Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.ClCCl.C[Si]([C:19]#[N:20])(C)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[Cl-].[Al+3].[Cl-].[Cl-].O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28])[CH:7]2[C:19]#[N:20]
Reactant: Brc1cccc2cnccc12
Reactant: O=C(Cl)c1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: N#CC1c2cccc(Br)c2C=CN1C(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A round bottomed flask was charged with 5-bromoisoquinoline (available from Aldrich; 4 g, 19.2 mmol), dichloromethane (DCM) (50 ml), trimethylsilyl cyanide (4.81 ml, 38.5 mmol) and aluminium chloride (15 mg, 0.112 mmol). To the mixture was added benzoyl chloride (4.46 ml, 38.5 mmol) slowly over a period of 5 minutes. The mixture was warmed to 30° C. for 3 h after which time it was treated with water (50 ml) and stirred at room temperature for 30 minutes. The organic layers were collected and washed sequentially with 2N HCl, 2N NaOH and brine. The organic layers were passed through a hydrophobic frit before being concentrated in vacuo to give an orange solid. The solid was triturated with diethyl ether and the slurry filtered. The isolated solid was dried in vacuo to give the title compound as a grey solid (3.9 g).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:19]=1[CH:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.O>COCCOC.C(OCC)C>[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:19]=1[CH:28]1[CH2:33][CH2:32][C:31](=[CH:5][C:3]#[N:4])[CH2:30][CH2:29]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COCOc1ccc(C2CCC(=O)CC2)c(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: COCOc1ccc(C2CCC(=CC#N)CC2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.4 %

Procedure:
To a round bottomed flask equipped was added sodium hydride (40 mg, 60% dispersion in mineral oil) and 1, 2-dimethoxyethane (10 ml). Diethyl cyanomethylphosphonate (102 μl, 0.95 mmol) was added and the reaction mixture allowed to warm to room temperature. 4-[(2,4-Bis(methoxymethoxy)phenyl)]cyclohexanone (200 mg) was added as a solution in 1,2-dimethoxyethane (10 ml) and the reaction mixture stirred for 17 hr at room temperature. The reaction mixture was poured into a separating funnel containing water (50 ml) and diethyl ether (50 ml). The layers were separated and the aqueous phase extracted with diethyl ether (2×20 ml). The combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, to give an oil. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:2, v/v) afforded the title compound (141 mg, 66%) as a pale yellow oil. δH (CD3OD) 1.57-1.70 (2H, m), 2.02-2.25 (2H, m), 2.34-2.49 (2H, m), 2.60 (1H, m), 3.03 (1H, m), 3.24 (1H, m), 3.47 (3H, s), 3.52 (3H, s), 5.17 (2H, s), 5.23(2H, s), 5.33 (1H, s), 6.68 (1H, dd), 6.83 (1H, d), 7.09 (1H, d).
Reaction SMILES: OC1C=C2C(CCC2=O)=CC=1OC.[N:14]1C=CC=CC=1.[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28]/[N:29]=[C:30]2\[CH2:31]C[CH2:33][C:34]3[C:39]\2=[CH:38][C:37]([O:40]C)=[C:36]([O:42][CH3:43])[CH:35]=3)=[CH:25][CH:24]=1)([O-:22])=O.C(OCC)(=O)C.CCCCCC>C(O)C>[N:20]1[O:22][N:14]=[C:24]2[CH:25]=[C:26]([CH2:27][O:28]/[N:29]=[C:30]3\[CH2:31][CH2:33][C:34]4[C:39]\3=[CH:38][C:37]([OH:40])=[C:36]([O:42][CH3:43])[CH:35]=4)[CH:44]=[CH:45][C:23]=12
Reactant: c1ccncc1
Reactant: COc1cc2c(cc1OC)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CCC2
Agent: COc1cc2c(cc1O)C(=O)CC2
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1O)/C(=N/OCc1ccc3nonc3c1)CC2
Yield: 9 %

Procedure:
6-Hydroxy-5-methoxy-1-indanone (76 mg, 0.43 mmol) was subjected to reaction with 0-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)hydroxylamine hydrochloride (97 mg, 0.48 mmol) in ethanol (2 mL) and pyridine (0.2 mL, 2.58 mmol) under the same conditions as described for (E)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one O-4-nitrobenzyl oxime. Subjection of the material obtained on work up to flash chromatography (3:7 v/v ethyl acetate/hexane elution) afforded the title compound as off-white crystals (13 mg, 9%), m.p. 145° C. (with decomposition), Rf 0.3.
Reaction SMILES: [C:1](OC1C=CC(C(C2C=CC(OC(=O)C=C)=CC=2)(C2C=CC(OC(=O)C=C)=CC=2)C)=CC=1)(=[O:4])[CH:2]=C.[C:36]1([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:43]=2[OH:54])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(=O)OCCO1.[I-].[K+].CN(C)C=O>C(OCC)(=O)C>[C:48]1([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:43]=2[O:54][CH:1]([OH:4])[CH3:2])[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: C=CC(=O)Oc1ccc(C(C)(c2ccc(OC(=O)C=C)cc2)c2ccc(OC(=O)C=C)cc2)cc1
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C1OCCO1
Solvent: CN(C)C=O
Product: CC(O)Oc1c(-c2ccccc2)cccc1-c1ccccc1

Procedure:
To a 50 ml 1 neck round bottom was added 2,6-diphenylphenol (10 g, 1 eq), ethylene carbonate (3.9 g, 1.1 eq), potassium iodide (0.07 g, 0.01 eq), dimethylformamide (1 g, 0.3 eq) and heated to 150 C. After 4 hours the reaction was cooled to 40 C, added 30 ml ethyl acetate and washed 2 times with 20 ml sodium chloride brine, 3 times with 20 ml DI water and again with 20 ml brine. The ethyl acetate was dried with (1 g) magnesium sulfate, filtered and concentrated invacuo to recover an off-white solid. Mp 77-78
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([N:31]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:39][CH:40]=2)[CH3:32])[CH2:27][CH:28]([CH3:29])[CH3:30])[C:17](=[O:23])[NH:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)Cc1ccc(C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
2-(Methyl-amino)-4-methyl-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.5 mmol) was dissolved in THF (10 mL) and treated with 4-tert-butyl-benzyl bromide (0.75 mmol) and diisopropylethylamine (1.5 mmol). The reaction was stirred at 50° C. for 15 hours. Then the reaction mixture was allowed to cool to room temperature and concentrated to dryness. The residue was chromatographed on silica gel eluting with a gradient of 25% EtOAc/Hexanes to give the title compound with the yield of 40%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][OH:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH:20]=[O:21])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
A solution of oxalyl chloride (0.27 ml, 3.15 mmole) in dry dichloromethane (8 ml) was cooled to −78° C. Dimethyl sulfoxide (0.45 ml, 6.29 mmole) in dichloromethane (1 ml) was added dropwise maintaining the reaction temperature at −40° C. The reaction mixture was stirred for 5 minutes and a solution of (3-hydroxy-propyl)-carbamic acid tert-butyl ester (0.50 g, 2.86 mmole) in dichloromethane (3 ml) was added dropwise. After stirring for 15 minutes, triethylamine (1.99 ml, 14.3 mmole) was added and the mixture allowed to warm to ambient temperature. The reaction was quenched by adding water (10 ml), extracted with dichloromethane and the organic extracts were washed with aqueous hydrochloric acid solution (2M), saturated sodium bicarbonate solution and water. The organic layer was dried under magnesium sulfate and the solvent removed in vacuo to afford the title compound (0.45 g). 1H NMR (CDCl3) δ 9.81 (1H, s), 3.45-3.40 (2H, t, J=5 Hz), 2.72-2.69 (2H, t, J=5 Hz), 1.43 (9H, s).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1(C(C2C=CC=CC=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1.[C:31]([Cl:34])(=[O:33])[CH3:32]>C1COCC1>[ClH:34].[NH2:18][CH:19]([C:31](=[O:33])[CH3:32])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride was prepared as described in J. Med. Chem. 1996, 39, 957. LiHMDS (50 mL, 50 mmol, 1 M in THF) was slowly added to a solution of ethyl N-(diphenylmethylidene)glycinate in THF (62.5 mL) at −78° C. under N2. The yellow slurry was stirred for 45 min. and was then transferred via cannula to a solution of acetyl chloride (4.2 mL, 59 mmol) in THF (25 mL) at −78° C. Additional THF (125 mL) was added to the anion solution to facilitate transfer to the acetyl chloride solution. The reaction mixture was allowed to warm to RT and stirred for 4 h. The reaction was then quenched with 2 N HCl (57.5 mL). The THF was evaporated and the resultant aqueous solution was extracted with EtOAc (2×50 mL). The organic phases were discarded and the aqueous phase was concentrated in vacuo. The residue was treated with EtOH (75 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (9.6 g, >99%) as a light-yellow solid which was used in next step without purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:15][C:16]([NH:18][C@H:19]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CCOC(C)=O>[Br-:1].[C:11]([O:15][C:16]([NH:18][C@H:19]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N+:25]([CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
2-Bromo-1-phenylethanone (27.6 mg, 0.14 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-2-phenylacetate (Diasteroisomer 1 of C1) (50 mg, 0.14 mmol) in EtOAc (3 ml). The reaction was stirred at RT overnight. The precipitate was collected by suction filtration and washed with Et2O to obtain (R)-3-((R)-2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (65 mg; 84% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=C1.[H-].[Na+].Cl[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1.O.C[N:21](C=O)C>>[N:1]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=[N:21]1
Reactant: c1cc[nH]c1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(-n2cccn2)nc1
Reaction time: 5 h
Yield: 64 %

Procedure:
To a suspension of pyrrole (0.356 g, 5.23 mmol) in DMF (20 ml) was added sodium hydride (60% in oil, 0.233 g, 5.81 mmol). After stirring for 5 hrs., methyl 6-chloronicotinate (1.00 g, 5.81 mmol) was added, and the mixture was further stirred for 27 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgSO4). After concentration under reduced pressure, the precipitated solid was collected by filtration and washed with hexane to give the title compound (0.683 g, 64%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:18]([OH:20])=[O:19])[CH2:15][CH:16]=[CH2:17])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.[N+](=[CH2:31])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:18]([O:20][CH3:31])=[O:19])[CH2:15][CH:16]=[CH2:17])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1
Reactant: C=[N+]=[N-]
Reactant: C=CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Product: C=CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)OC

Procedure:
In the manner given in Example 10, a solution of 7-chloro-2-[(1-carboxy-3-butenylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-3-butenylidene]hydrazino]-5-(o-chlorphenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]#[N:37]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:35][C:36]#[N:37])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(Cl)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2c(Cl)ccc(OCC#N)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-ol (0.80 g), N,N-dimethylformamide (10 mL), potassium carbonate (1.0 g) and bromoacetonitrile (0.25 mL) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and this mixture was washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a light brown solid, 0.90 g.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH2:28]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([CH:28]1[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:27]1=[O:34])=[O:6]
Reactant: O=C1CCCC(=O)C1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Br)c1OCCOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Br)c1OCCOC
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2-Bromo-3-(2-methoxyethoxy)-4-ethylsulfonyl benzoic acid (6.1 g, 0.018 mol) was diluted in 50 mL of methylene chloride and 2 drops of DMF were added, followed by the slow addition of oxalyl chloride (3.81 g, 0.03 mol). After the addition was complete, the solution was refluxed for 1 hour, cooled and concentrated under vacuum. The crude acid chloride was diluted in 25 mL of methylene chloride and 2.24 g (0.02 mol) of 1,3-cyclohexanedione was added, followed by an excess of triethylamine (4.0 g). After stirring overnight, the organic layer was washed three times with dilute (1 N) hydrochloric acid, dried and concentrated. The crude enol ester was dissolved in 25 mL of acetonitrile and ten drops of acetone cyanohydrin and 4 mL of triethylamine were added and this reaction mixture was stirred at room temperature for 48 hours. The organic phase was washed three times with 1 N hydrochloric acid and then extracted with base. The base extracts were combined and acidified and extracted three times with 50 mL of methylene chloride. The methylene chloride extracts were dried, concentrated and chromatographed on silica gel using ether/methylene chloride/acetic acid to give 3.96 g of pure 2-[2'-bromo-3'-(2-methoxyethoxy)-4'-ethylsulfonylbenzoyl]-1,3-cyclohexanedione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:44]([CH3:48])([CH3:47])[C:45]#[N:46])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[O:33])=[CH:28][N:27]=4)[C:22](=[O:40])[N:21]([CH3:41])[N:20]=3)[C:14]=1[CH:42]=[O:43])[CH:8]=[CH:7]2.[BH4-].[Na+]>CO.ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:44]([CH3:48])([CH3:47])[C:45]#[N:46])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[O:33])=[CH:28][N:27]=4)[C:22](=[O:40])[N:21]([CH3:41])[N:20]=3)[C:14]=1[CH2:42][OH:43])[CH:8]=[CH:7]2
Reactant: Cn1nc(-c2cccc(-n3ccc4cc(C(C)(C)C#N)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cn1nc(-c2cccc(-n3ccc4cc(C(C)(C)C#N)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reaction time: 0.17 h

Procedure:
A solution of 2-[8-fluoro-2-(2-formyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile (224 mg, 0.35 mmol) in methanol (2.8 ml) and dichloromethane (4.3 ml) was cooled in an ice bath. To this was added a solution of sodium borohydride (65 mg, 1.7 mmol) in water (0.75 ml), via slow drop-wise addition. The mixture was stirred for 10 minutes and additional sodium borohydride (as describe above was added twice more over 20 minutes. The aqueous upper phase was carefully removed from the biphasic reaction solution. Methanol (1 ml) was added and with rapid stirring 3 more additions of aqueous sodium borohydride were made (as described above) over about 25 minutes. Water (60 ml) and dichloromethane (60 ml) were added and the material was transferred to a separatory funnel and the organic phase was collected. This was washed with an equal volume of 50% diluted brine solution and the dichloromethane phase collected. The aqueous phases were back extracted with dichloromethane (2×40 ml). The combined organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC on silica gel, eluting with 1% to 8% methanol/dichloromethane to provide the desired product which was further purified by crystallization from hot dichloromethane/hexane to provide desired product as a white solid (120 mg). (M+H)+=650 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H) 3.53-3.81 (m, 8H) 3.83-3.91 (m, 1H) 3.92 (s, 3H) 4.26-4.45 (m, 2H) 6.62 (dd, J=7.55, 1.89 Hz, 1H) 7.00 (d, J=8.31 Hz, 1H) 7.22 (dd, J=12.46, 1.89 Hz, 1H) 7.33 (d, J=7.18 Hz, 1H) 7.42 (dd, J=7.93, 1.51 Hz, 1H) 7.53 (d, J=1.89 Hz, 1H) 7.57 (t, J=7.93 Hz, 1H) 7.65-7.70 (m, 1H) 7.78 (dd, J=8.69, 2.27 Hz, 1H) 8.41-8.47 (m, 2H) 8.70 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:11]=[C:6]2[NH:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][N:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][N:7]2[CH:8]=[CH:9][CH:10]=[C:5]3[N:4]=[C:3]([S:2][CH3:1])[N:11]=[C:6]23)=[CH:17][CH:18]=1
Reactant: CSc1nc2ccc[nH]c-2n1
Reactant: ClCc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CSc1nc2cccn(Cc3ccc(Cl)nc3)c-2n1
Yield: 48.1 %

Procedure:
A solution of 2-methylsulfanyl-4H-imidazo[4,5-b]pyridine (900 mg, 5.45 mmol), 2-chloro-5-(chloromethyl)pyridine (1.32 g, 8.17 mmol) and triethylamine (1.1 mL, 8.17 mmol) in benzene (18 mL) was stirred at 100° C. for 12 h (microwave). After cooling to room temperature the benzene was decanted off and the resulting solid was triturated with boiling benzene (3×15 mL). The benzene phases were combined and the solvent was removed under reduced pressure. The resulting solid was triturated with CH2Cl2, filtered and dried under reduced pressure to yield 760 mg (2.62 mmol, 48%) of compound E1.4.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=CC(C=C)=CC=1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([CH:24]=[CH2:25])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: C=Cc1ccc(N)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: C=Cc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-aminostyrene (97 mg, 0.81 mmol), and acetic acid (0.1 ml) were used to give 10 mg (0.030 mmol, 7% yield) of the title compound.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O>ClCCl>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[C:20]([CH:3]=[O:4])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(-c2cc3cccc(Cl)n3n2)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(-c2nn3c(Cl)cccc3c2C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
N,N-Dimethylformamide (150 mL) was cooled to 0° C. and treated with phosphorous oxychloride (8.8 mL, 94 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. To this was added 7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine (16.3 g, 67 mmol) and the resultant solution was stirred overnight. Water was added, followed by dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from diethyl ether and hexanes to give 7-chloro-2-(3-methylphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (14.3 g, 79%) as a pale yellow solid. 1H NMR (CDCl3): δ 10.11 (s, 1 H), 8.41 (dd, 1H), 7.63 (s, 1H), 7.58 (d, 1H), 7.49 (dd, 1H), 7.42 (t, 1H), 7.33 (d, 1H), 7.20 (dd, 1H), 2.45 (s, 3H); MS m/z 271 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH2:22])[CH:21]=1>>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:20]([NH:22][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 2g (65 mg, 0.3 μmol) was reacted with the product from Example 1f (68 mg, 0.31 mmol) for 24 h following the procedure from Example 1g giving the title compound as a hydrochloride salt as a solid which was triturated with ether giving (10 mg, 84%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 2.38 (qnt, J=7.35 Hz, 2H) 2.99 (dd, J=7.35 Hz, J=7.72 Hz, 2H) 6.31 (d, J=7.35 Hz, 1H) 7.23 (s, 5H) 7.35 (m, 4H) 7.79 (d, J=8.46 Hz, 1H) 8.38 (d, J=6.98 Hz, 1H) 9.01 (d, J=8.46 Hz, 1H) 11.10 (s, 1H) 14.35 (br s, 1H); MS (ESI+) m/z 386 (M−Cl)+; (ESI−) m/z 384 (M−HCl)−.