Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>>[N+:1]([C:4]1[N:5]([CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1nccn1CC(O)CCl

Procedure:
Epichlorohydrin (100 mL) was added to a mixture of 2-nitroimidazole (11.3 g, 0.1 mol) and 1 g of potassium carbonate and the solution refluxed for 15-20 min until all 2-nitroimidazole was dissolved. The hot solution was filtered and the yellow crystal was collected to give compound (5, 17 g, 83%). 1H NMR (DMSO-d6, δppm): 3.61 (m, 2H, Cl—CH2—), 4.06 (m, 1H, HO—CH—), 4.32 (dd, 1H, N—CHa—, J=13.8 Hz, 8.4 Hz), 4.63 (dd, 1H, N—CHb—, J=13.8 Hz, 3.6 Hz), 5.67 (d, 1H, OH, J=5.7 Hz), 7.15 (s, 1H, —CH═), 7.56 (s, 1H, —CH═). 13C NMR (DMSO-d6, δppm):46.81, 52.27, 68.75, 127.40, 128.45, 144.98.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:30][OH:31])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22](=[O:29])(=[O:28])[N:23]=[CH:24][N:25]([CH3:27])[CH3:26])(C)(C)C.[ClH:33]>C(#N)C.O1CCOCC1>[NH2:7][CH:8]([CH2:30][OH:31])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])(=[O:29])=[O:28].[ClH:33]
Reactant: CN(C)C=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCCC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CN(C)C=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCCCC(N)CO
Reaction time: 4 h

Procedure:
A solution of 212 mg (0.45 mmol) of (S)-{4-[2-(dimethylaminomethylene-sulfamoyl)-5-nitro-phenoxy]-1-hydroxymethyl-butyl}-carbamic acid-tert-butyl ester in 5 ml of acetonitrile is mixed at room temperature with 0.75 ml of a 4 molar solution of hydrochloric acid in dioxane. After 4 hours, the batch is concentrated by evaporation, and 2-(4-amino-5-hydroxy-pentyloxy)-N-dimethylaminomethylene-4-nitro-benzenesulfonamide is obtained in the form of hydrochloride.
Reaction SMILES: [CH2:1]1[CH2:6][CH:5]([C:7]2([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[O:24])[N:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH2:18][CH2:19][CH3:20])[C:8]2=[O:21])[CH2:4][CH2:3][CH2:2]1.[C:38]([BH3-])#N.[Na+].C=O>CO.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.O>[CH2:3]1[CH2:4][CH:5]([C:7]2([NH:22][C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:30][CH:31]=3)=[O:24])[N:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH2:18][CH2:19][CH3:20])[C:8]2=[O:21])[CH2:6][CH2:1][CH2:2]1
Reactant: [BH3-]C#N
Reactant: CCCN1C(=O)C(NC(=O)Nc2ccc(N3CCNCC3)cc2)(C2CCCCC2)N=Cc2ccccc21
Agent: C=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCN1C(=O)C(NC(=O)Nc2ccc(N3CCN(C)CC3)cc2)(C2CCCCC2)N=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
To a cooled (0° C.) and stirred solution of N-[3(R,S)-5-cyclohexyl-2,3-dihydro-2-oxo-1-propyl-1H-1,4-benzodiazepin-3-yl]N'-[4-(N-piperazinyl)phenyl]urea (96 mg) in methanol (4 ml) and glacial acetic add (49 μl) was added sodium cyanoborohydride (24 mg) followed by dropwise addition of a solution of formaldehyde (37 μl of a 38% (w/v) solution in water) in methanol (2 ml). The solution was stirred at 0° C. for 20 min then at room temperature for 1 h. After this time the solvent was removed in vacuo and the residue partitioned between dichloromethane (20 ml) and saturated potassium carbonate solution (20 ml). The organic phase was separated and the aqueous layer washed with dichloromethane (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (Na2SO4) and evaporated in vacuo to afford a white solid. This was then chromatographed on silica gel, eluting with 90:10:1:1 dichloromethane:methanol:acetic acid:water to afford the title compound (60 mg) as a white solid. 1H NMR (360 MHz, D6 -DMSO) δ 0.73 (3H, t, J=7.4 Hz), 0.89-0.95 (1H, m), 1.10-1.70 (11H, m), 2.20 (3H, s), 2.40-2.43 (4H, m), 2.94-3.01 (5H, m), 3.60-3.70 (1H, m), 4.15-4.22 (1H, m), 5.02 (1H, d, J=8.9 Hz), 6.81 (2H, d, J=9 Hz), 7.12 (1H, d, J=8.6 Hz), 7.17 (2H, d, J=9 Hz), 7.35-7.39 (1H, m), 7.61-7.63 (2H, m), 7.76 (1H, d, J=7.8), 8.74 (1H, s). MS (CI, NH3) 517 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])[CH2:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:36])=[C:21]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[CH:22]=1.O>N1C=CC=CC=1>[Cl:36][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)=[CH:22][C:21]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1
Reactant: O=C(Cl)c1cccc(N2CCOCC2)c1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2Cl)cc1OC
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3)ccc2Cl)cc1OC
Temperature: 115 °C
Yield: 36.4 %

Procedure:
3-Morpholinobenzoyl chloride (0.15 g) was added to a stirred solution of N-(5-amino-2-chlorophenyl)-3,4-dimethoxybenzamide (0.17 g) in pyridine (3 ml). The reaction mixture was stirred and heated to 115° C. for 18 hours. The mixture was allowed to cool and poured into water. The mixture was extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated. The resultant solid was azeotroped with toluene and triturated under diethyl ether to give the title compound (0.1 g), m.p. 147.9-148.3° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12]O)=[CH:7][C:6]=2[CH:14]=1.CCN(C(C)C)C(C)C.CS([Cl:28])(=O)=O.C(OCC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][Cl:28])=[CH:7][C:6]=2[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1=Cc2cc(Br)ccc2CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: ClCC1=Cc2cc(Br)ccc2CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a solution of (2-bromo-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol from step A5 (150 mg, 0.593 mmol) in dichloromethane (2 mL) was added DIEA (0.310 mL, 1.78 mmol) followed by methanesulfonyl chloride (0.053 mL, 0.681 mmol) at 0° C. The mixture was gradually warmed up to rt and stirred for 18 h. Diethyl ether (50 mL) was added, the mixture was washed with water, the organic layer was partioned and concentrated. The residue was purified using silica gel column chromatography (hexanes-10% EtOAc) to give 2-bromo-8-(chloromethyl)-6,7-dihydro-5H-benzo[7]annulene (135 mg, 0.497 mmol, 84% yield). 1H NMR (500 MHz, chloroform-d) δ 7.31-7.29 (m, 1H), 7.26 (dd, J=8.2, 1.8 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 6.51 (s, 1H), 4.21 (s, 2H), 2.80-2.74 (m, 2H), 2.48 (t, J=6.7 Hz, 2H), 2.10-2.02 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:7]([CH:10]([OH:23])[C:11](C)([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:32](OC(=O)C)(=[O:34])[CH3:33].O>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:32]([O:23][CH:10]([C:7]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1)[CH:11]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:34])[CH3:33]
Reactant: CCCCc1ncc(C(O)C(C)(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCc1ncc(C(OC(C)=O)C(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Reaction time: 2 h
Yield: 113.5 %

Procedure:
A solution of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-(4-pyridyl)-methylpropanoate (3.32 g, 7.5 mmol) methylene chloride (50 mL), 4-dimethylaminopyridine (150 mg, 1.3 mmol) and acetic anhydride (7.1 mL, 75 mmol) was stirred at ambient temperature for 18 hours. Water (5 mL) was added, the mixture was stirred for 2 hours and then diluted with methylene chloride and 5% sodium bicarbonate solution. The organic phase was washed with 5% sodium bicarbonate solution and brine, dried and concentrated to give 4 g of the crude title compound. TLC on silica gel with 5% methanol ethyl acetate showed essentially one spot material with an Rf of 0.86. No starting material was detected. This material was not purified further.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH:2]=C.[CH2:20]([O:23]CCOCCOC1C=CC(C(OC)=O)=CC=1)[CH:21]=[CH2:22].[OH-].[Na+]>CO>[CH2:20]([O:23][CH2:2][CH2:1][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH:21]=[CH2:22]
Reactant: C=CCOCCOCCOc1ccc(C(=O)OC)cc1
Reactant: C=CCOCCOCCOc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOCCOCCOCCOc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
These compounds were synthesized by similar methods. The representative synthesis of 4-(2-(2-allyloxyethoxy)ethoxy)benzoic acid (11) is presented. A mixture of 8.39 grams (0.03 mole) of the obtained methyl 4-(2-(2-allyloxy-ethoxy)ethoxy)benzoate (7), 6 ml of 50% aqueous sodium hydroxide solution and 150 ml of methanol was stirred under reflux for three hours. Methanol was distilled off (100 ml) and water 600 ml was added. The reaction mixture was acidified with hydrochloric acid. After cooling to 0° C., a white solid was filtered and set aside. The filtrate was extracted with dichloromethane and the extracted material was evaporated to a white solid which was combined with the set-aside material. The combined material was dried under vacuum to yield 4.4 g of product (94.3%). 1H-NMR (CDCl3, TMS): d=3.81-4.25 (m, 10H, --CH2 --(OCH2CH2)2 -- ), 5.23 and 5.9 (m, 3H, CH2 =CH--), 6.95 and 8.05 (2d, 4 aromatic protons), 12.2 (s, 1H, --COOH).
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2S[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[C:22]1(S(C=C)=O)C=CC=C[CH:23]=1.C(#N)C>C1(C)C(C)=CC=CC=1>[C:16]1([C:4]2[C:3](=[O:2])[N:7]3[C:6](=[CH:22][CH:23]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CS(=O)c1ccccc1
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccccc1-2
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CC#N
Product: O=c1c(-c2ccccc2)ccc2n1CCc1ccccc1-2

Procedure:
be) from 5,6-dihydro-3-hydroxy-2-phenylthiazolo[2,3-a]isoquinolinium hydroxide (internal salt) and phenylvinyl sulfoxide in xylene there was obtained 6,7-dihydro-3-phenyl-4H-benzo[a]quinolizine-4-one of m.p. 139.5°-140.5° (from acetonitrile):
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[Na+].[I-].ClC([SiH3])(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=CC=1C(O)=O.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][C:46]1=[O:51]>C(#N)CC.[Cu]I>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][C:46]2=[O:51])[N:7]=1)[CH3:10]
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: O=C1COCCN1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: CCC#N
Product: CCSc1nc(N2CCOCC2=O)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 110 °C
Yield: 5.1 %

Procedure:
A solution of 1.0 g (2.95 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) in propionitrile (20 ml) was treated with 1.33 g (8.87 mmol) NaI and 1.0 ml (8.28 mmol) trichloromethylsilane. Subsequently the solution was heated at 110° C. for 16 h. The mixture was then partitioned between a 2M aq. NaOH sol and EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dioxane (10 ml) and 2.26 g (7.0 mmol) Cs2CO3 and 114 mg (0.92 mmol) picolinic acid were added. This mixture was degassed for 30 min followed by the addition of 88 mg (0.46 mmol) CuI and 470 mg (4.65 mmol) 3-morpholinone. The reaction solution was then heated to 100° C. for 16 h and subsequently concentrated in vacuo. The residue was dissolved in water and was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 60 mg (0.15 mmol, 5%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide (example 312). [M+H]+404.1.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([CH2:21][C:22]#[N:23])[CH:14]=1)=O.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([CH2:21][C:22]#[N:23])[CH:14]=1)[CH3:25]
Reactant: COc1ccc(CC#N)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetonitrile and ethylamine (2M in MeOH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:24]2[CH:23]=[CH:22][C:21]3[O:16][CH2:17][CH2:18][O:19][C:20]=3[CH:25]=2)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)OCCO3)n1
Reaction time: 24 h
Yield: 69 %

Procedure:
To a solution of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine (95 mg, 0.39 mmoles) in tetrahydrofuran (2 ml) was added a solution of 1,4-benzodioxan-6-amine (64 mg, 0.42 mmoles) and triethylamine (0.07 ml, 0.50 mmoles) in tetrahydrofuran (0.5 ml). After stirring for 24 hours, the mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with a solution composed of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1:1, 2×10 ml), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate-hexanes to provide CT-32028 (97 mg, 69% yield). 1H NMR (d6-DMSO) δ 9.88–10.28 (m, 2H), 7.60–7.85 (m, 2H), 7.20–7.40 (m, 3H), 6.96–7.10 (m, 2H), 6.77–6.81 (m, 1H), 4.21 (s, 4H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]([OH:28])[CH2:25][O:26][CH3:27])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:41].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:41][C:17]([C:19]4[S:20][C:21]([CH:24]([OH:28])[CH2:25][O:26][CH3:27])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: COCC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1-hydroxy-2-methoxyethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.36 g), ammonium acetate (1.33 g) and acetic acid (15 mL) was stirred at 100° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, 2M aqueous sodium hydroxide solution (1.3 mL), tetrahydrofuran (6 mL) and methanol (6 mL) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (1.27 g, yield 90%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 517 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:27]([F:30])([F:29])[F:28])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.Cl>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:27]([F:30])([F:28])[F:29])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 78.6 %

Procedure:
(4-Methoxyphenyl)[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (0.174 g) and pyridine hydrochloride are heated at 200° C. for 2 h and then cooled. The resulting solid is taken into methylene chloride and 2N aq HCl. The layers are separated, the aqueous layer is extracted again, and the combined organics are washed with saturated sodium bicarbonate and dried over MgSO4. The residue is chromatographed eluting with 25:75 ethyl acetate:hexane to afford the title compound as a white solid (0.132 g). MS (ES) m/z 392.1; HRMS: calcd for C23H14F3NO2—H, 392.08984; found (ESI, [M−H]−), 392.0883.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:8]#[N:9].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[CH2:8][NH2:9]
Reactant: COCOc1cc(C#N)ccc1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCOc1cc(CN)ccc1-c1ccncc1
Reaction time: 0.17 h

Procedure:
3-Methoxymethoxy-4-pyridin-4-yl-benzonitrile (122 mg, 0.51 mmol) is dissolved in ether (10 mL). The resulting solution is slowly added to a suspension of LiAlH4 (100 mg, 2.6 mmol) in Et2O. After addition, the mixture is stirred for another 10 min before quenched with H2O and 5 N NaOH. After which, EtOAc is added and the organic layer is collected and washed with brine and dried over Na2SO4. Removal of the solvent provided the crude amine, which is used directly in the next step. MS (ESI): 245 (M+1)+1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH:12]2[CH2:15][CH:9]1[CH:10]=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH:12]2[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C=CC1C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(=O)C2CCC1C2
Yield: 105.2 %

Procedure:
In a Parr pressure bottle, 3-oxo-2-aza-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid tert-butyl ester (1.77 g, 8.46 mmol) was dissolved in methanol (12 ml) and 10% palladium on carbon (wet, 170 mg, 0.16 mmol) was carefully added. The bottle was placed on a Parr hydrogenator and shaken under 40 psi hydrogen pressure for 2 h. The reaction mixture was filtered over Celite and rinsed with methanol/ethyl acetate. The filtrate was concentrated to give 1.88 g of 3-oxo-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a light grey oil which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH:6]=[CH:7][CH:8]=O)([O-:3])=[O:2].[OH-].[Na+].[CH:16]1C=CC=C[CH:17]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[CH:6]=[CH:7][CH:8]=[CH:16][CH3:17])([O-:3])=[O:2]
Reactant: c1ccccc1
Reactant: O=CC=Cc1ccccc1[N+](=O)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Product: CC=CC=Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
10 g of o-nitrocinnamaldehyde was dissolved in 150 ml of benzene. Thereto were added 25 g of ethyltriphenylphosphonium bromide and 150 ml of a 5 N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 2 hours. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distil-lation under reduced pressure. The residue was purified by column chromatography (eluant: toluene) to obtain 10.4 g (yield: 98%) of 1-nitro-2-(1,3-pentadienyl)-benzene as a light yellow oily material.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O-:4])=[O:3]>CCO>[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:12][CH2:5][CH2:6][CH:7]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=CCCC=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of 0.76 g of sodium in 50 ml of absolute EtOH was added 12.25 g of butane-1,4-bis-triphenyl phosphonium bromide. Ten minutes later, 5 g of p-nitrobenzaldehyde was then added. The reaction mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was treated with CH2Cl2. The organic solution was washed with H2O, dried with (MgSO4), and concentrated to give 0.5 g of product as a yellow solid.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[CH2:24]([O:26][C:27]([C:29]1[C:34]([NH2:35])=[CH:33][CH:32]=[C:31](Br)[N:30]=1)=[O:28])[CH3:25].CC1(C)C(C)(C)OB([C:45]2[CH:46]=[N:47][N:48]([CH2:50][CH2:51][CH2:52][CH2:53][OH:54])[CH:49]=2)O1>>[NH2:35][C:34]1[C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[N:30][C:31]([C:45]2[CH:46]=[N:47][N:48]([CH2:50][CH2:51][CH2:52][CH2:53][OH:54])[CH:49]=2)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2cnn(CCCCO)c2)OC1(C)C
Reactant: CCOC(=O)c1nc(Br)ccc1N
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CCOC(=O)c1nc(-c2cnn(CCCCO)c2)ccc1N
Yield: 52.8 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-6-bromopyridine-2-carboxylic acid ethyl ester (Compound 6E, 300 mg, 1.22 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-1-ol (Compound 14C, 358 mg, 1.35 mmol) to afford 196 mg of the title compound (55%). 1H NMR (400 MHz, CDCl3) δ 8.12 (br. s., 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 5.94 (br. s., 2H), 4.23 (t, J=6.9 Hz, 2H), 3.70 (q, J=5.9 Hz, 2H), 3.03 (d, J=5.1 Hz, 3H), 2.03 (quin, J=7.3 Hz, 2H), 1.60-1.67 (m, 3H) [OH proton obscured].