Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[NH:14][CH:15]1[CH2:17][CH2:16]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]1[CH2:16][CH2:17]1
Reactant: Cn1ncc2c1C(=O)C(Cl)=C(NC1CC1)C2=O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)N(C1=C(Cl)C(=O)c2c(cnn2C)C1=O)C1CC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
6-Chloro-5-cyclopropylamino-1-methyl-1H-indazole-4,7-dione (3 grams prepared as in Example II) was added to acetic anhydride (10 milliliters) containing a few drops of concentrated sulphuric acid. The mixture was stirred at 50° C for 15 minutes and then poured into ice-water. The aqueous mixture was extracted with methylene chloride and the extracts washed with aqueous sodium bicarbonate solution and dried. The solvent was then removed under reduced pressure to give a yellow solid which on recrystallization from ethanol gave the desired product having a melting point of 171° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=1.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([O:12][CH2:11][C:8]3[N:6]4[CH:7]=[C:2]([C:25]#[N:26])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(Br)cn34)ccnc2c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc2c(OCc3nnc4ccc(C#N)cn34)ccnc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
4-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (0.050 g, 0.13 mmol) was dissolved in DMF (1 mL) then added zinc cyanide (0.023 g, 0.19 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.0072 g, 0.013 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.0059 g, 0.0065 mmol). The reaction mixture was heated at 100° C. for 8 hours. Additional zinc cyanide (0.012 g, 0.095 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.004 g, 0.0065 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.003 g, 0.0032 mmol) were added and heating was continued at 100° C. for 6 hours. The reaction mixture was concentrated under vacuum. The sample was purified by preparative TLC eluting with 10% 7N ammonia in methanol/dichloromethane to afford 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (23 mg, 53% yield) as a white solid. MS (ESI pos. ion) m/z: 332.1 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][CH2:27][O:28]C4CCCCO4)=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9]>CO>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][CH2:27][OH:28])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCOC1CCCCO1
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCO
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
3.00 ml of concentrated hydrochloric acid are added dropwise to 21.30 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[3-(tetrahydropyran-2-yloxy)-propyloxy]-6-nitro-quinazoline in 200 ml of methanol. A yellow precipitate is formed. The suspension is stirred for about another 3.5 hours at 50° C. For working up the methanol is distilled off in vacuo using a rotary evaporator. The residue is combined with ethyl acetate and some ice-water and made alkaline with sodium hydroxide solution. The organic phase is washed with water and saturated sodium chloride solution and left to stand overnight at ambient temperature, whereupon a yellow precipitate is formed. This is suction filtered, washed with ethyl acetate and dried. The filtrate is evaporated down and the evaporation residue is recrystallised from ethyl acetate. The crystals thus obtained are combined with the previously suction filtered precipitate and again recrystallised from ethyl acetate. The desired product is obtained in the form of slightly yellowish crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 95 %

Procedure:
To a solution of 3-chloro-4-hydroxy-benzaldehyde (5.0 g, 32 mmol) and BnBr (6.6 g, 38 mmol) in CH3CN (100 mL) was added K2CO3 (8.8 g, 64 mmol). The mixture was heated at reflux for 2 hours. The resulting mixture was poured into water (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/EtOAc 15:1) to give 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.47-7.34 (m, 5H), 7.08 (d, J=8.8 Hz, 1H), 4.26 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:11](C(=O)C2C=CC=CC=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
45 g (0.1 mol) of di-tert-butyl 1-(1-acetylpiperidin-4-yl)-2-benzoylhydrazine-1,2-dicarboxylate were dissolved in 1 L of tetrahydrofuran and a solution of 5.8 g (0.14 mol) of lithium hydroxide monohydrate in 1 L of water were added. The mixture was stirred at room temperature for 16 hours, the tetrahydrofuran removed in vacuo and the aqueous layer extracted several times with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to dryness, giving 32 g (84% yield) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](C4CCCN(C)C4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:28]([CH2:31]OC)OC>>[C:1]([C:4]1[CH:25]=[CH:24][C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:8]4[CH2:31][CH2:28][NH:10][CH2:6][CH2:7]4)[CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(C2CCCN(C)C2)c1
Reactant: COCCOC
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(N2CCNCC2)c1
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 5-acetyl-1-(3-(1-acetylpiperazin-4-yl)phenyl)benzimidazole (see Example 12) (8.3 g, 23.0 mmol) in dimethoxyethane (140 ml) was added aqueous sodium hydroxide (70 ml, 1M) and the mixture was heated to 80° C. overnight. The organic solvent was removed under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic phase was concentrated and purified by column-chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) as the eluent. The concentrated eluate was triturated with diethyl ether to yield 5-acetyl-1-(3-(piperazin-1-yl)phenyl)benzimidazole (4.81 g, 65%) as red crystals. This product (2.0 g, 6.25 mmol) was dissolved in refluxing ethanol (20 ml). O-isopropylhydroxylamine, hydrochloride (0.7 g, 6.25 mmol) was added and reflux was continued for 5 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between aqueous sodium hydroxide (1M) and dichloromethane. The organic phase was dried and concentrated and eluted through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) to yield 5-acetyl-1-(3-(1-piperazinyl)phenyl)-benzimidazole O-i-propyl oxime (1.75 g, 74%). This product was alkylated with methyl bromoacetate in anhydrous DMF on the presence of triethylamine at room temperature to yield 5f1 (0.48 g, 77%). M.p. 120-121° C.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.C1C=CC=CC=1>O>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 40 ml (R)-(−)-2,2 dimethyl-1,3-dioxolane-4-methanol, 55 grams of powdered potassium hydroxide and 109 ml hexadecyl bromide were added to 500 ml benzene, and the reaction mixture was stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 150 ml. The reaction mixture was then cooled to room temperature and stirred at this temperature overnight. Thereafter, 150 ml water was added, and the obtained mixture was extracted thrice with 150 ml diethyl ether. The combined organic phase was washed with 150 ml water and the solvent was then removed under reduced pressure. The residue was dissolved in 200 ml of a mixture of 90:10:5 (volume/volume) methanol:water:concentrated HCl, and the resulting solution was refluxed for 2 hours. After cooling to room temperature and adding 200 ml water, the product was extracted with 250 ml chloroform. The organic phase was washed consecutively with 250 ml water, 200 ml saturated aqueous solution of sodium carbonate, and again with 200 ml water. The solvent was removed under reduced pressure and the product was then crystallized from hexane (500 ml) to give 81.25 grams (yield 79%) of pure 1-hexadecyl-glycerol, which was dried in a desiccator under reduced pressure.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].[Cl-].[NH4+]>CS(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To 9.4 g of sodium hydride was added 195 ml of dimethyl sulfoxide, followed by the dropwise addition of 22.37 ml of dimethyl malonate. At the end of the addition, the mixture was heated to 100° C. and maintained at that temperature for 40 minutes. At this point, 25 g of 1,4-dibromo-2-nitrobenzene was added all at once. The reaction mixture was maintained at 100° C. for 4 hours and then it was added to 1.0 liter of saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate and the extracts were washed with ammonium chloride solution, water and saturated sodium chloride. The dried (MgSO4) solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 22.45 g of dimethyl 2-(4-bromo-2-nitrophenyl)malonate.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:26]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)nc1
Reactant: C#Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccc(F)cc4)nc3)no2)cn1
Temperature: 50 °C
Reaction time: 5 h
Yield: 18.9 %

Procedure:
To a mixture of (6-(4-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (25 mg) described in Manufacturing Example 75-1-4 and tetrahydrofuran (1 mL) were added 5-ethynyl-pyridin-2-ylamine (6.0 mg, 0.051 mmol) described in Manufacturing Example 28-1-3 and triethylamine (14 μL, 0.10 mmol), which was stirred for 5 hours at 50° C. The reaction mixture was allowed to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (3.5 mg, 19%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[NH:7][C:8]([C:10]3[C:14]([NH:15][C:16]([CH:18]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)=[O:17])=[CH:13][NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1.C1(OC)C=CC=CC=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH3:34][O:33][C:32]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:9][C:8]([C:10]3[C:14]([NH:15][C:16]([CH:18]4[O:23][CH2:22][CH2:21][NH:20][CH2:19]4)=[O:17])=[CH:13][NH:12][N:11]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: COc1cc2nc(-c3n[nH]cc3NC(=O)C3CN(C(=O)OC(C)(C)C)CCO3)[nH]c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)C3CNCCO3)[nH]c2cc1OC
Reaction time: 3 h

Procedure:
N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-rac-4-BOC-2-morpholine carboxamide (65 mg, 0.14 mmol) and anisole (60 μl, 0.56 mmol) were dissolved in a mixture of trifluoroacetic acid and dichloromethane (1:1; 2 ml). After 3 hours at room temperature, the mixture was evaporated to dryness to give N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-rac-2-morpholine carboxamide-trifluoroacetic acid salt (73 mg) as a colourless solid (LC/MS (acidic method): Rt 1.42 min, [M−H+]− 371.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:13][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([F:1])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:17])[CH3:16]
Reactant: COc1c(O)cc(C(=O)O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1c(F)cc(C(=O)O)cc1OC(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The compound of step 2 (169 mg, 913 mmol) was suspended in acetic anhydride (1.75 ml) and heated at 100° C. for 3 h. The solution was cooled, water (2 ml) was added, and the mixture was stirred at 60° C. for 1 h. Upon cooling, crystals formed which were filtered off and dried in vacuo to give 120 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:29])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)[CH3:26]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH2:23][N:24]([CH3:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:16]=[CH:15]2)[C:7](OCC)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)[N+]([O-])=C(C)C=C2)C[O:46][C:47](=O)[C:48]([CH3:51])([CH3:50])[CH3:49])(C)(C)C>>[C:47]([O:8][CH2:7][C@@H:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]1[C:13]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH2:23][N:24]([CH3:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:16]=[CH:15]2)(=[O:46])[C:48]([CH3:51])([CH3:50])[CH3:49]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CN(C)c3ccccc3)ccc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(CN(C)c3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl)quinolin-6-yl)ethyl pivalate was prepared following the procedure used to prepare compound (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl)quinolin-6-yl)acetate of Example 14, except that (S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide was used instead of (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide. LCMS-ESI+ (m/z): 573.3, 575.4 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:23][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13](=[O:32])[N:12]1[CH:8]([CH2:9][CH:10]([O:33][C:34]([N:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][C:42]=4[F:45])[CH2:37]3)=[O:35])[CH2:11]1)[C:7](=[O:46])[NH:6]2)=[O:4].C1COCC1.CO.[OH-].[Li+]>CCOC(C)=O.O>[C:28]([O:27][C:25]([NH:24][CH:14]1[C:13](=[O:32])[N:12]2[CH:8]([CH2:9][CH:10]([O:33][C:34]([N:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][C:42]=4[F:45])[CH2:37]3)=[O:35])[CH2:11]2)[C:7](=[O:46])[NH:6][C:5]2([C:3]([OH:4])=[O:2])[CH:22]([CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)C12CC1CCCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(=O)N3Cc4cccc(F)c4C3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCCCCCC2CC2(C(=O)O)NC(=O)C2CC(OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To 14-tert-butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadecane-4-carboxylic acid methyl ester (319 mg, 0.49 mmol) in a 1:1:1 mixture of THF:MeOH:H2O (6 mL) was added lithium hydroxide (104 mg, 2.47 mmol). The resulting slurry was stirred at room temperature overnight then diluted with EtOAc and washed with 1 N HCl and brine. The resulting organic layer was dried over sodium sulfate and concentrated to provide the crude 14-tert-butoxycarbonylamino-18-(4-fluoro-1,3-dihydro-isoindole-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadecane-4-carboxylic acid (300 mg, 97% yield). LCMS found 630.8 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]([CH2:20][O:21][CH3:22])[C:8]([CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9][C:5]=2[CH:4]=1.COC1C=CC2N=C(CN(C)C(=O)OC(C)(C)C)N(COC)C=2C=1.ClCCl.[Br:52]N1C(=O)CCC1=O>CCOC(C)=O>[Br:52][C:24]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[N:7]([CH2:20][O:21][CH3:22])[C:6]=2[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(OC)ccc21
Agent: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2ccc(OC)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(OC)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a mixture of a mixture (946 mg) of tert-butyl {[5-methoxy-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-methoxy-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and dichloromethane (10 mL) was added N-bromosuccinimide (527 mg) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with a saturated aqueous NaHCO3 solution and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=85/15-60/40) to obtain a mixture (855 mg) of tert-butyl {[6-bromo-5-methoxy-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[5-bromo-6-methoxy-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[C:8]2[N:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:7]1=2)=[O:5].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[CH3:22][N:18]1[C:8]2[C:9](=[O:17])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:6]([C:4](=[O:5])[CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:7]=2[C:20]([CH3:21])=[CH:19]1
Reactant: CN1CCNCC1
Reactant: Cc1cn(C)c2c1N(C(=O)CCBr)c1ccccc1NC2=O
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CCN1CCN(C)CC1)c1ccccc1NC2=O
Yield: 76 %

Procedure:
1.5 g of 4-(3-bromopropionyl)-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one and 0.85 g of N-methylpiperazine are warmed at 80° C. for 15 hours in 50 ml of dioxane. The thus-obtained mixture is concentrated to dryness in vacuo. 20 ml of saturated aqueous sodium carbonate solution are added thereto with stirring, and the mixture is then extracted three times with ethyl acetate. The combined extracts are dried over sodium sulfate, and the solvent is stripped off in vacuo. The resulting residue is chromatographed on neutral silica gel (methylene chloride/methanol 95/05). 1.2 g of the title compound of m.p. 187° C. (from isopropanol) are obtained).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])=[CH:28][CH:29]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: COc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: COc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid.