Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[CH2:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])[CH:4]=O)[CH3:2].C(O)(=O)C(O)=O.[CH2:34]([O:36][P:37]([CH2:42][CH2:43][NH2:44])(=[O:41])[O:38][CH2:39][CH3:40])[CH3:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:39]([O:38][P:37]([CH2:42][CH2:43][NH:44][CH2:4][C:3]([CH2:1][CH3:2])=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[CH2:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])(=[O:41])[O:36][CH2:34][CH3:35])[CH3:40]
Reactant: CCOP(=O)(CCN)OCC
Reactant: CCC(C=O)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCNCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC)OCC
Reaction time: 8 h
Yield: 66.1 %

Procedure:
2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal (26.6 mg, 0.068 mmol) and aminoethylphosphonic acid diethylester oxalate salt (20.4 mg, 0.075 mmol) were dissolved in DMF (0.8 mL). Acetic acid (20.5 mg, 0.342 mmol) was added, followed by sodium triacetoxyborohydride (27.6 mg, 0.137 mmol). After 8 hrs, the crude reaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide 24.9 mg (65%) of the desired product after lyophilization. 1H NMR (300 MHz, CDCl3): δ=0.05 (s, 9H), 1.10-1.24 (m, 8H), 1.35 (t, J=7.5 Hz, 6H), 2.19 (s, 3H), 2.23 (m, 2H), 2.35 (q, J=7.8 Hz, 2H), 2.70 (q, J=7.2 Hz, 2H), 3.25 (m, 2H), 3.56 (m, 4H), 4.15 (m, 4H), 4.29 (m, 2H), 5.15 (s, 2H), 5.47 (m, 1H) ppm; 31P NMR (121 MHz, CDCl3): δ=27.71 ppm; MS=554 [M++1].
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si](C(C)C)(C(C)C)C(C)C)=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2=[O:34])=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[CH:8]2[OH:34])=[CH:35][CH:36]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2O

Procedure:
To a solution of 13 (0.699 g, 1.38 mmol) in 14 mL of a 1:1 solution of dry MeOH: CH2Cl2 under a N2 atmosphere was added sodium borohydride (NaBH4, 156 mg, 4.13 mmol). The reaction mixture was dried after 5 hours and the residue was loaded onto a silica column. The product was eluted with a 10% EtOAc-Hex to provide the product 20. 1H NMR (300 MHz, CDCl3) δ 1.10 (d, 9H, J=8 Hz), 1.16 (d, 9H, J=7 Hz), 1.52 (septet, 3H, J=8 Hz), 3.72 (d, 1H, J=11 Hz), 4.11 (s, 3H), 4.23 (d, 1H, J=15 Hz), 4.85 (d, 1H, J=15 Hz), 5.79 (d, 11H, J=11 Hz), 6.97 (t, 2H, J=9 Hz), 7.27 (dd, 2H, J=6, 9 Hz), 7.43 (dd, 1H, J=4, 8 Hz), 8.43 (dd, 1H, J=2, 8 Hz), 8.81 (dd, 1H, J=2,4 Hz); 13C NMR (75 MHz, CDCl3) δ 14.8. 18.2,41.3, 61.6, 78.6, 115.3, 115.6, 116.6, 122.3, 126.0, 126.8, 130.1, 130.2, 131.1, 132.8, 143.1, 143.8, 148.3, 162.1 (d, J=244 Hz), 165.2; EI MS (m/z) 511.5 [MH+], 533.4 [M+Na].
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:21]([N:23]1[CH2:34][CH2:33][CH2:32][C@H:24]1[C:25]([NH:27][CH2:28][C:29]([NH2:31])=[O:30])=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=O)C1C=CC=CC=1>[Pd].CO>[ClH:1].[NH2:12][C@H:13]([C:21]([N:23]1[CH2:34][CH2:33][CH2:32][C@H:24]1[C:25]([NH:27][CH2:28][C:29]([NH2:31])=[O:30])=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reaction time: 8 h

Procedure:
A solution of 21.2 g. of Nα -benzyloxycarbonyl-L-arginyl-L-prolyl-glycinamide hydrochloride (Example 1, part m) in 200 ml. of methanol with 1.0 g. of 20% palladium-on-carbon is stirred under hydrogen gas for four hours and allowed to stand overnight. The solution is filtered and the filtrate evaporated at 40° C. under reduced pressure to a white foam which is suitable for use without further purification.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:22]([O:24]CC)=[O:23])[C:14]([NH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:9]2[CH:8]=[N:7]1)[CH2:4][CH3:5]>C(O)C.O>[CH2:3]([N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:22]([OH:24])=[O:23])[C:14]([NH:15][CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[C:9]2[CH:8]=[N:7]1)[CH2:4][CH3:5]
Reactant: CCCn1ncc2c(NC3CCOCC3)c(C(=O)OCC)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
2M-Sodium hydroxide solution (0.7 ml) was added to a stirred suspension of Intermediate 38 (0.23 g) in ethanol (5 ml) and water (1.5 ml). After stirring overnight at room temperature, a further quantity of 2M-sodium hydroxide solution (0.7 ml) was added, and the reaction mixture was heated at 43° C. for 2.5 hours. The reaction solution was concentrated, diluted with water (5 ml) and acidified with 2M-hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give Intermediate 39 as a white solid (0.14 g). LCMS showed MH+=305; TRET=2.42 min.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[O:17])=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[O:17][CH2:4]1
Reactant: O=C(c1ccc(F)cc1)c1ccccc1Cl
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(C2(c3ccccc3Cl)CO2)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.03 mol) and powdered trimethyl oxosulphonium iodide (0.03 mol) in dry dimethylsulphoxide (DMSO; 30 ml). A solution of o-chlorophenyl p-fluorophenyl ketone (0.025 mol) in DMSO (10 ml) was added dropwise at room temperature. The solution was then heated at 50° for 11/2 hours, cooled to room temperature and poured into water. The solution was extracted with diethyl ether (100 ml), washed with water (3×100 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave 1-o-chlorophenyl-1-p-fluorophenyl ethylene oxide (90%) as a colourless liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CN1CCCC1=O.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>C(#N)C>[C:22]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: O=C(OCCCO)c1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: C=C(C)C(=O)OCCCOC(=O)c1ccc(O)cc1
Temperature: 0 °C

Procedure:
To a solution of 23 g of 4-hydroxybenzoic acid (3-hydroxypropyl)ester in 100 ml of acetonitrile was added 20 ml of N-methylpyrrolidone with stirring, followed by 16 g of methacryloyl chloride. After the mixture was reacted with stirring at 35° C. for 8 hours, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate/n-hexane to give 4-hydroxybenzoic acid (3-methacryloyloxypropyl)ester (Ph-1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH3:15][O:14][C:10](=[O:13])/[CH:11]=[CH:12]/[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C#N)cc1
Yield: 94 %

Procedure:
Table 1, Entry 2. In the reaction tube were mixed 4-bromobenzonitrile (0.182 g, 1.0 mmol), methyl acrylate (0.108 g, 1.25 mmol), palladium acetate (0.00225 g, 0.01 mmol), tri-o-tolylphosphine (0.0122 g, 0.04 mmol), triethylamine (0.127 g, 1.25 mmol) and 0.50 ml DMF.under nitrogen. The contents of the flask were irradiated for 3.50 min with an effect of 60 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml water and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane/diethyl ether (1/1) as the eluent. The yield was 94% (pale yellow crystals).
Reaction SMILES: S(=O)(=O)(O)O.C1(CC(O)=[O:14])C=CC=CC=1.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[CH:25]1([NH:24][C:23]([NH:22][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:14])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.25 h

Procedure:
A freshly prepared mixture of 26 mg of concentrated sulfuric acid in 2.5 ml of absolute pyridine (suspension of pyridinium sulfate) is added, at 20° C. and while stirring, to a solution of 1.1 g (0.0025 mol) of prednisolone 17-ethyl carbonate and 1.2 g (0.0088 mol) of phenylacetic acid (dried at about 50°-60° C. in vacuo over P2O5 for 5 h.) in 6 ml of absolute pyridine. After stirring for 15 min., 720 mg (0.0035 mol) of N,N'-dicyclohexylcarbodiimide are added. A crystalline precipitate of the N,N'-dicyclohexylurea which has been formed soon appears in the initially clear solution. Stirring is continued until TLC no longer detects starting material and detects the reaction product at RF =0.8 (as a rule, a reaction period of 16 hours; a longer reaction period, e.g. standing or stirring over the weekend, does not impair the reaction result). After this, 0.3 ml of acetic acid are added and the mixture is left to stand for a further 1 h. at 20° C. and then 24-48 h. in a deep-freeze (about -15° C.). The precipitated N,N'-dicyclohexylurea is filtered off and washed with cold pyridine (about -15° C.), and the filtrate is stirred into about 400 ml of a quarter-saturated aqueous solution of sodium chloride; about 5 ml of ethanol are added and the oily-crystalline precipitate is filtered off, washed several times with water and then taken up in about 20 ml of methylene chloride. After drying with sodium sulfate, the solvent is distilled off and the residue is crystallized by adding diethyl ether or diisopropyl ether. 1.1 g of prednisolone 17-ethyl carbonate 21-phenylacetate with a melting point of 179°-183° C. are obtained and can be recrystallized from tertbutanol/diethylether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)O

Procedure:
Methyl 4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylate (2.26 g), 2N aqueous sodium hydroxide (20 ml), methanol (20 ml) and tetrahydrofuran (20 ml) were stirred together at room temperature for 1 hour. After adding 5N aqueous hydrochloric acid and distilling off 10 ml of the organic solvent, the precipitated solid was filtered out. The solid was washed with a methanol and water mixed solvent to obtain 2.0 g of the target substance as a faint red powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1nccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Temperature: 200 °C
Yield: 44.2 %

Procedure:
A mixture of 259 (420mg, 2.76 mmol), 2-fluoro-4-nitrophenol (651 mg, 4.14 mmol) and K2CO3(1.14 g, 8.28 mmol) in Ph2O (15 mL) was heated at 200° C. for 6 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried and concentrated. The residue was purified by flash column chromatography with gradient elution from hexane to hexane/EtOAc (3:1), to afford the title compound 260 (333 mg, 44% yield) as a yellowish solid. MS (m/z): 274.1(M+H) (found).
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][C:57]=2[CH2:58][O:59][C:60](=[O:62])[CH3:61])[CH:53]([NH:63][C:64](=[O:79])[CH2:65][C:66]2[N:67]=[C:68]([C:71]4[C:76]([OH:77])=[CH:75][CH:74]=[CH:73][C:72]=4[OH:78])[S:69][CH:70]=2)[C:52]3=[O:80])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[C:60]([O:59][CH2:58][C:57]1[CH2:56][S:55][CH:54]2[N:51]([C:52](=[O:80])[CH:53]2[NH:63][C:64](=[O:79])[CH2:65][C:66]2[N:67]=[C:68]([C:71]3[C:76]([OH:77])=[CH:75][CH:74]=[CH:73][C:72]=3[OH:78])[S:69][CH:70]=2)[C:50]=1[C:48]([OH:49])=[O:47])(=[O:62])[CH3:61]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(-c4c(O)cccc4O)n3)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4c(O)cccc4O)n3)C2SC1
Yield: 87.9 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8e (181 mg, 0.270 mmol), Et3SiH (0.431 mL, 2.70 mmol), and trifluoroacetic acid (0.832 mL, 10.8 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9e (120 mg, 88%) as a white solid after crystallization from EtOAc/CH2Cl2 /hexane. mp 145° C. (dec); IR (KBr) 3650-2500 (br), 1775, 1736, 1466, 1237 cm-1 ; 1H NMR (DMSO-d6) δ1.98 (3H, s, CH3), 3.43 (1H, d, J=18.1 Hz ), 3.58 (1H, d, J=18.1 Hz), 3.76 (2H, s, CH2), 4.64 (1H, d, J=12.8 Hz), 4.95 (1H, d, J=12.8 Hz), 5.05 (1H, d, J=5.0 Hz), 5.64-5.70 (1H, m), 6.42 (2H, d, J=8.0 Hz), 7.07 (1H, t, J=8.0 Hz), 7.41 (1H, s), 9.12 (1H, d, J=8.1 Hz, NH), 12.17 (2H, br s, OH), 13.60 (1H, br s, CO2H); FDMS m/z 505 (M+), 506 (M+ +1); Anal. Calcd for C21H19N3O8S2 : C, 49.89; H, 3.79; N 8.31. Found. C 50.15; H 3.79; N 8.60.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:20][C:19]1[C:14]2[N:15]([C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:3][OH:2])[CH2:10][CH2:9]3)=[N:12][C:13]=2[C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1nccn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C

Procedure:
A solution of trans-4-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester (150.0 mg, 0.3390 mmol) in THF (10 mL, 0.1 mol) was cooled to −78° C., and 1.0 M of LiAlH4 in THF (1.50 mL) was added dropwise. The solution was allowed to warm to rt. Sat. NaHCO3 (10 mL) was added to quench, and the THF was removed in vacuo. DCM was added, and the mixture was transferred to a separatory funnel. The organic layer was extracted with sat. NaHCO3, washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=1.15-1.27 (m, 2H), 1.65-1.70 (m, 1H), 1.84-1.96 (m, 2H), 1.98-2.05 (m, 2H), 2.10-2.16 (m, 2H), 2.87-2.97 (m, 1H), 3.56 (d, J=6.3 Hz, 2H), 5.06 (br. s., 2H), 7.07 (dd, J=6.9, 1.9 Hz, 3H), 7.10-7.18 (m, 3H), 7.23 (d, J=5.1 Hz, 1H), 7.35-7.40 (m, 2H), 7.60-7.63 (m, 2H). MS (ES+): m/z 416.34 (100) [MH+]. HPLC: tR=2.34 min (polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:22].[C:23]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)(=[O:25])[CH3:24]>CN1CCCC1=O>[C:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:29]4[CH2:30][CH2:31][CH:27]([NH:26][C:23](=[O:25])[CH3:24])[CH2:28]4)[CH:11]=3)[C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(-c2ccccc2)c2cc(Cl)c(F)cc2c1=O
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccccc2)C1
Temperature: 100 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
To a solution of 1.5 g 7-chloro-1-phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (product of Example 1(d)) in 20 ml of 1-methyl-2-pyrrolidinone at 115° C. is added 3 g of 3-acetamido-pyrrolidine. After stirring at 100° C. for 20 hours, the solvent is removed by reduced pressure to dryness. Ethanol is added to the residue and washed with ether and then diluted cold hydrochloric acid and then water. The solid is dried, yielding 1.60 g 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-acetamido-1-pyrrolidinyl)-quinoline-3-carboxylic acid (9) ##STR43## R-phenyl).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Br.Br[CH2:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:12][CH2:13][CH2:14][NH2:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: NCCCBr
Reactant: Cc1cc(Cl)ccc1N
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)ccc1NCCCN
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-2-methylaniline (8 g) and 3-bromopropylamine hydrobromide (5 g) was heated at 100° C. for fifteen minutes. After cooling to room temperature, the resulting crystalline solid was dissolved in water (50 mL) and one equivalent of sodium hydroxide was added. This solution was then washed with ethyl ether and basified with excess sodium hydroxide. It was then extracted with dichloromethane, the combined extracts were dried over anhydrous potassium carbonate and evaporated to dryness.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][O:9][C:4]2=[CH:3][CH:2]=1.CN(C)[CH:12]=[O:13].P(Cl)(Cl)(Cl)=O>>[O:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH:7]=[C:8]1[CH:12]=[O:13]
Reactant: c1ccc2occc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2ccccc2o1
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a mixture of 2,3-benzofuran (23.63 g, 0.2 mol) and N,N-dimethylformamide (22 g, 0.3 mol) was added phosphorous oxychloride (46 g, 0.3 mol) dropwise. Upon completion of addition, the mixture was stirred for 1 hr, then warmed to 50° C. and kept at that temperature for 60 hrs. It was then poured into ice (250 mL). The resulting aqueous mixture was neutralized to pH6 by the addition of aqu. 2N NaOH and extracted with ether (3×300 mL). The organics were combined, dried with MgSO4 and concentrated. The residue was distilled to afford 9.21 g of 2-benzofurancarboxaldehyde as a pale yellow oil (b.p.=98°-100° C. at 0.6 mm Hg).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])([O-])=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:9]2[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Oc2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
EX-634A) Dinitrobenzene (1.68 g, 10 mmol) and 4-fluorophenol (1.13 g, 10 mmol) were dissolved in anhydrous dimethylsulfoxide (25 mL), and powdered cesium carbonate (8 g, 24.8 mmol) was added. The mixture was stirred and heated to 100° C. using a reflux condenser under a nitrogen atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4×60 mL). The combined ether layers were washed with 3% HCl, 5% sodium hydroxide, and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the recovered oil was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:25) to give 1.68 g (69%) of the desired 3-(4 -fluorophenoxy)nitrobenzene product as orange crystals, 97% pure by HPLC analysis. MS m/z=234 [M+H+.
Reaction SMILES: [N:1]#[C:2]Br.Cl.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH:13][C:14]1[N:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]2=[N:16][C:15]=1[C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([NH:28][NH2:29])=[O:27].C(=O)([O-])O.[Na+]>O>[NH2:1][C:2]1[O:27][C:26]([C:25]2[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=2[C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]3[C:14]=2[NH:13][C:7]2[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=2[CH3:5])=[N:28][N:29]=1
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)NN)nc2ccc(F)cn12
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Nc1c(-c2ccccc2-c2nnc(N)o2)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
2.4 16.9 mg (0.160 mmol) of cyanogen bromide are added to a solution of 60 mg (0.141 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoro-imidazo[1,2-a]pyridin-2-yl]benzohydrazide hydrochloride and 29.4 mg (0.350 mmol) of sodium hydrogencarbonate in 10 ml of water, and the mixture is stirred at RT for 2 hours. The precipitated product is filtered off with suction, dried and purified by preparative thin-layer chromatography, giving 10 mg (17%) of {2-[2-(5-amino-1,3,4-oxadiazol-2-yl)phenyl]-6-fluoroimidazo[1,2-a]pyridin-3-yl}-(2,6-dimethylphenyl)amine (“B1”) as solid; MS-FAB (M+H+)=415.8; Rf (HPLC, polar method): 1.07 min.;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:13]2[CH2:14][CH2:15][CH:10]([C:8]([C:4]3[S:5][CH:6]=[CH:7][C:3]=3[Cl:2])=[O:9])[CH2:11][CH2:12]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(c1sccc1Cl)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3sccc3Cl)CC2)CC1

Procedure:
From (3-chloro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (100 mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate C, 91 mg) by procedure A. 1. Yield: 85 mg (50%). White foam. MS (m/z): 455.3 ([M+H]+).