Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (65 mg, 0.189 mmol) and benzenesulfonyl chloride (0.029 mL, 0.227 mmol), the title compound was obtained as an off white solid (60 mg, 65% yield). MS (ESI): 484 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][CH2:30]Br>CC(CC)=O>[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:20][C:19]=1[CH2:29][CH2:30][O:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCBr
Reactant: Oc1cccc2sccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc2sccc12
Reaction time: 72 h
Yield: 77.2 %

Procedure:
5.15 g (0.034 mol) 4-hydroxybenzothiophene was dissolved in 130 ml methylethylketone and admixed with 9.4 g (0.068 mol) K2CO3 and 20 g (0.068 mol) 5-methyl-2-phenyl-4-(2-bromoethyl)oxazole. The preparation was boiled for 72 hours under reflux, evaporated, taken up in ethyl acetate and extracted three times by shaking with 2N NaOH. After cooling and evaporation of the organic phase, it was crystallized from ethyl acetate/isohexane. 8.8 g 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzothiophene of melting point 130°-132° C. is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=[CH:6][C:5]=1[NH:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=[CH:6][C:5]=1[NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2N)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (298 mg, 1 mmol) and 4-(aminomethyl)benzonitrile (132 mg, 1 mmol) in acetonitrile (1 mL) was added DIPEA (2 mL, 12 mmol). The mixture was stirred at 80° C. overnight. The mixture was cooled to RT, water (20 mL) was added, and the mixture was extracted with DCM (3×20 mL). The organics were combined, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to dryness. The residue was recrystallized from ethanol to give 4-((2-nitro-4-(quinolin-2-ylmethoxy)phenylamino)methyl)benzonitrile. The recrystallized 4-((2-nitro-4-(quinolin-2-ylmethoxy)phenylamino)methyl)benzonitrile (307 mg, 0.75 mmol) was then dissolved in ethanol (20 mL) and SnCl2.2H2O (1 g, 4.5 mmol) was added. The resulting mixture was stirred at 90° C. overnight. The mixture was cooled to RT and the pH adjusted to ˜pH 8-9 by the addition of sat. aq. NaHCO3. The aqueous mixture was stirred at RT for 30 min. and then extracted with DCM (3×20 mL). The organics were combined, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to dryness to afford the title compound, which was used without further purification. MS (ESI): mass calcd. for C24H20N4O, 380.16; m/z found, 381.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:14]=[CH:13]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH3:20][O:19][C:17]([C:15]1[N:14]([CH:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH:13]=[N:12][CH:16]=1)=[O:18]
Reactant: COC(=O)c1c[nH]cn1
Reactant: OC1CCc2cc(F)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CCc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a solution of 5-fluoro-indan-1-ol (0.293 g, 1.925 mmol) and methyl 4-imidazolecarboxylate (CAS#17325-26-7, 0.163 g, 1.290 mmol) in THF (10 mL) at 0° C. is added pMe2NPhP(Ph)2 (0.619 g, 1.925 mmol) and diisopropyl azodicarboxylate (94%, 0.414 g, 1.925 mmol). After 1 hour the mixture is warmed to room temperature and after 18 hours it is diluted with ethyl acetate and extracted with 1M aqueous HCl. The extracts are cooled to 0° C., and the pH is adjusted to ca. 9 with ice-cold 4M aqueous NaOH. The basic aqueous phase is extracted three times with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered through a cotton plug, and concentrated. The resulting residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 1:0 to 99:1 to 49:1) to afford 3-(5-fluoro-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 261.0 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(5-fluoro-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; 1H NMR (400 MHz, CDCl3) δ ppm 2.06-2.20 (m, 1 H), 2.71-2.85 (m, 1 H), 2.87-3.00 (m, 1 H), 3.00-3.14 (m, 1 H), 3.87 (s, 3 H), 6.47 (dd, J=7.7, 4.7 Hz, 1 H), 6.88-6.97 (m, 1 H), 7.01 (dd, J=8.6, 2.3 Hz, 1 H), 7.16 (dd, J=8.6, 5.1 Hz, 1 H), 7.19 (s, 1 H), 7.77 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:4][CH:3]=1.[O-:28][C:29]#[N:30].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH:19]1([C:15]2[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12](=[O:27])[N:11]3[C:16]=2[C:17]([CH3:18])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH2:30])=[O:28])=[CH:7][CH:6]=2)[CH:9]=[CH:10]3)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(N)=O)cc3)ccn2c1=O
Reaction time: 3 h
Yield: 87.7 %

Procedure:
54 mg of ethyl 8-(4-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 2) was dissolved in a mixture of 3 ml of acetic acid and 2 ml of water. 2 ml of an aqueous solution of 19 mg of sodium cyanate was added to the obtained solution at 35° C. and they were stirred at that temperature for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 53 mg of ethyl 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureidophenyl)-4H-quinolizine-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11](=[C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23]3)[S:10]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][N:34]([CH2:36][C:37](Cl)=[O:38])[CH3:35]>C(Cl)(Cl)Cl>[CH2:14]([N:13]1[C:12](=[O:21])[C:11](=[C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2)[S:10][C:9]1=[N:8][C:4]1[CH:3]=[C:2]([NH:1][C:37](=[O:38])[CH2:36][N:34]([CH3:35])[CH3:33])[CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(=C2SC(=Nc3cccc(N)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CC(=O)Nc1cccc(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)c1
Yield: 17.8 %

Procedure:
To a solution of 2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one (160 mg, 360 μmol) in chloroform (8 mL) was added N,N-dimethylaminoacetyl chloride hydrochloride (90 mg, 0.58 mmol) and TEA (150 μL, 1.1 mmol). The reaction solution was heated at reflux for 20 h, cooled, and concentrated in vacuo. The crude material was chromatographed (silica gel, 0-50% EtOAc/Hex) to give the title compound (34 mg, 18%) as a yellow solid. 1H-NMR (CDCl3): δ 9.03 (1H, s), 7.50 (2H, d), 7.37 (2H, t), 7.17-7.26 (5H, m), 7.11 (1H, m), 7.05 (1H, t), 6.88 (1H, d), 6.68 (1H, d), 5.03 (2H), 3.60 (3H, s), 3.00 (2H, s), 2.28 (6H, s); MS(ESI): 530 (MH+).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([C:17]1[CH:18]=[C:19]([O:26][CH3:27])[C:20]([OH:25])=[C:21]([CH:24]=1)[CH:22]=O)[CH:15]=[CH2:16]>>[CH2:14]([C:17]1[CH:18]=[C:19]([O:26][CH3:27])[C:20]([OH:25])=[C:21]([CH:24]=1)[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1)[CH:15]=[CH2:16]
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: C=CCc1cc(C=O)c(O)c(OC)c1
Product: C=CCc1cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c(O)c(OC)c1

Procedure:
6-[4-(5-Allyl-2-hydroxy-3-methoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-allyl-2-hydroxy-3-methoxybenzaldehyde (available from Acros Organics, Geel, Belgium). 1H NMR (400 MHz, CDCl3) δ 2.58-2.63 (m, 4H), 3.27-3.29 (m, 2H), 3.58-3.65 (m, 4H), 3.71 (s, 2H), 3.91 (s, 3H), 5.03-5.08 (m, 2H), 5.39 (s, 1H), 5.88-5.95 (m, 1H), 6.43 (s, 1H), 6.65 (s, 1H), 7.84 (s, 1H), 10.40 (br s, 1H), 12.80 (br s, 1H). Mass spectrum (ES) MH+=357.
Reaction SMILES: FC1C=C(C2C(C)=C(O)C(=O)N(CC(C)C)N=2)C=CC=1C.[C:22]([C:25]1[C:26](=[O:45])[N:27]([CH2:41][CH:42]([CH3:44])[CH3:43])[N:28]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:30]=1)(O)=[O:23]>>[OH:23][CH2:22][C:25]1[C:26](=[O:45])[N:27]([CH2:41][CH:42]([CH3:43])[CH3:44])[N:28]=[C:29]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)[CH:30]=1
Reactant: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(C(=O)O)c1=O
Agent: Cc1ccc(-c2nn(CC(C)C)c(=O)c(O)c2C)cc1F
Product: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(CO)c1=O
Yield: 28.1 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as colorless fine-needles (yield: 28.1%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].N1CCCCC1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:17][C:16]=1[CH:34]=O.C(OC(C)C)(C)C>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:17][C:16]=1[CH:34]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 5 h

Procedure:
0.97 ml of methyl cyanoacetate and 0.3 ml of piperidine were added to a solution of 3.3 g of 3-(4-chloro-3-formylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 100 ml of tetrahydrofuran. After the mixture had been stirred for 5 hours at the reflux temperature, a further 0.97 ml of methyl cyanoacetate was added and refluxing was continued for a further 5 hours. The reaction mixture was evaporated down and the oil obtained was chromatographed (dichloromethane). The solid obtained was stirred with diisopropyl ether, isolated, washed with petroleum ether and dried.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[CH:2]=[N:1][N:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=34)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cnn2c1CCCC2
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnn2c1CCCC2
Yield: 55.5 %

Procedure:
The title compound was prepared as described in Example 34(d), starting from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid (0.127 g, 0.767 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified by flash-chromatography. Yield 55.5%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 1.66-1.75 (m, 2H), 1.85-1.95 (m, 2H), 2.87 (t, 2H), 4.02 (t, 2H), 4.22-4.23 (m, 2H), 4.32-4.42 (m, 1H), 6.94 (d, 1H), 7.72 (d, 1H), 7.80 (d, 1H), 7.83 (s, 1H), 7.91 (dd, 1H), 7.97 (d, 1H), 8.06 (d,
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH:12]1[N:16]=[CH:15][N:14]([C:17](N2C=NC=C2)=[O:18])[CH:13]=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:17]([N:14]3[CH:13]=[CH:12][N:16]=[CH:15]3)=[O:18])[S:8][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(Br)cc2s1
Solvent: ClCCl
Product: O=C(Nc1nc2ccc(Br)cc2s1)n1ccnc1

Procedure:
A suspension of 6-bromo-benzothiazol-2-ylamine (5 g, 21.83 mmol) in DCM (250 ml) is treated with CDI (3.54 g, 21.83 mmol) and the reaction mixture is heated to reflux for 2 hours. The reaction mixture is filtered and the resulting solid is dried in the vacuum oven overnight to afford the title compound.
Reaction SMILES: [CH:1]([S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[OH-].[Na+:20]>CO>[Na+:20].[CH:1]([S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH3:18])[C:15]([NH-:17])=[O:16])=[CH:10][CH:9]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Nc1ccc([C@@H](C)C(N)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)S(=O)(=O)Nc1ccc([C@@H](C)C([NH-])=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(2R)-2-{(4-[(Isopropylsulfonyl)amino]phenyl propanamide (1) (500 mg, 1.85 mmol) was dissolved in CH3OH (15 mL). NORMEX 1N NaOH (1.85 mL, 1.85 mmol) was added by dripping and the resulting solution was left stirring at room temperature for 2 h. After solvent evaporation, water (3 mL) was added and the clear solution was frozen and then lyophilized to give (2R)-2-{4-[(isopropylsulfonyl]amino}phenyl)propanamide sodium salt (541 mg, 1.85 mmol) as pale yellow powder. Quantitative yield. [α]D25 (c=0.4, CH3OH): −11.75°; 1H-NMR (D2O) δ 7.32 (d, 2H, J=7 Hz), 7.15 (d, 2H, J=7 Hz), 3.82 (q, 1H, J=7 Hz), 3.35 (m, 1H), 1.54 (d, 3H, J=7 Hz), 1.35 (d, 6H, J=7 Hz).
Reaction SMILES: CC[NH+](CCOC1C(C2ON=C(C)C=2)=CC=CC=1)CC.[Cl-].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39]>>[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccccc1F
Agent: CC[NH+](CC)CCOc1ccccc1-c1cc(C)no1
Agent: [Cl-]
Product: O=[N+]([O-])c1ccc(Oc2ccccc2F)cc1

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-221 using 4-fluoro-nitrobenzene and 2-fluorophenol (heat 2 hours at 60° C.). Purify the material by silica gel chromatography (Prep. 2000) eluting with methylene chloride/hexane 1:1 to provide the title compound as a yellow solid. Mass spectrum (m/e): 233.1 (M*). (Bruker 300) 1H NMR (CDCl3) 8.17-8.22 (2H, d), 7.14-7.28 (4H, m), 6.96-700 (2H, d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-bromopicolinic acid (2.0 g, 9.94 mmol) in MeOH (2 ml)/toluene (20 ml) was added TMS-diazomethane (20M in diethyl ether; 5.47 ml, 10.94 mmol, Matrix Scientific) dropwise. The reaction was stirred at room temperature for 3 hours. An additional 0.2 eq (0.99 mL) of TMS-diazomethane was added and the reaction stirred for 1.5 hours. The reaction was concentrated and the brown solid was carried to next step without further work up. MS m/z [M+H]+=217.9. Calculated from C7H6BrNO2: 216.032
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[N:6][C:7]=1[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:16][C:17]1[C:18]([O:15][C:4]2[CH:5]=[N:6][C:7]([O:8][C@@H:9]([CH3:14])[C:10]([F:11])([F:12])[F:13])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]
Reactant: C[C@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(O[C@@H](C)C(F)(F)F)c(Cl)c3)cc2F)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a mixture of 5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-ol (Preparation 231, 60 mg, 0.25 mmol) and 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 26, 70 mg, 0.25 mmol) in DMSO (1 mL) was added K2CO3 (69 mg, 0.50 mmol) at room temperature under N2 and the resulting mixture was stirred for 4 hours. The reaction mixture was warmed up to 50° C. and stirred for 1 hour before cooling to room temperature and stirring for 18 hours. The reaction was quenched with water and partitioned between water and DCM (3×5 mL). The mixture was filtered through a phase separation cartridge, the organic phase was washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by silica gel column chromatography eluting with 0-20% EtOAc in heptane to give the title compound (108 mg, 86%) as colourless gum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH2:15](Br)[CH:16]=[C:17]([CH2:19][CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18]>CN(C=O)C>[CH3:18]/[C:17](/[CH2:19][CH2:20]/[CH:21]=[C:22](\[CH3:23])/[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[CH:16]\[CH2:15][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/COc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (114 mg, 0.7 mmol) and 4 mL of anhydrous DMF were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask and the solution was kept stirring at 0° C. for 30 minutes. Farnesyl bromide (450 μL, 1.66 mmol) in 1 mL of anhydrous DMF was cooled to 0° C. and added drop-wise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen at room temperature for 14 hours. The desired product was isolated via column chromatography using a solvent system of 100% Hexanes, 20:1 Hexanes:Ethyl acetate, 15:1 Hexanes:Ethyl acetate, 10:1 Hexanes:Ethyl acetate, 7:3 Hexanes:Ethyl acetate, and 2:1 Hexanes:Ethyl acetate. The purified product was characterized by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). 1H-NMR (300 MHz, CDCl3): δ 1.60-1.76 (12H), 1.96-2.12 (8H), 4.56 (d, 2H, J=6 Hz), 5.09 (m, 2H), 5.48 (t, 1H), 6.43 (d, 1H, J=9 Hz), 6.92-7.66 (4H); 13C-NMR (75 MHz, CDCl3): δ 15.93, 16.29, 17.70, 25.71, 26.29, 27.04, 39.53, 39.69, 109.75, 117.00, 117.83, 119.14, 123.31, 123.77, 128.33, 131.38, 135.56, 141.96, 143.27, 148.40, 155.33, 161.05. HRMS (CI) Calcd. for C24H31O3: 367.22733. found: 367.22801.
Reaction SMILES: [Na].[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](OCC)(=[O:15])[CH3:14].Cl>O>[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH2:11][C:13](=[O:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)CCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(=O)CC(=O)CCc1ccccc1

Procedure:
Sodium (23 g) was added in small portions to a solution of 4-phenyl-2-butanone (148 g, 1 mol) and ethyl acetate (264 g) at 20°-60° C. with stirring under nitrogen and then the reaction mixture was refluxed for 2 h with stirring. After cooling, the mixture was taken up in H2O (1l), neutralized with hydrochloric acid, the organic layer was separated, washed with H2O, dried over anhydrous Na2SO4 and then evaporated. The resultant residue (171 g) was distilled under reduced pressure to give the title compound as a colorless oil; yield: 73.4 g; bp 128°-133° C./3-4 mmHg (Lit. bp 133°-136° C./5 mmHg; C. R. Hauser, T. M. Harris, J. Am. Chem. Soc., 80, 6360 (1958)).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl>[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:24]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1CCCNc2ncccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-5-one and 0.234 g of triethylamine in 6 ml of dichloromethane is added 0.506 g of 2-chloro-4-nitrobenzoyl chloride in 2 ml of dichloromethane. The mixture is stirred at room temperature overnight under argon. The solution is washed with H2O, 10% NaHCO3 and dried (MgSO4). The solvent is removed to give a brown oil which crystallizes. The mixture is chromatographed on silica with a waters Prep-500 instrument with ethyl acetate-hexane (1:1) as solvent to give 2.4 g of off-white crystals, m.p. 162°-164° C. (identified as O-2-chloro-4-nitrobenzoyl derivative (2-chloro-4-nitrobenzoyl enolate of product) and 0.80 g of product as crystals, m.p. slowly decomposes 160°-220° C.