Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH2:27])[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][CH2:9][C@H:10]([NH:27][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc2nc([C@H](COCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccc3)c2c1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
A mixture of (R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (298 mg, 0.83 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (200 mg, 0.83 mmol) and DIPEA (700 μL, 4.2 mmol) in n-butanol (5 mL) was heated at 90° C. in a sealed vial for 48 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a colourless oil (256 mg, 64%). LCMS (Method B): RT 3.26 min [M+H]+ 480.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:28]([O:30]C)=[O:29])[C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=2[O:17][C@@:16]([CH3:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:15]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:28]([OH:30])=[O:29])[C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=2[O:17][C@@:16]([CH3:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:15]1=[O:39])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c(cc1C(F)(F)F)O[C@@](C)(c1ccccc1)C(=O)N2CCNC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@]1(c2ccccc2)Oc2cc(C(F)(F)F)c(C(=O)O)cc2N(CCNC(=O)OCc2ccccc2)C1=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 184.7 %

Procedure:
Methyl (2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoro-methyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (1.1117 g) was dissolved in 1,4-dioxane (20 ml), and thereto was added 4N-aqueous sodium hydroxide solution (20 ml), and the mixture was stirred at 50° C. for 6 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure to remove 1,4-dioxane. The residue was diluted with water, and the pH value thereof was adjusted to pH 1 with 3N-hydrochloric acid. The precipitated white solid was collected by filtration to give (2S)-4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2-methyl-3-oxo-2-phenyl-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (1.016 2 g). Thus obtained carboxylic acid (717.7 mg) was dissolved in DMF (6 ml), and thereto were added triethylamine (0.75 ml), dimethylaminopyridine (82.0 mg), tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate (1.3400 g), CIP reagent (1.1922 g), and the mixture was stirred at 60° C. under nitrogen atmosphere for 7 hours. To the mixture were additionally added triethylamine (0.57 ml) and CIP reagent (747.7 mg), and the mixture was further stirred at 60° C. for 4 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography to give the title compound (588.4 mg).
Reaction SMILES: N[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:24].[K+]>CS(C)=O.O>[I:24][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1N
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
3-Amino-4-methyl-2-nitrobenzoic acid (13 g, 66 mmol) was taken up in 50 mL of DMSO and 30% aqueous sulfuric acid (150 mL) was added. The mixture was cooled to 0° C. and sodium nitrite (7 g, 99 mmol) dissolved in 20 mL of water was added slowly. The mixture was stirred for 1 h and potassium iodide (28 g, 166 mmol) dissolved in 50 mL of water was added. The mixture was allowed to stir at RT for 1 h. The mixture was extracted with ethyl acetate and the organic layer washed with an aqueous solution of 2 M sodium sulfite, water and brine. The organic layer was dried with sodium sulfate and concentrated under vacuum to give 3-iodo-4-methyl-2-nitrobenzoic acid (17 g, 84%) as a light brown solid. MS (M+H)+ 308.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(F)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CCCBr)cc1F
Yield: 84.8 %

Procedure:
Compound 53-2 (3.11 g) was dissolved in methylene chloride (60 ml), triphenylphosphine (5.21 g) and N-bromosuccinimide (3.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.6 g) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([Cl:26])[CH:18]=1)([OH:16])=[O:15]>>[Cl:26][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Reactant: COc1ccc2nc(Cl)ncc2c1
Product: O=C(O)c1ccc(-c2ncc3cc(O)ccc3n2)c(Cl)c1

Procedure:
Prepared according to Scheme 6, B conditions, starting from Intermediate 8 and 4-carboxy-2-chlorophenylboronic acid. 1H NMR (DMSO-d6 400 MHz): δ 10.60 (brs, 1H), 9.56 (s, 1H), 8.10-7.89 (m, 4H), 7.62 (dd, J=9.2, 2.8 Hz, 1H), 7.38 (d, J=2.8 Hz, 1H). MS (ESI): m/z 300.8 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][N:12]1[C@H:17]([CH3:18])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:30]>>[ClH:30].[C:1]([NH:5][C:6](=[O:7])[C:8]1[CH:29]=[CH:28][CH:27]=[C:10]([CH2:11][N:12]2[C@H:13]([CH3:26])[CH2:14][NH:15][CH2:16][C@@H:17]2[CH3:18])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1cccc(C(=O)NC(C)(C)C)c1
Agent: Cl
Product: C[C@@H]1CNC[C@H](C)N1Cc1cccc(C(=O)NC(C)(C)C)c1

Procedure:
(3S,5R)-tert-Butyl 4-(3-(tert-butylcarbamoyl)benzyl)-3,5-dimethylpiperazine-1-carboxylate (0.07 g, 0.17 mmol) was treated with an ethanolic solution of hydrochloric acid (2 mL, 14.5 wt % hydrochloric acid in ethanol). The resultant mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, azeotroped with dichloromethane (×2) and dried under vacuum to afford the title compound (0.052 g) as a white foamy solid. MS (ESI) m/z 304.4 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3[NH:8][C:9](=[O:15])[C:10]4[N:11]([CH:12]=[CH:13][N:14]=4)[C:6]=3[CH2:5][C:4]=2[CH:3]=1.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21]>CN(C)C=O>[CH2:26]([O:25][C:23]([CH2:22][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3[NH:8][C:9](=[O:15])[C:10]4[N:11]([CH:12]=[CH:13][N:14]=4)[C:6]=3[CH2:5][C:4]=2[CH:3]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CN=C=O
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12

Procedure:
The preparation is carried out as in Example 7, from 3 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one and 2 times 2.8 ml of ethyl 2-isocyanatoacetate in 170 ml of dimethylformamide. The insoluble material thus obtained is filtered and recrystallized from dimethylformamide. After filtration, washing with water and drying under reduced pressure (1 mm Hg, 0.13 kPa) at 60° C., there are obtained 2.6 g of 8-(3-ethoxycarbonylmethylureido)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a pink solid, the melting point of which is greater than 260° C. (Analysis C18H17N5 O4.0.75H2O.0.20DMF, % calculated C: 58.85, H: 4.66, N: 19.06, % found C: 58.9, H: 5.0, N: 18.9).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:30])[CH2:9][C@@H:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si](C)(C)C)=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+].C(OCC)(=O)C>CO>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C@H:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:30])=[CH:16][CH:15]=1)#[CH:18]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C#C[Si](C)(C)C)cc2)c2ccccc2C)ccn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a solution of (R)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-3-(4-trimethylsilanylethynyl-phenyl)-propan-1-one (100 mg) in methanol (5 mL) was added at 0° C. potassium carbonate (3.4 mg). The reaction mixture was stirred at room temperature for 20 h. A saturated aq. solution of ammonium chloride and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (15% to 50% ethyl acetate in n-heptane) to yield the title compound as a colourless oil (60 mg, 95%), MS (ESI+): m/z=340.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To 10 g (63.7 mmol) of 5-fluoro-2-nitrophenol in 100 ml of methyl ethyl ketone was added 10.5 g (76.4 mmol) of finely ground potassium carbonate followed by 10.7 g (70.1 mmol) of methyl bromoacetate. The resulting suspension was refluxed for 6 hours and then stirred at room temperature overnight. During this time it went from a deep red color to pale yellow. The reaction was poured into one liter of water, the layers were separated and the aqueous layer was extracted twice more with EtOAc (2×100 ml). The organics were combined, dried (Na2SO4), filtered and evaporated to dryness in vacuo to give 13.3 g (91% yield) of methyl 5-fluoro-2-nitrophenoxyacetate as a light yellow solid (m.p. 85°-87° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:11][C@@H:10]([C:27](=[O:47])[N:28]([CH:44]2[CH2:46][CH2:45]2)[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:49][CH2:50][N:51]1[C:59](=[O:60])[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]1=[O:61].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([CH2:49][CH2:50][N:51]2[C:52](=[O:61])[C:53]3[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:59]2=[O:60])[S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:11][C@@H:10]([C:27](=[O:47])[N:28]([CH:44]2[CH2:46][CH2:45]2)[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NS(=O)(=O)c3ccccc3[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N(CCN3C(=O)c4ccccc4C3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To a solution of (3R*,5S*)3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-(2-nitro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.60 mmol), 2-(2-hydroxyethyl) isoindole-1,3-dione (171 mg, 0.9 mmol), and PPh3 (315 mg, 1.2 mmol) in THF is added DEAD (208 mg, 1.2 mmol) at room temperature, then the mixture is stirred at 60° C. After 13 h, the reaction mixture is quenched by H2O (20 mL) and extracted with EtOAc (50 mL). The organic phase is successively washed with 5% aqueous KHSO4, H2O, and brine, then dried over Na2SO4 and concentrated in reduced pressure. The residue is purified by silica gel column chromatography to afford the title compound as yellow amorphous material. MS: 843 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 4.41 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[CH:20][N:21]=[CH:22][C:14]2=3)=[S:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.N1CCNCC1.[Br-].[Li+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[CH:19]=[CH:20][N:21]=[CH:22][C:14]2=3)=[S:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=S)N2CCOc3ccncc32)cc1Br
Agent: C1CNCCN1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1c(Br)cc(C(=S)N2CCOc3ccncc32)cc1Br
Reaction time: 15 h
Yield: 105.7 %

Procedure:
In a 25 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanethione (100 mg, 0.22 mmol) was dissolved in N,N-dimethyl formamide, and piperazine (28.4 mg, 1.5 equivalents) and lithium bromide (76.4 mg, 4 equivalents) were added thereto and then stirred at 1000 for 15 hours. N,N-dimethyl formamide was removed under reduced pressure and water was added the residue. The mixture in suspension was adjusted to pH 6 to 7 by using 1N hydrochloric acid and stirred for 30 minutes. The mixture was filtered and the resulting solid was stirred in methanol solvent and then filtered to give the target compound 51 as yellow solid (100 mg, quantitative yield).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[NH:22][C:23](=O)[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:3][C:4](=[O:11])[NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.O1CCCC1>CN(C)C1C=CN=CC=1.O>[OH:1][C:2]1[C:12]2[C:13](=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:16][CH:17]=2)[N:22]=[C:23]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[C:3]=1[C:4]([NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 93.9 %

Procedure:
7.3 g of the product of Step B, 140 ml of tetrahydrofuran and 2.4 g of 4-dimethylamino-pyridine were stirred for 1 hour at ambient temperature and the solvent was eliminated under reduced pressure. The residue was taken up in 100 ml of water and 20 ml of N hydrochloric acid and the solution was extracted with a mixture of ethyl acetate and tetrahydrofuran. After washing the organic phase with water and drying and concentrating the filtrate under reduced pressure, 7 g of crude product were obtained which was triturated in ether, separated, washed with ether and dried under reduced pressure at 60° C. to obtain 6.6 g of 1,1-dimethylethyl N-[[4-hydroxy-8-(trifluoromethyl)-3-[(2-thiazolylamino)-carbonyl]quinolin-2-yl]-methyl]-carbamate melting at 238° C.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29](=O)[C:28]4[C:27]([C:31]([O:33]C)=O)=[CH:26][CH:25]=[CH:24][C:23]=4[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[NH2:42][NH2:43]>CO>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29]4=[N:42][NH:43][C:31](=[O:33])[C:27]5[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=54)[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C(C)C)CC3)c1)C(c1ccncc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccncc3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
A mixture of methyl 3-(3-(4-isobutyryl piperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (140 mg, 0.26 mmol) in 85% hydrazine monohydrate (10 mL) and methanol (3 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give compound 9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (11 mg, yield 8%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.11-1.13 (m, 6H), 2.95-2.98 (m, 1 H), 3.26-3.68 (m, 8H), 4.40-4.42 (d, J=8.4 Hz, 1H), 4.82-4.84 (d, J=8.4 Hz, 1H), 7.19-7.32 (m, 4H), 7.36-7.39 (m, 3H), 7.59-7.68 (m, 2H), 8.41-8.42 (d, J=6.0 Hz, 2H); LC-MS (ESI) m/z: 523 (M+1)+.
Reaction SMILES: [CH3:1][NH2:2].S(C1C=CC(C)=CC=1)(O[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=O)=O>O1CCCC1>[CH3:1][NH:2][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3.23 g of methylamine is condensed in a solution of 4.33 g of 7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl tosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred overnight in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 3.2 g of methyl-(7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl)-amine is obtained as a crude product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:23][C@@H:24]([CH3:28])[C:25](Cl)=[O:26])(=[O:22])[CH3:21]>CO>[C:20]([O:23][C@@H:24]([CH3:28])[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:26])(=[O:22])[CH3:21]
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Solvent: CO
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 80-85° C. 1H-NMR (CDCl3) δ: 10.81 (1H, br s), 8.37 (1H, d, J=8.8 Hz), 8.31 (1H, br s), 7.82-7.77 (2H, m), 7.70-7.53 (3H, m), 7.29 (1H, d, J=1.5 Hz), 7.12 (1H, dd, J=1.5, 8.8 Hz), 5.44 (1H, q, J=7.0 Hz), 2.33 (3H, s), 1.61 (3H, d, J=7.0 Hz) [α]D23 −42.30 (MeOH, c=0.87)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([C:39]([F:40])([F:41])[F:42])=[CH:38][C:32]=3[F:31])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(C(F)(F)F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)cc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 11.9 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 2-fluoro-4-(trifluoromethyl)aniline (0.071 g, 0.396 mmol), THF (10.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.017 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.14 (s, 2H), 7.33-7.54 (m, 3H), 7.62 (d, J=8.7 Hz, 2H), 7.81 (d, J=11.1 Hz, 1H), 8.73 (t, J=7.8 Hz, 1H), 10.34 (s, 1H), 11.25 (s, 2H); MS [M+H]+: 537.48.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CNc1nc(Cl)nc2c1c(I)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(Cl)nc2c1c(-c1cccnc1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.175 g, 0.38 mmol), Pd(PPh3)2Cl2 (0.053 g, 0.076 mmol) and pyridine-3-ylboronic acid (0.102 g, 0.83 mmol) in dioxane (2 mL) was added a solution of Na2CO3 (0.12 g, 1.14 mmol) in water (1 mL). After degassing, the mixture was heated at 100° C. for 1.5 h. The mixture was purified by flash column chromatography (Hexane/EtOAc=1:1) to give 2-chloro-N-methyl-5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.084 g).