Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:8]([CH:10]=O)[O:9][C:5]=2[CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:10]/[C:8]1[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:18]=[CH:17][C:6]=2[C:7]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCc1c(C=O)oc2cc(OC)ccc12
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCCc1c(/C=C/C(=O)OC)oc2cc(OC)ccc12
Yield: 76.9 %

Procedure:
As in Example 111, 6-methoxy-3-pentyl-2-benzofurancarboxaldehyde (4.82 g) and (carbomethoxymethylene)triphenylphosphorane (6.7 g) in dichloromethane (75 mL) was stirred at room temperature for 42 hours. Purification of the crude reaction product by HPLC (diethyl ether-hexane; 1:12) gave 4.55 g of (E)-3-(6-methoxy-3-pentylbenzofuran-2-yl)-2-propenoic acid methyl ester as an oil.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:9]1>>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([CH2:12][CH:10]4[CH2:11][N:8]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: O=C1C=COCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C4CCOCC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 2H-pyran-4(3H)-one underwent reductive amination with 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine to give 503. 517.3 (MH+)
Reaction SMILES: O[Li].O.[CH3:4][C@H:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[C@H:7]([O:27]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:6]1.C1COCC1>O>[OH:27][C@H:7]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:13]=2[C@H:5]([CH3:4])[CH2:6]1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
LiOH—H2O (0.499 g, 11.9 mmol) was added to a 0° C. solution of tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (2.30 g, 4.76 mmol) in 2:1 THF:H2O (40 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour. The THF was removed by rotary evaporation. Saturated NaHCO3 was then added, and the mixture was extracted with ethyl acetate. The combined extracts were washed (1×) with saturated NaHCO3, dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.59 g, 100.0% yield) as a foam. HPLC after workup just product gave greater thab 98% area pure. LC/MS (APCI+) m/z 335 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]4[N:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]3[C:29]=2[C:30]2[CH:35]=[CH:34][C:33]([C:36]3([NH:40]C(=O)OC(C)(C)C)[CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[ClH:48].O1CCOCC1>C(Cl)Cl>[ClH:48].[ClH:48].[ClH:48].[NH2:40][C:36]1([C:33]2[CH:32]=[CH:31][C:30]([C:29]3[N:15]4[C:16]5[CH:28]=[CH:27][CH:26]=[N:25][C:17]=5[NH:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:14]4=[N:13][C:12]=3[C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=3)=[CH:35][CH:34]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NS(C)(=O)=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 77.9 %

Procedure:
tert-Butyl {1-[4-(2-{4-[(methylsulfonyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (30.9 mg, 0.0476 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 13.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (24.4 mg, 77.9%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 9.90 (s, 1H), 8.76 (br s, 2H), 8.67 (s, 1H), 8.12 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=8.0, 1.6 Hz, 1H), 7.59-7.53 (m, 2H), 7.49-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.36-7.29 (m, 3H), 7.18-7.11 (m, 3H), 6.90 (dd, J=8.0, 1.6 Hz, 1H), 6.76 (dd, J=8.0, 4.8 Hz, 1H), 3.02 (s, 3H), 2.62-2.53 (m, 4H), 2.27-2.13 (m, 1H), 1.88-1.75 (m, 1H); LCMS: 549 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:33])[C:16](=[O:32])[C:17]([CH3:31])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[CH:23]=[CH:24][CH:25]=3)[C:13]=2[C:12](=[O:34])[N:11]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:10]1=[O:44].C[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:14]1[N:15]([CH3:33])[C:16](=[O:32])[C:17]([CH3:31])=[C:18]2[C:13]=1[C:12](=[O:34])[N:11]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[C:10](=[O:44])[N:19]2[C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4cccc(CCC(N)=O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(CCC(N)=O)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 3-(3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl) propanamide (1b) (1.7 gm, 2.396 mmol) in THF (8 ml) was added sodium methoxide (30% solution in MeOH) (0.431 mg, 2.396 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr and quenched by addition of 2N HCl solution. The resulting mixture was concentrated under vacuum and residue was re-crystallized in IPA, methanol and water to yield the titled compound (1c) (1.5 g, 88%) [m/z=710.20 (M+1)].
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].S(Cl)(Cl)=O.C(O)(=O)C(CCC)CCC.[NH2:25][C:26]([NH2:28])=[O:27]>C(#N)C>[CH2:3]([CH:2]([CH2:6][CH2:7][CH3:8])[C:1]([NH:25][C:26]([NH2:28])=[O:27])=[O:9])[CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: NC(N)=O
Agent: CCCC(CCC)C(=O)O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCCC(CCC)C(=O)NC(N)=O

Procedure:
Valproyl chloride (0.057 mol), prepared by coupling of thionylchloride and valproic acid according to a published method [24], was dissolved in dry acetonitrile (50 ml), and the resulting solution was slowly added to a boiling solution of urea (0.14 mole) in dry acetonitrile (100 ml) and allowed to reflux for 2 hours. Thereafter the organic solvent was evaporated under reduced pressure and the product was dissolved in ethyl acetate (100 ml) and washed three times with 20 ml of distilled water. The organic fraction was dried over MgSO4, filtered and evaporated under reduced pressure. The products were purified by crystallization from ethyl acetate.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:17]([CH:33]2[CH2:35][CH2:34]2)[C:18]([C@@H:20]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)=[O:19])[CH3:16])=[CH:11][C:10]=1[O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])C1C=CC=CC=1>CO.[Pd]>[CH:33]1([N:17]([C@@H:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:11]=2)[CH3:16])[C:18]([C@@H:20]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:21]2)=[O:19])[CH2:34][CH2:35]1
Reactant: COCCCOc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCCOc1cc([C@@H](C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)ccc1O
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of tert-butyl (2R)-2-{[{1-[4-(benzyloxy)-3-(3-methoxypropoxy)phenyl]ethyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (1.45 g) in methanol 912 mL) was added 10% palladium on carbon (200 mg), and the mixture was stirred under hydrogen for 2 hours. An insoluble was filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1→1/2) to give tert-butyl (2R)-2-[(cyclopropyl{(1R)-1-[4-hydroxy-3-(3-methoxypropoxy)phenyl]ethyl}amino)carbonyl]morpholin-4-carboxylate [Ex(169-1)] (913 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][NH2:27])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[N:4]=1)[CH3:2].[CH3:36]OC(OC)OC>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[O:25][CH:36]=[N:27][N:26]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NN)ccn34)c12
Reactant: COC(OC)OC
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5nnco5)ccn34)c12
Temperature: 110 °C
Yield: 32.7 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(hydrazinecarbonyl)imidazo[1,2-a]pyridine-3-carboxamide (15 mg, 0.0320 mmol) was added trimethoxymethane (340 mg, 3.20 mmol). The reaction mixture was sealed and heated to 110° C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH 10:1) gave the final product (5 mg). MS (ES+APCI) m/z=479 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.ClC1C=C(C(F)(F)F)C=CN=1>>[CH3:8][C:4]([O:3][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1)([CH3:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C)(O)C(=O)O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: FC(F)(F)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O

Procedure:
The title compound was prepared following the procedure described in Reference Example 91, Step A with 1.5 extra equivalent of sodium hydride substituting lithium lactate with hydroxyisobutyric acid and 2-chloro-4-trifluoromethylpyridine 2-chloro-5-trifluoromethylpyridine. 1H NMR (500 MHz, CD3OD): δ 8.38 (br, 1H), 7.94 (dd, 1H), 6.93 (d, 1H), 1.69 (s, 6H).
Reaction SMILES: [C:1](=[O:3])=O.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11]C=2)[CH:7]=[CH:6][CH:5]=1>>[OH:3][C:1]1[CH:13]=[C:8]([CH2:7][CH2:6][C:5]#[N:4])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C=O
Reactant: c1ccc2ncccc2c1
Product: N#CCCc1cccc(O)c1
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A 300 ml. flask equipped with a magnetic stirrer, cold water condenser, CO2 outlet and bubbler, and a heated oil bath was charged with 21 g. of crude α-cyano-m-hydroxydihydrocinnamic acid (above) and freshly redistilled quinoline (10 ml.). The acid underwent smooth decarboxylation at an oil bath temperature of 150°C with CO2 evolution ceasing after about 2.5 hr. For workup, the cooled mixture was treated with 200 ml. of 5N HCl and extracted thoroughly with several portions of diethyl ether totalling 350 ml. The ether was washed with water (1 × 100 ml.), saturated NaHCO3 (4 × 50 ml.), brine (1 × 100 ml.), and dried over anhydrous Na2SO4. Concentration of the ether solution gave 11.15 g. (69% yield) of β-(m-hydroxyphenyl)propionitrile as a pale yellow solid. Recrystallization from ethyl acetate/hexane gave the pure compound as light yellow crystals, m.p. 64°-66°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(C1C2C(=NC=CC=2C2C=CSC=2)NN=1)(C)C>>[CH:11]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[C:19]2[CH:20]=[N:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[NH:8][N:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1n[nH]c2nccc(Cl)c12
Reactant: COc1ccc(B(O)O)cn1
Agent: CC(C)c1n[nH]c2nccc(-c3ccsc3)c12
Product: COc1ccc(-c2ccnc3[nH]nc(C(C)C)c23)cn1
Yield: 60 %

Procedure:
According to Example 1(4), a crude product of 3-isopropyl-4-(6-methoxypyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine was prepared using compound (6b) instead of compound (1c) and using 6-methoxypyridin-3-yl-boronic acid instead of quinoline-3-boronic acid and was used in the subsequent reaction without being purified. According to Example 1(5), compound (18a) (the second stage yield: 60%) was prepared using 3-isopropyl-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine instead of compound (1d).
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[N:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:5][C:6]1[N:7]=[N:8][C:9]([O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:22])[F:23])=[CH:10][CH:11]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1ccccc1Oc1ccc(Cl)nn1
Yield: 92.4 %

Procedure:
80 ml of a dimethylsulfoxide solution containing 3.50 g of 3,6-dichloropyridazine, 6.44 g of 2-trifluoromethylphenol and 3.58 g of potassium carbonate, was reacted at 100° C. for 2.5 hours under stirring. After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract layer was dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off. The residue was purified by silica gel column chromatography, whereby 5.96 g of 3-chloro-6-(2-trifluoromethylphenoxy) pyridazine was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[C:10](=[O:22])[C:11]2[C:16]([C:17](=[O:20])[C:18]=1Br)=[CH:15][C:14]([F:21])=[CH:13][CH:12]=2>C(O)C>[O:20]=[C:17]1[C:18]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[C:9]=2[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([F:21])=[CH:15][C:16]1=2
Reactant: Nc1ccccn1
Reactant: O=C1C(Br)=C(Br)C(=O)c2cc(F)ccc21
Solvent: CCO
Product: O=C1c2cc(F)ccc2C(=O)c2c1nc1ccccn21
Yield: 24.7 %

Procedure:
1.4 g (15 mmol, 2 eq) of 2-aminopyridine are added to a suspension of 2.5 g (7.5 mmol, 1.0 eq) of 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene in 50 mL of ethanol. The reaction mixture is brought to reflux of the solvent for 20 h, then brought to ambient temperature. The tan precipitate formed is filtered and washed profusely with ethanol. The solid obtained is purified by flash chromatography on a column of silica gel (support: silica 6-35 mm; (10 cm φ, 25 cm h; eluant: dichloromethane/ethyl acetate, 70/30). 494 mg of 6,11-dihydro-6,11-dioxo-8-fluoronaphtho[2',3':4,5]imidazo[1,2-a]pyridine or 6,11-dihydro-6,11-dioxo-9-fluoronaphtho[2',3':4,5]imidazo-[1,2-a] pyridine or 5,6-dihydro-5,6-dioxo-3-fluoronaphtho[1',2':4,5] imidazo[1,2-a]pyridine are obtained in the form of yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[OH:32][C:33]1[N:38]=[C:37]([OH:39])[C:36](B(O)O)=[CH:35][N:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[OH:32][C:33]1[N:38]=[C:37]([OH:39])[C:36]([C:2]2[N:7]=[C:6]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:35][N:34]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cnc(O)nc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cnc(O)nc2O)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 15.1 %

Procedure:
To a degassed solution of 0.20 g (0.44 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 10 ml of 1,2-dimethoxyethane was added 0.138 g (0.88 mmol) of 2,4-dihydroxy-pyrimidine-5-boronic acid, 0.051 g (0.044 mmol) of tetrakis-(triphenylphosphine)-palladium and 0.031 g (0.088 mmol) of 2-(dicyclohexylphosphino)biphenyl, followed by 0.071 g (0.67 mmol) of sodium carbonate and 3.4 ml of H2O. Finally, the reaction mixture was warmed up to 80° C. After 48 hours, it was cooled down to RT, poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.035 g (15%) of the title compound as off-white solid. MS: 528.2 (MH+).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([N+:26]([O-:28])=[O:27])[CH:9]=1.CO>CN(C)C=O.ClCCl>[Br:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:11]([C:12]([O:14][CH3:1])=[O:13])=[C:10]([N+:26]([O-:28])=[O:27])[CH:9]=1
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Oxalyl chloride (1.4 mL, 16.6 mmol) was added dropwise to a 0° C. suspension of Example 324a (5.47 g, 14.6 mmol) and dichloromethane (65 mL). 3 drops dimethylformamide was added and the reaction mixture was stirred at ambient temperature for 2 hours. After cooling to 0° C., methanol (12 mL, 296 mmol) was added dropwise. The solution was stirred for 15 minutes at 0° C. and for 2.5 hours at ambient temperature. The solution was diluted with dichloromethane and was washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (5.42 g, 96% yield).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@:7]([CH3:9])([OH:8])[CH:6]=[CH:5][CH2:4]1.C(=O)(O)[O-:11].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:4][C@H:5]2[C@H:6]([O:11]2)[C@:7]1([CH3:9])[OH:8]
Reactant: C[C@]1(O)C=CC[C@H]1CO
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](CO)C[C@@H]2O[C@@H]21
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a solution of (1S,5S)-5-(hydroxymethyl)-1-methylcyclopent-2-en-1-ol (0.181 g, 0.00141 mol) in DCM (18.0 mL) was added sodium bicarbonate (237 mg, 2.82 mmol) and the mixture was cooled to 0° C. To this mixture was added 3-chloroperbenzoic acid (380. mg, 1.69 mmol) and the reaction was stirred at rt for 4 h. The solvent was removed in vacuo and silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM afforded the title compound (200 mg, 98%). LC/MS: Rt=0.52 min, ES+ 145 (AA standard).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[F:10][C:11]1[CH:20]=[CH:19][C:18]2[NH:17][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)[C:15]([CH3:34])([CH3:33])[CH2:14][C:13]=2[C:12]=1[C:35](O)=[O:36].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:20]=[CH:19][C:18]2[NH:17][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:22]=3)[C:15]([CH3:33])([CH3:34])[CH2:14][C:13]=2[C:12]=1[C:35]([NH:9][S:6]([CH:3]1[CH2:5][CH2:4]1)(=[O:8])=[O:7])=[O:36]
Reactant: CC1(C)Cc2c(ccc(F)c2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(ccc(F)c2C(=O)NS(=O)(=O)C2CC2)NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (102 mg, 2.5 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (315 mg, 2.6 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (100 mg, 0.26 mmol) and 1,1′-carbonyldiimidazole (106 mg, 0.65 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-amide (25.3 mg, 20%) as a white solid: LC/MS m/e calcd for C25H30FN3O4S (M+H)+: 488.60, observed: 488.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[Cl:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[Cl:26][C:27]([F:32])([F:31])[C:28]([O:30][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:29]
Reactant: ON=C1CCOCC1
Reactant: O=C(O)C(F)(F)Cl
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)C(F)(F)Cl)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 2-chloro-2,2-difluoroacetate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and chlorodifluoroacetic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 4.06-4.23 (2H, m), 3.52-3.86 (2H, m), 2.27-2.70 (2H, m), 1.72-2.07 (2H, m).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[N:30]=[C:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=[CH:27][CH:26]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1cccc(N)n1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)Cc1cccc(NC(=O)C(OC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Yield: 46.2 %

Procedure:
The compound of example A9 was obtained by similar method described in example A1 using 2-(4-cyclopropanesulfonyl-phenyl)-2-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 4; 0.990 g, 2.91 mmol), ethyl 2-(6-amino-2-pyridyl)acetate (0.35 g, 1.94 mmol), HOBt (0.65 g, 4.81 mmol), and EDCl (0.92 g, 4.81 mmol), N-methyl morpholine (0.64 mL, 5.83 mmol) in DMF (25 mL) to provide the title compound (0.45 g).