Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(F)c1
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Titanium tetrachloride (1.70 mL, 15.5 mmol) was added dropwise to a suspension of zinc powder (2.12 g, 32.4 mmol) in anhydrous THF (60 mL) at RT. After refluxing for 1 h, a mixture of 82 (1.18 g, 4.00 mmol) and cyclohexanone (1.18 g, 12.0 mmol) dissolved in THF (20 mL) was added dropwise. Refluxing was continued for 30 min. The reaction mixture was cooled to RT and filtered through Celite. Water (250 mL) was added and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.15 g (80%) of compound 83 as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ1.58 (br s, 6H), 2.20 (m, 4H), 5.10 (br s, 1H), 6.77 (m, 2H), 6.89 (t, J=8.6 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][N:7]2[C:12]=1[C:11](=O)[NH:10][CH:9]=[N:8]2)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:11]1[C:12]2=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][N:7]2[N:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1ccn2nc[nH]c(=O)c12
Product: CC(C)c1ccn2ncnc(Cl)c12
Temperature: 25 °C

Procedure:
5-Isopropylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.035 g, 0.198 mmol, 1.0 equiv) was added to phosphorous oxychloride (2.0 ml, 21.5 mmol, 109 equiv) under a nitrogen atmosphere. The reaction mixture was heated to reflux for 1.5 h. The mixture was cooled to room temperature then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic washes were dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a tan solid that was used in the next step without further purification. MS(ESI+) m/z 196 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[N:2]2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: c1cnc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ncc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1H-pyrazolo[3,4-b]pyridine (300 mg) in DMF (3.0 mL) was added sodium hydride (101 mg) (60% in mineral oil) with ice-cooling. The mixture was stirred at room temperature for 30 min, and then 1-fluoro-4-nitrobenzene (355 mg) was added. After stirring at room temperature for 2 h, the mixture was warmed up to 50° C. The mixture was stirred at 50° C. for 12 h. Cesium carbonate (821 mg) was added and the mixture was stirred at 100° C. for 12 h, and treated with water and AcOEt. The insoluble material was filtered off. The organic layer was separated and the aqueous layer was extracted with AcOEt. The organic layer was combined, dried over MgSO4 and concentrated in vacuo. The residue was used for the next reaction.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:15][N:16]([CH3:20])[C:17](=[S:19])[S-:18].C[NH2+]C>C(=S)=S>[CH3:15][N:16]([CH3:20])[C:17](=[S:18])[S:19][CH:8]([CH2:9][N+:10]([O-:12])=[O:11])[C:7]1[CH:13]=[CH:14][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CN(C)C(=S)[S-]
Reactant: CC(C)c1ccc(C=C[N+](=O)[O-])cc1
Agent: C[NH2+]C
Solvent: S=C=S
Product: CC(C)c1ccc(C(C[N+](=O)[O-])SC(=S)N(C)C)cc1

Procedure:
As in Example 17, reaction of p-isopropyl-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave p-isopropyl-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 119° C.-120° C. after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].CCN(CC)CC.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].O>ClCCl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
A solution of 1-acetylpiperazine (1.30 g) and Et3N (1.23 g) in dichloromethane (10 ml) was added dropwise to a solution of 4-nitrophenyl chloroformate (2.05 g) in dichloromethane (20 ml) under ice-cooling. After stirring at 0° C. for 30 minutes and at room temperature for 1 hour, water was added to the reaction solution, and the reaction solution was extracted with dichloromethane. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (1.70 g) as colorless crystals.
Reaction SMILES: C([Mg]Cl)C(C)C.C(Cl)C(C)C.[Mg].[F:13][C:14]([F:26])([F:25])[CH:15]([OH:24])[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC.[CH-]1[C-]=[C-][C-]=[C-]1.[CH-]1[C-]=[C-][C-]=[C-]1.Cl[Ti]Cl>[F:13][C:14]([F:25])([F:26])[CH:15]([OH:24])/[CH:16]=[CH:17]\[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC(C#Cc1ccccc1)C(F)(F)F
Agent: Cl[Ti]Cl
Agent: CC(C)C[Mg]Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(C)CCl
Product: OC(/C=C\c1ccccc1)C(F)(F)F
Reaction time: 1 h
Yield: 53 %

Procedure:
In an isobutylmagnesium chloride solution that was prepared by reacting isobutyl chloride (2.34 g, 25 mmol) and magnesium (0.66 g, 27 mmol) in dry ether (30 ml) at 0° C., dichlorobis(π-cyclopentadienyl)titanium (0.14 g, 0.56 mmol) and 1,1,1,-trifluoro-4-phenyl-3-butyne-2-ol (2g, 10 mmol) were slowly added at 0° C. After 1 hour agitation at the same temperature, the reaction mixture was treated by a method similar to the one in the above Examples to obtain (Z)-1,1,1-trifluoro-4-phenyl-3-butene-2-ol (b.p.: 78°-80° C./3 mmHg) at a yield of 53%. The above product gave the following analytical data:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14](OCC)=[O:15])[N+:10]([O-:19])=[C:9]([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:8]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1>CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:10]3[O:19][C:14](=[O:15])[N:13]=[C:11]3[N:12]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Nc1nc(N2CC=CCC2)nc(NC(=O)OCC)[n+]1[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1nc(N2CC=CCC2)nc2nc(=O)on12
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
4.8 g. of diethyl 6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine-2,4-dicarbamate-3-oxide are mixed with 100 ml of absolute dimethylformamide and stirred at 140° C. for 30 minutes. The solvent is then evaporated off under reduced pressure and the residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure ethyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazine-7-carbamate having a melting point of 220°-225° C.(decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CON(C)C(=O)[C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([NH2:38])=[CH:33][C:32]=1[O:39][CH3:40]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1.O>[NH2:38][C:34]1[C:35]([Cl:37])=[CH:36][C:31]([C:16](=[O:18])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[C:32]([O:39][CH3:40])[CH:33]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N(C)OC
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
3-[1-(tert-Butoxycarbonyl)piperidin-4-yl]propionic acid (4.6 g, 18 mmol), prepared as in Example 1, was dissolved in HMPA (10 mL) and THF (10 mL), and this solution was added to a -20° solution of lithium diisopropylamide (60 mmol). The mixture was warmed to 0° C., stirred for 30 minutes, and then cooled to -40° C. N-Methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (4.9 g, 20 mmol), prepared as in Example 2, was dissolved in HMPA (10 mL) and THF (10 mL) and this solution was added to the mixture. The mixture was allowed to warm to 0° C. over 1 hour, then diluted with water, washed with ether, acidified with hydrochloric acid, and extracted into methylene chloride. The methylene chloride extract was concentrated in vacuo and the residue was heated in an oil bath to 140° C. for 30 minutes. The mixture was cooled, partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with 5% sodium hydroxide and then brine, dried over sodium sulfate, and evaporated. Purification by silica gel chromatography (40% ethyl acetate-hexane) gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(tert-butoxycarbonyl)piperidin-4-yl]-propan-1-one (1.5 g, 3.8 mmol), m.p. 133°-134° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A solution of methyl 2-hydroxy-4-(4-chlorobenzyloxy)benzoate (5.2 g) in dry dimethylformamide (DMF) (50 mL) is treated with NaH (60% dispersion, 0.71 g) and stirred at 25° C. for 20 minutes. Benzyl bromide (2.12 mL) is added and the solution heated at 60° C. for 2 hours. The solution is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried, and evaporated. The residue is recrystallized from ethyl acetate to yield methyl 2-benzyloxy-4-(4-chlorobenzyloxy)benzoate as colourless crystals (5.1 g, 75%), m.p. 99-101° C. 1H NMR (DMSO) 3.8(3H,s),5.18 (2H,s), 5.21(2H,s), 6.7(1H,d), 6.85(1H,s), 7.3-7.5(9H,m), 7.75(1H,d).
Reaction SMILES: [OH-].[Na+:2].Cl[C:4]1[S:5][C:6]([Cl:12])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10].[S:13]([O-:16])([OH:15])=[O:14].[Na+]>O>[Cl:12][C:6]1[S:5][C:4]([S:13]([OH:16])(=[O:15])=[O:14])=[C:8]([C:9]([O-:11])=[O:10])[CH:7]=1.[Na+:2]
Reactant: O=C(O)c1cc(Cl)sc1Cl
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(Cl)sc1S(=O)(=O)O
Reaction time: 24 h

Procedure:
59 g. of sodium hydroxide are dissolved in 637 ml. of water. The solution is heated to 90°, and 290.7 g. of 2,5-dichlorothiophene-3-carboxylic acid are added and dissolved by stirring. 156 g. of sodium hydrogen sulfite dissolved in 430 ml. of water is added to the solution and the pH thereof is adjusted to 7.5-7.7 with approximately 167 ml. of 30% caustic soda. 12 g. of finely powdered cuprous chloride are added to the clear solution, which is then boiled for 24 hours under reflux. The solution is filtered hot from the copper oxide and the filtrate is acidified with 400 ml. of concentrated HCl and cooled to 5°. The precipitate that has separated out is suction filtered without rewashing and dried in vacuo at 110° to constant weight. The precipitate is then boiled up with 3×500 ml. portions of methylene chloride. The residue is dried at 70° in vacuo, and sodium 5-chloro-2-sulfothiophene- 3-carboxylate is obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:19]=2[C:20](OCC)=[O:21])=[CH:11][CH:10]=1)#[N:8]>C1COCC1>[OH:21][CH2:20][C:19]1[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:17]=[N:16][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(-c2ccc(C#N)cc2)ncn1COCC[Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(C#N)cc2)c1CO
Temperature: -50 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of LiAlH4 (114 mg, 3.36 mmol, 3.00 equiv) in anhydrous THF (5 mL) maintained under nitrogen at −50° C. was added dropwise a solution of ethyl 4-(4-cyanophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (371 mg, 1.00 mmol, 1.00 equiv) in anhydrous THF (2 mL). The reaction was stirred at −50° C. for 1 h and then quenched by the addition of 1 mL of water. The resulting mixture was extracted with 4×20 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column eluted with 0-50% of ethyl acetate in petroleum ether to give 110 mg (33%) of 4-(5-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)benzonitrile as a pale yellow solid. 1H-NMR (300 MHz, CDCl3): δ 7.92-7.85 (m, 2H), 7.71-7.65 (m, 3H), 5.39 (s, 2H), 4.79 (s, 2H), 3.56 (t, J=11.2 Hz, 2H), 0.94 (t, J=11.2 Hz, 2H), 0.01 (s, 9H) ppm. LCMS (method A, ESI): RT=1.27 min, m/z=330.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[O:28][C:29]=1[CH3:30]>>[Cl:37][C:33]1[CH:32]=[C:31]([C:27]2[O:28][C:29]([CH3:30])=[C:25]([CH2:24][N:15]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:21])([F:22])[F:1])=[CH:14][CH:13]=3)[N:26]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Product: Cc1oc(-c2cccc(Cl)c2)nc1CN(CC(F)(F)F)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
In analogy to example 22.2, from 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol and 4-chloromethyl-5-methyl-2-(3-chloro-phenyl)-oxazole was prepared 2-{4-[[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, yellow solid, MS: 547 (MH+, 1Cl).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[F:21][C:22]([F:38])([F:37])[C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34]I)[N:33]=2)[CH:26]=[CH:27][CH:28]=1>>[F:38][C:22]([F:21])([F:37])[C:23]1[CH:24]=[C:25]([C:29]2[O:30][C:31]([CH3:36])=[C:32]([CH2:34][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:33]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CI
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(C(F)(F)F)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-trifluoromethylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 54 of molecular weight 503.52 (C27H28F3NO5), MS(ESI): 504.37 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K11) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (339 mg, 67%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH2:29])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:33][C:34](=[O:52])[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.C(N(C(C)C)CC)(C)C.C(O)=O>O1CCOCC1>[CH:34]([OH:52])=[O:33].[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Solvent: O=CO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)CC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
Intermediate 14c (120 mg, 0.31 mmol) was dissolved in 1,4-dioxane (2.0 mL) and [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 124 mg, 0.31 mmol) and diisopropylethylamine (106 μL, 0.61 mmol) were added. The reaction was heated to 60° C. for 20 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and extracted into EtOAc (3 x). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, then further purified by HPLC (C18X-select column, 20-70% MeCN in H2O, 0.1% formic acid) to give the title compound as the formic acid salt (103 mg, 0.16 mmol, 52%). LCMS (Method 5): Rt 3.63 min, m/z=648 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.90-1.99 (1H, m), 1.99-2.07 (1H, m), 2.10-2.19 (1H, m), 2.21-2.30 (1H, m), 2.37 (3H, s), 2.38 (3H, s), 2.52-2.67 (8H, br s), 4.05-4.09 (1H, d, J=14.3 Hz), 4.11-4.15 (1H, d, J=14.3 Hz), 4.88-4.93 (1H, dd, J 8.9, 5.6 Hz), 5.41-5.44 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.22-7.36 (11H, m), 7.63-7.67 (1H, d, J=10.0 Hz), 8.21-8.22 (1H, d, J=1.9 Hz), 8.44-8.45 (0.25H, s).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([OH:36])[CH:35]=1>C1COCC1>[OH:36][C:34]1[CH:35]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:31]=[CH:32][C:33]=1[O:37][CH3:38]
Reactant: COc1ccc(N)cc1O
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cccs5)c4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 100 mg, 0.256 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (43 mg, 0.309 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 75% yield (0.098 g, 0.1916 mmol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][CH2:17][C:18](=[O:25])[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:2]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:55][C:56]([CH3:58])=O>C(Cl)Cl.C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][CH2:17][C:18]([N:19]2[CH2:20][CH2:21][N:22]([CH:56]([CH3:58])[CH3:55])[CH2:23][CH2:24]2)=[O:25])[N:2]=1
Reactant: CC(C)=O
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1cc2ccccc2cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCN(C(=O)CC[C@@H](COC(=O)Nc2cc3ccccc3cn2)N(C)C(=O)NCc2cccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl isoquinolin-3-ylcarbamate (610 mg, 1.07 mmol) in acetone (1 mL) and DCM (1 mL) was added acetic acid (4 drops, ˜0.2 mL). The reaction mixture was stirred at RT for 30 min. To this mixture was added solid NaBH(OAc)3 and the resulting mixture was stirred at RT for 1 h and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrle and water (0.1% HCOOH buffer). The fractions was collected, concentrated to dryness, and re-dissolved in EtOAc. The organic mixture was washed with Na2CO3, dried over Na2SO4, filtered, and concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(4-isopropylpiperazin-1-yl)-5-oxopentyl isoquinolin-3-ylcarbamate (540 mg, 82%) as white solid. LRMS (M+H+) m/z 613.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[N:19][C:18]=1[O:24][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Br:26])=[C:9]1[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[N:19][C:18]=1[O:24][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nnc(Cl)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Product: COc1nnc(Cl)cc1-c1c(Br)c2ccccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg of 2-(6-chloro-3-methoxy-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester is dissolved in 5 ml dimethoxythane and 75 mg of N-bromosuccinimide is added. The solution is stirred at RT for 16 h. The resulting solution is used in the subsequent reaction without further purification.