Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[H][H]>CCOC(C)=O.[Pd]>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(2-fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (27.13 g, 74.04 mmol) was taken up in EtOAc (1000 mL) and 10% Palladium on Carbon was added as a slurry in EtOAc. The reaction was placed under a balloon of hydrogen gas and was allowed to stir at rt for 3 days. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound of step F without further purification (24.25 g, 97%). MS (M+H, ES+) 337.
Reaction SMILES: Cl.[F:2][C@H:3]1[C@:8]([CH2:11][OH:12])([O:9][CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.Cl[C:30]1[N:38]2[C:34](=[N:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=32)[C:33]([C:43]([NH2:45])=[O:44])=[C:32]2[CH2:46][C:47]([CH3:50])([CH3:49])[CH2:48][C:31]=12>O>[F:2][C@H:3]1[C@:8]([CH2:11][OH:12])([O:9][CH3:10])[CH2:7][CH2:6][N:5]([C:30]2[N:38]3[C:34](=[N:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=43)[C:33]([C:43]([NH2:45])=[O:44])=[C:32]3[CH2:46][C:47]([CH3:50])([CH3:49])[CH2:48][C:31]=23)[CH2:4]1
Reactant: CC1(C)Cc2c(c(Cl)n3c(nc4ccccc43)c2C(N)=O)C1
Reactant: CO[C@]1(CO)CCNC[C@H]1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CO[C@]1(CO)CCN(c2c3c(c(C(N)=O)c4nc5ccccc5n24)CC(C)(C)C3)C[C@H]1F
Yield: 38.3 %

Procedure:
rel-[(3R,4S)-3-fluoro-4-methoxypiperidin-4-yl]methanol hydrochloride (399 mg) and DIPEA (523 μl) were added to an NMP (3 ml) solution of 11-chloro-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (314 mg), and heating and stirring were performed at 200° C. for 60 minutes under microwave irradiation. After adding water to the reaction liquid, the resulting precipitate was collected by filtration and dried under reduced pressure. The resulting solid was purified by silica gel column chromatography (MeOH/chloroform). The resulting crude purified matter was washed with chloroform-EtOAc-hexane to obtain rel-11-[(3R,4S)-3-fluoro-4-(hydroxymethyl)-4-methoxypiperidin-1-yl]-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (169 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12](O)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:22]1[CH:21]=[CH:20][C:19]([O:24][CH3:25])=[C:18]([CH3:17])[CH:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C
Reactant: O=C(NC(O)C(=O)O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(C(NC(=O)OCc2ccccc2)C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of benzyloxycarbonylamino-hydroxy-acetic acid (5.9 g, 26.2 mmol) (prepared according to the procedure of E. H. W. Bohme, et al., J. Med. Chem, 1980, 23, 405-412) and 2-methylanisole (3.2 g, 26.2 mmol) in acetic acid (150 mL) was added concentrated sulfuric acid (15 mL). The mixture was stirred at room temperature for 1 hour, then poured into ice/water and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give an oily residue. The residue was triturated in hexanes, the precipitate formed was collected by filtration and dried overnight to give crude benzyloxycarbonylamino-(4-methoxy-3-methyl-phenyl)-acetic acid as a white solid (8.6 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:19]=1[C:20]([NH:22][CH3:23])=[O:21].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:17][C:18]2[C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:24][C:25]([Cl:29])=[CH:26][C:27]=2[CH3:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: CNC(=O)c1cc(Cl)cc(C)c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (93.6% purity, 16.16 g, 50.0 mmol) and 2-amino-5-chloro-N,3-dimethylbenzamide (i.e. the product of Examples 1, 2 or 3) (10.43 g, 52.5 mmol) in acetonitrile (35 mL) was added 3-picoline (12.65 mL, 12.11 g, 130 mmol). The mixture was cooled to −5° C., and then a solution of methanesulfonyl chloride (4.64 mL, 6.89 g, 60 mmol) in acetonitrile (10 mL) was added dropwise at −5 to 0° C. The mixture was stirred for 15 minutes at this temperature, and then for 3 h at room temperature. Then water (15 mL) was added dropwise and the mixture was cooled to 0° C. for 1 h. The mixture was filtered, and the solids were washed with 3:1 acetonitrile-water (2×10 mL), and then with acetonitrile (2×10 mL), and dried under nitrogen to afford the title compound as a light tan powder, 23.98 g (92.9% uncorrected yield), m.p. 239-240° C.
Reaction SMILES: COC1C=CC=C(OC)C=1C(N[C@H]1CCC[C@@H]1NC1C=CC(C(F)(F)F)=CN=1)=O.Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[NH:37][C:38](=[O:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N:45]1[N:49]=[CH:48][CH:47]=[N:46]1.Cl[C:52]1[CH:57]=[N:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][N:53]=1>>[N:49]1[N:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([NH:37][C@H:33]2[CH2:34][CH2:35][CH2:36][C@@H:32]2[NH:31][C:52]2[CH:57]=[N:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][N:53]=2)=[O:50])[N:46]=[CH:47][CH:48]=1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2,6-dimethoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 1) from N-[(1S,2S)-2-amino cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 59 mg, 0.33 mmol). The crude reaction was filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][OH:25])[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1.S(Cl)(Cl)=O.[Cl-].[CH3:34][O-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][O:25][CH3:34])[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1
Reactant: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COCc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 282) (196 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with sodium methanolate (5.4M, 1 ml) in MeOH (5 ml)/CH2Cl2 (5 ml) according to the general procedure of Example 288. Obtained as an off-white solid (72 mg, 35%).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][P:21]([CH:24]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:25]([CH3:27])[CH3:26])([OH:23])=[O:22])[C:17]([OH:19])=[O:18])=O)C1C=CC=CC=1>O1CCOCC1.O.[OH-].[Pd+2].[OH-]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][P:21]([CH:24]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:25]([CH3:26])[CH3:27])([OH:23])=[O:22])[C:17]([OH:19])=[O:18]
Reactant: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)CC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)CC(CCCCN)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid (181 mg) obtained in the above step (g) was dissolved in a mixed solvent of dioxane and water (1:1) (4 ml). The solution was added with palladium hydroxide (37 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered with celite and the filtrate was concentrated. The residue was purified with HP-20 (Diaion, 20 cc, methanol:water=1:9 to acetone:water=1:1) to obtain the title compound: 6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid (74 mg, 54%) (a diastereoisomeric mixture of 3:1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([SH:10])=[S:9])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20](=[CH2:22])[CH3:21]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([S:10][C:20]([CH3:22])([CH3:21])[CH3:19])=[S:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Reactant: C=C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)SC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 110 °C

Procedure:
A solution of 14.1 g (0.05 mol) 3,5-di-t-butyl-4-hydroxydithiobenzoic acid and 5.6 g (0.1 mol) isobutylene in 20 ml toluene was placed in a glass bomb tube. The tube was sealed and heated at 110° C. for 2 hours. The tube was cooled and opened. The contents were removed and evaporated under reduced pressure to give the product as an orange solid, m.p. 128°-130° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1.Cl.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26].C(=O)(O)[O-].[Na+]>C(O)CCC>[OH:26][N:21]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]1[NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CCOC(=O)c1ccc2c(cnn2CCN)c1
Reactant: [O-][n+]1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)c1ccc2c(cnn2CCNC2C=CC=CN2O)c1
Reaction time: 24 h
Yield: 43.6 %

Procedure:
Ethyl 1-(2-aminoethyl)-1H-indazole-5-carboxylate (584 mg, 2.5 mmol, prepared as in step B), was added to dry n-butanol along with 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol). The reaction mixture was vigorously stirred and heated at 100C for 21 hr. Additional aliquots of 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol) were added and heating continued for 24 hours. The reaction was cooled and filtered and the filtrate concentrated. The residue was purified by flash chromatography (5% methanol-dichloromethane) and the product fractions concentrated to afford the product as an orange solid (358 mg, 44%). LRMS (ES): 327.1 ([M+H]+, 100%), 653.3 ([2M+H]+, 40%) 1HNMR (600.1343 MHz, CDCl3): 8.44 (s, 1H), 8.12 (s, 1H), 7.97 (d of t, 2H), 7.56 (bs, 1H), 7.45 (d, 1H), 7.06, (m, 1H), 6.45 (m, 1H), 6.35 (t, 1H), 4.68 (t, 2H), 4.37 (q, 2H), 3.90 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([CH2:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([CH2:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:8][CH2:9][CH2:10][C:6]#[N:7])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)c(CC)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(OCCCC#N)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 182.3 %

Procedure:
Add dropwise, 4-cyano-5-ethyl-3-(4-hydroxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-81) (300 mg, 1.0 mmol) in DMF (10 mL) to a stirring solution of 60% sodium hydride (60 mg, 1.5 Eq.) in DMF (30 mL) at room temperature under a nitrogen atmosphere. After 30 minutes, add dropwise, 4-bromobutryonitrile (179 mg, 1.2Eq.) in DMF (10 mL) to the reaction mixture while continuing to stir at room temperature. After 2 hours, pour mixture into water and extract the desired ether into ethyl acetate. Wash the organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 500 mg as an oil. Purify the material by silica gel chromatography (Chromatotron™) eluting with methylene chloride to provide 333 mg of the title compound as an oil. Mass spectrum (m/e): 366.2 (M*+1): (Bruker 300) 1H NMR δ (CDCl3) 7.27-7.32 (2H, d), 6.87-6.94 (2H , d) 4.03-4.16 (3H, m), 3.85-3.95 (3H, s), 2.78-2.88 (2H, dd), 2.54-2.64 (2H, t), 2.10-2.20 (2H, dd), 1.22-1.33 (4H, m), 1.00-1.10 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C=O)C.C(Cl)Cl>[CH3:30][O:29][N:28]([CH3:27])[C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:11][CH3:12]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of 5-chloro-o-anisic acid (50 g, 0.27 mol), oxalyl chloride (23 mL, 0.27 mol) and methylene chloride was stirred 1 hour at approximately 25° C. and then treated with DMF (2 drops). The mixture was stirred an additional hour, heated 45 minutes at reflux and then concentrated. The residue was dissolved in THF and the solution was reconcentrated. The residue was dissolved in THF-(approximately 200 mL) and the solution was added in a thin stream to a mixture of triethylamine (96 mL, 0.7 mol), N,O-dimethylhydroxylamine hydrochloride (26.3 g, 0.27 mol) and methylene chloride (approximately 300 mL). After an exothermic reaction had ensued, the mixture was allowed to cool to 25° C. and stirred approximately 16 hours. The mixture was filtered, concentrated and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water (2×), sodium bicarbonate. (2×), 2% hydrochloric acid (1×) and brine (1×), dried (K2CO3), filtered and concentrated to give N-methoxy-N-methyl-5-chloro-2-methoxy-benzamide (52.3 g, 0.23 mmol), m.p. 80°-83° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Br)cc(Cl)cc1C(C)=O
Temperature: 60 °C
Yield: 96.8 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-hydroxyphenyl)ethanone (5.0 g, 20 mmol) in N,N-dimethylformamide (40 mL) was treated with potassium carbonate (5.5 g, 40 mmol) followed by methyl iodide (1.9 mL, 30 mmol) and heated at 60° C. overnight. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The organic layers were washed with water (3×100 mL) and brine, dried with sodium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography using ethyl acetate in hexanes (0%-5%-25%) gave the desired product (5.1 g, 96%). LCMS for C9H9BrClO2 (M+H)+: m/z=262.9, 264.9. Found: 262.9, 264.9.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([C:18]([O:21][CH3:22])([CH3:20])[CH3:19])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH2:23])[CH2:10]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@@:26]21[CH2:44][C:36]1=[N:37][CH:38]=[C:39]([C:41](O)=[O:42])[CH:40]=[C:35]1[CH2:34]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([C:18]([O:21][CH3:22])([CH3:19])[CH3:20])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH:23][C:41]([C:39]2[CH:40]=[C:35]3[CH2:34][C@@:26]4([C:27]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:33][C:25]4=[O:24])[CH2:44][C:36]3=[N:37][CH:38]=2)=[O:42])[CH2:10]1
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1cccc(F)c1F)C[C@@H]2N
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(C)(C)c1cnc2n1C[C@H](c1cccc(F)c1F)C[C@@H]2NC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.75 h
Yield: 25.2 %

Procedure:
To a solution of (6S,8S)-6-(2,3-difluorophenyl)-3-(2-methoxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-amine (11.0 mg, 0.034 mmol) in N,N-dimethylformamide (342 μL) were added (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (10.6 mg, 0.038 mmol), 1-hydroxy-7-azabenzotriazole (0.5 mg, 3.4 μmol), N-methylmorpholine (4.1 μL, 0.038 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.2 mg, 0.038 mmol). The mixture was stirred 45 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (5 mg). HRMS 585.2403 (M+1). 1H NMR (400 MHz, DMSO): δ 11.12 (s, 1H); 9.08 (d, J=8.5 Hz, 1H); 8.89 (d, J=2.0 Hz, 1H); 8.12 (d, J=1.9 Hz, 1H); 8.09 (dd, J=5.3, 1.6 Hz, 1H); 7.47 (dd, J=7.3, 1.6 Hz, 1H); 7.41−7.38 (m, 1H); 7.33−7.25 (m, 2H); 6.93 (dd, J=7.3, 5.3 Hz, 1H); 6.83 (s, 1H); 5.50−5.43 (m, 1H); 4.48 (dd, J=11.9, 4.0 Hz, 1H); 3.88 (d, J=11.9 Hz, 1H); 3.40 (d, J=16.6 Hz, 2H); 3.31 (m, 2H); 2.98 (s, 3H); 2.67 (q, J=1.9 Hz, 1H); 2.34−2.31 (m, 2H); 1.51−1.43 (m, 6H).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[N:17]1[C:21]2=[N:22][C:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)=[N:24][C:25](=[O:26])[C:20]2=[C:19]([CH:35]([CH3:37])[CH3:36])[NH:18]1.CCN(CC)CC.Cl.[CH3:46][C:47]([OH:50])([CH3:49])[CH3:48]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[N:17]1[C:21]2=[N:22][C:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][S:2]([NH:5][C:6]([O:50][C:47]([CH3:49])([CH3:48])[CH3:46])=[O:7])(=[O:4])=[O:3])=[CH:30][CH:29]=3)=[N:24][C:25](=[O:26])[C:20]2=[C:19]([CH:35]([CH3:37])[CH3:36])[NH:18]1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NS(=O)(=O)NC(=O)OC(C)(C)C)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a stirred, cooled solution of 0.11 mL (1.26 mmol) of chlorosulfonyl isocyanate in 5 mL of CH2Cl2 was added 0.13 mL of t-BuOH. The solution was stirred 10 min. and added to a stirred, cooled (0° C.) solution of 231 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.2 mL (1.4 mmol) of Et3N in 5 mL of CH2C1-2. The solution was stirred 1 h warming to ambient temperature, and it was then poured into 1 N aq. HCl. The mixture was extracted with EtOAc, and the organic extract was washed (brine), dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel (elution with 1:1 EtOAc-hexanes, then EtOAc) to afford 250 mg (78%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(t-butoxycarbonylaminosulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid. 1H NMR (300 MHz, DMSO) δ 12.44(s, 1H); 11.12(br. s, 1H); 9.70(br. s, 1H); 7.97(s, 2H); 7.21(d, 2H, J=8.4 Hz); 7.02(d, 2H, J=8.4 Hz); 3.78(s, 2H); 3.19-3.30(m, 1H); 1.27(d, 6H, J=6.9 Hz); 1.21(s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=O)[CH:7]=1.S(Cl)(Cl)=O.N[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[N:29]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C[N:48](C=O)C>>[N:29]1[C:30]2[C:25](=[CH:24][CH:33]=[CH:32][CH:31]=2)[C:26]([NH:48][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:17][CH3:18])([CH3:16])[CH3:15])=[CH:27][CH:28]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(=O)O
Reactant: Nc1cccc2ncccc12
Reactant: CN(C)C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O=S(Cl)Cl
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C(=O)Nc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
540 mg (2.13 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid (WO 00/32584) in 15 ml of DMF is mixed at −5° C. under argon with 0.18 ml of thionyl chloride. After 20 minutes of stirring at −3° C. to +3° C., 470 mg (3.26 mmol) of 5-aminoquinoline is added. It is allowed to heat to room temperature, stirred for another 16 hours, mixed with 10% citric acid, extracted with ethyl acetate, the organic phase is washed with water and dried (Na2SO4). After chromatography on silica gel with hexane-ethyl acetate (0-75%), 680 mg of N-(quinolin-4-yl)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid amide is obtained, which is dissolved in 22 ml of DMF and cooled to 0° C. The solution is mixed with 1.80 ml of (trifluoromethyl)trimethylsilane and 2.43 g of cesium carbonate and stirred for 16 hours at room temperature. Water is added, extracted with ethyl acetate, the organic phase is washed with water and dried on sodium sulfate. The intermediate product that is concentrated by evaporation is taken up in 10 ml of THF, and 5.5 ml of a 1 M solution of tetrabutylammonium fluoride is added. It is stirred for 1.5 hours, water is added, extracted with ethyl acetate, the organic phase is washed with water and dried on sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 420 mg of product is obtained.