1 (M+H)+