Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([NH:21][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:20][CH2:19]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.4 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cyclopropylamine (30 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (5 mg) and a syn-form compound (12 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[N:14]([C:15](=[O:38])[C@@H:16]([NH:20]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH:17]([CH3:19])[CH3:18])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2].N1CCCCC1>C(#N)C>[NH2:20][C@@H:16]([CH:17]([CH3:18])[CH3:19])[C:15]([N:14]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH:6]1[C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[O:38]
Reactant: CCNC(=O)C1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCNC(=O)C1Cc2cccnc2N1C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (2S)-1-(2-(ethylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (85 mg, 166 μmol, Eq: 1.00) in acetonitrile (4 mL) was added piperidine (0.1 mL, 1.01 mmol, Eq: 6.09) and the resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM/EtOAc (˜1:10) and the combined organic layers were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 10% MeOH in DCM) to give 1-((S)-2-amino-3-methylbutanoyl)-N-ethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (39 mg), m/z=291 (M+H).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I>C(#N)C>[I:34][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1
Reactant: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC[C@@H](C(N)=O)N1CC(CI)CC1=O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
In a 10 l 3 necked vessel, fitted with mechanical stirrer and reflux condenser under inert atmosphere, 400 g (2 mole, 1 eq) of (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 are dissolved in 3 l of acetonitrile. 629 g (2.4 moles, 1.2 eq) of triphenylphosphine are added, followed by 608 g (2.4 moles, 1.2 eq) of iodine in three portions over 5 min. The mixture is heated up to 60° C. in 30 min, and stirred at that temperature for 5 hours. After cooling down, the mixture is concentrated to dryness, the residue suspended in a solution of 750 g of Na2S2O3 in 10 l of water and stirred at 50° C. for 4 hours. The precipitate is filtered off and washed with 3×1 l of water. The combined aqueous phases are treated with 1 kg of NaCl, and extracted with 6×1 l of CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness to give 482 g of crude 10. It is crystallised from toluene. Several crops are recrystallised together from ethyl acetate to give 425 g of pure 10, 68%.
Reaction SMILES: [ClH:1].F[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1.[Cl-].[Cl:22]C1C=CC(C[Zn+])=CC=1>>[ClH:22].[Cl:1][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[N:11]=[CH:10][C:9]3[C:12]([CH3:15])([CH3:16])[CH2:13][NH:14][C:8]=3[CH:7]=2)=[CH:3][CH:20]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)ncc21
Agent: Cl
Agent: [Cl-]
Product: CC1(C)CNc2cc(Cc3ccc(Cl)cc3)ncc21

Procedure:
Prepared in an analogous manner to 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (Preparation 119) using 4-chlorobenzylzinc chloride instead of 2-fluorobenzylzinc chloride. MS: [M+H]+=273.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:13]([NH:12][CH3:11])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol) in anhydrous CH2Cl2 was added methyl isocyanate (0.15 mL, 2.49 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and residue partitioned between EtOAC and 1N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (80% EtOAc in hexanes) to provide the desired product (0.60 g, 94%) as a white solid. 1H NMR (CDCl3) δ: 1.42 (d, J=7.0 Hz, 3H), 2.72 (d, J=4.9 Hz, 3H), 4.25 (brs, 1H), 4.73 (brs, 1H), 4.74-4.81 (m, 1H), 7.20 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H). ESIMS (MNa+): 258.
Reaction SMILES: C(N)C1C=CC=CC=1.C(N)C.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.[F:21][C:22]1[CH:44]=[CH:43][C:25]([CH2:26][N:27]2[CH2:31][CH2:30][N:29]([C:32]3[CH:33]=[C:34]([CH:39]=[CH:40][N:41]=3)[C:35](OC)=[O:36])[C:28]2=[O:42])=[CH:24][CH:23]=1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:35](=[O:36])[C:34]2[CH:39]=[CH:40][N:41]=[C:32]([N:29]3[CH2:30][CH2:31][N:27]([CH2:26][C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:44][CH:43]=4)[C:28]3=[O:42])[CH:33]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ccc(F)cc1
Agent: CCN
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 50 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 4-fluorobenzylamine ethanamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, N-(4-fluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 50% yield: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.41-7.39 (m, 1H), 7.31-7.21 (m, 4H), 7.04-6.96 (m, 4H), 6.84 (br s, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.40 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.36 (t, J=8.1 Hz, 2H); MS (ES+) m/z 423.2 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[OH-].[Na+].CS(C)=[O:21]>O>[OH:21][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: CC(Oc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(Oc1cc(O)ccc1[N+](=O)[O-])C(=O)O
Reaction time: 8 h

Procedure:
5 Grams (21.8 moles) of 2-(5-fluoro-2-nitrophenoxy)propionic acid was heated for two hours with 5 ml of 25 percent (by weight) aqueous sodium hydroxide and 100 ml of DMSO and allowed to stand overnight. The mixture was diluted with water and extracted with 1,1,1-trichloroethane (organic discarded), then with ether. The aqueous layer was acidified and extracted with ether. The ether solution was stripped to give 2.5 g of solid product which was recrystallized from ethanol/chloroform to give 1.7 g (35 percent) of the desired product. M.P.=190°-195° C. NMR and IR spectra supported the identification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8](Cl)=[CH:9][C:10]=1[CH3:11])=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Yield: 30.4 %

Procedure:
A solution of 5.2 g (23.7 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester, 3.94 g (28.5 mmol) K2CO3 and 2.06 ml (23.7 mmol) morpholine in DMF (48 ml) was heated to 60° C. for 16 h. Then the mixture was poured into water and 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 4:1) provided 1.95 g (7.2 mmol, 30%) 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Cl[C:18]1[CH:19]=[CH:20][N:21]2[C:26]([CH:27]=1)=[C:25]([CH2:28][CH3:29])[C:24]1[S:30][NH:31][C:32](=[O:33])[C:23]=1[C:22]2=[O:34]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:18]2[CH:19]=[CH:20][N:21]3[C:26]([CH:27]=2)=[C:25]([CH2:28][CH3:29])[C:24]2[S:30][NH:31][C:32](=[O:33])[C:23]=2[C:22]3=[O:34])=[CH:5][CH:4]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: CCc1c2s[nH]c(=O)c2c(=O)n2ccc(Cl)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c2s[nH]c(=O)c2c(=O)n2ccc(-c3ccc(CN)cc3)cc12

Procedure:
Under an atmosphere of argon, tetrakis(triphenylphosphine)palladium(0) (20.4 mg, 0.018 mmol), 4-aminomethylphenylboronic acid (110.0 mg, 0.587 mmol), and a 1 M aqueous solution of sodium bicarbonate (1.75 mL, 1.75 mmol) were added sequentially to a solution containing 7-chloro-9-ethyl-1-thia-2,4a-diazacyclopenta[b]naphthalene-3,4-dione (33.0 mg, 0.118 mmol) and dimethylformamide (3.0 mL). The resulting orange mixture was irradiated in a microwave for 15 min (110° C.; 300 W) to give a red mixture. The solvent is evaporated under reduced pressure (˜10 mm Hg, 50° C.), and the remaining orange solid is washed with diethyl ether (3×15 mL).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[OH-:19].[K+].CO>>[OH:15][C:16]1[C:8]([S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:18])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]([OH:19])=[O:17]
Reactant: [OH-]
Reactant: Cc1ccccc1Sc1cccc2c1OC(=O)C2
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1Sc1cccc(CC(=O)O)c1O

Procedure:
Thus obtained 7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one was hydrolyzed by treating with potassium hydroxide-methanol to give 2-[2-hydroxy-3-(o-tolylthio)phenyl]acetic acid, mp. 96°-97° C.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[C:4](=O)[CH2:3][CH2:2]2.C1(C)C=CC(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=1.C(O)C.CC(C)([O-])C.[K+]>C(COC)OC>[N:1]12[CH2:9][C@H:5]([CH2:6][CH2:7][CH2:8]1)[C@H:4]([C:20]#[N:21])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCCC1C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#C[C@@H]1CCN2CCC[C@H]1C2
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a solution of 2.00 g of 1-azabicyclo[3.3.1]nonan-4-one in 100 ml of dimethoxyethane, 3.65 g of p-toluenesulfonylmethylisocyanide and 1.13 g of ethanol were added, followed by cooling to 5° C. Then, 4.00 g of potassium tert-butoxide was added while keeping the internal temperature below 10° C. The mixture was stirred at room temperature for 30 minutes, followed by further stirring at 40° C. for 30 minutes. The precipitate thus formed was removed by filtration. The residue obtained by evaporation of the solvent was purified by an alumina column chromatography (eluent: chloroform:hexane=1:1). The resulting crude product was then purified by silica gel column chromatography (eluent: chloroform:methanol=20:1), whereby 1.01 g of (4R*,5R*)-1-azabicyclo[3.3.1]nonane-4-carbonitrile was obtained.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:37]3[CH:38]=[N:39][CH:40]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=O>O1CCCC1>[CH2:2]([O:3][C:4]([C:6]([CH3:7])=[CH:24][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:37]3[CH:38]=[N:39][CH:40]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(-c2cccc3cncn23)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(-c2cccc3cncn23)cc1
Reaction time: 0.17 h

Procedure:
Triethyl 2-phosphonopropionate (0.61 g) is added to a solution of lithium diisopropylamide (from 0.32 g of diisopropylamine and 1.7 ml of 1.64M n-butyllithium) in 20 ml of tetrahydrofuran at 0° under nitrogen. After stirring for 10 minutes, 5-(p-formylphenyl)-imidazo[1,5-a]pyridine (0.50 g) is added dropwise in a solution of 5 ml of tetrahydrofuran. The reaction mixture is stirred for two hours at 0° and quenched with 25 ml of water. The layers are separated and aqueous phase is extracted with ethyl acetate (2×10 ml). The organic phases are combined, dried over sodium sulfate, filtered and evaporated to yield an oil which is chromatographed on silica gel with ethyl acetate as eluent to yield 5-[p-(2-ethoxycarbonylprop-1-enyl)phenyl]imidazo[1,5-a]pyridine; IR (CH2Cl2) 1700 cm-1.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1>COCCOCCOC>[N+:21]([C:20]1[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:12][C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[C:19]=1[NH:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1c(Cl)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1c(Oc2ccccc2)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
A 200 mL round bottom flask was charged with 60% sodium hydride (2.5 g, 0.06 mol, 1.7 equivalents) and washed with hexane (50 mL). A solution of phenol (5.7 g, 0.06 mol, 1.6 equivalents) in diglyme (25 mL) was then slowly added to the sodium hydride. The reaction was maintained with stirring at room temperature for 1.5 hours. To the phenol anion solution was slowly added a solution of 2-chloro-3-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine (14.8 g, 0.04 mol) in diglyme (25 mL). The stirred reaction mixture was heated to 60° C. and maintained overnight. The reaction was quenched by pouring onto ice (1000 mL). The product oiled out of solution. The mixture was extracted with dichloromethane (4×100 mL). The combined extracts were concentrated to dryness. The residue was taken up in 1:1 hexane/ethyl acetate (250 mL) and washed with water (2×50 mL). The organic layer was concentrated to dryness. The residue was found to contain excess phenol. The phenol was removed by taking the residue up in diethyl ether (500 mL) and stirring over 10% sodium hydroxide (250 mL) overnight. The layers were separated. The ether layer was concentrated to provide 3-nitro-2-phenoxy-N-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinolin-4-amine as a pale orange syrup (12.0 g, 71%). TLC=(10% MeOH/CH2Cl2, Rf=0.58).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=2[F:20])[CH:10]=[N:9]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:16]2[CH:17]=[CH:18][C:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[CH:12]=3)=[C:14]([F:20])[CH:15]=2)=[CH:31][N:32]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(-c2ccc(Br)cc2F)cn1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cn1cc(-c2ccc(-c3cnc(N)nc3)cc2F)cn1
Temperature: 120 °C

Procedure:
To a solution of tert-butyl[4-(4-bromo-2-fluorophenyl)-1H-pyrazol-1-yl]acetate (400 mg, 0.001 mol) in 1,4-dioxane (3 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (270 mg, 1.2 mmol), potassium phosphate (640 mg, 3.0 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol). The solution was degassed with N2, and heated at 120° C. for 3 h. The solution was cooled to RT, poured into water, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatograph on a silica gel column with EtOAc in Hexanes (50%) to afford the desired compound. LCMS: (M+H)=370.1.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:13]([O:32][CH2:33][CH2:34][CH2:35][OH:36])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:36][CH2:35][CH2:34][CH2:33][O:32][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:5]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Reactant: O=C(Cl)c1cc(I)cc(I)c1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)c1cc(I)cc(I)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,5-Triiodobenzoyl chloride (1.54 g, 3.08 mmol) was added to a mixture of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 2.97 mmol) and triethylamine (1 ml) in methylene chloride (80 ml) and the resulting mixture stirred overnight at room temperature under nitrogen. The mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane) to yield 1-(2,3,5-triiodobenzoyloxy)-3-(z,z,z-octadeca-6,9,12-trienoyloxy)propane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[CH:6][C:7]=1[F:8].[Br:11]B(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCc1ccc(F)c(Br)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Fc1ccc(CBr)cc1Br
Reaction time: 1 h

Procedure:
(3-Bromo-4-fluorophenyl)methanol (0.264 g, 1.29 mmol) was dissolved in DCM (3 mL). The solution was cooled to 0 deg, and tribromoborane (1.0 M in DCM, 0.863 ml, 0.863 mmol) was added. The mixture was stirred at 0 deg for 1 h, then rt for 1 h. The reaction was quenched with water, and the mixture was transferred to a separatory funnel with half-saturated NaHCO3 (15 mL), and the aqueous phase was extracted with DCM (3×20 mL). The organics were combined, washed with half-saturated brine (5 mL), dried over sodium sulfate and concentrated. Purification of the residue through silica gel (40 mL) using 5% EtOAc-hexane afforded the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[N:20]=[C:19]2[NH2:34].C1(N=C=NC2CCCCC2)CCCCC1.C>CC(C)=O.O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19]([NH2:34])=[N:20][C:21]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([CH:2]4[O:1][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3]4)=[O:13])[CH2:32][CH2:33]3)=[N:22][C:23]2=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: O=C(O)C1COc2ccccc2O1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Temperature: 22.5 °C
Reaction time: 0.12 h
Yield: 93.6 %

Procedure:
In a reaction vessel, 0.25 mol (45.0 g) of 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid, tetrahydrofuran (328 ml) and 6,7-dimethoxy-2-(piperazin-1-yl)quinazolin-4-amine (0.22 mol; 63.58 g) were charged and contents were stirred at 20-25° C. for 5-10 min. To the resulting mixture dicyclohexylcarbodiimide (0.26 mol; 54.0 g) was added and stirring continued at 20-25° C. for 1.5 hr. To the resulting reaction mass charcoal was added and contents were stirred at 26-28° C. for 45 min. The contents were filtered through celite and washed with tetrahydrofuran. The solvent was distilled out at 35° C. under reduced pressure to obtain solid residue. Acetone (1000 ml) was added to the solid and contents were refluxed for 2 hr. On cooling to 25-28° C., the slurry was filtered, washed with acetone and dried at 60° C. under reduced pressure to obtain 93 g of doxazosin base (HPLC purity −99.0%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[CH:7]1[CH2:11][CH2:10][O:9][CH2:8]1)C.Cl.[NH2:15][C:16]([NH2:18])=[NH:17].CC(C)([O-])C.[K+]>CO.O>[NH2:17][C:16]1[NH:18][C:4](=[O:3])[CH:5]=[C:6]([CH:7]2[CH2:11][CH2:10][O:9][CH2:8]2)[N:15]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)C1CCOC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1nc(C2CCOC2)cc(=O)[nH]1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
To a solution of 3-oxo-3-(tetrahydro-furan-3-yl)-propionic acid ethyl ester (4.0 g, 21.5 mmol) and guanidine hydrochloride (2.6 g, 27.2 mmol) in MeOH (125 mL) at 23° C. was added potassium tert-butoxide in portions (3.4 g, 30.3 mmol) over 5 min. The reaction was heated at 80° C. for 18 h. The mixture was filtered while warm to remove insoluble salts, and the filtrate was concentrated to afford an oil which was diluted with water (˜25 mL) and extracted with EtOAc (8×50 mL). The combined organic layers were washed with satd. aq. NaCl, dried, and concentrated to give a residue. The aqueous portion was concentrated to afford a solid residue that was collected and rinsed with MeOH. The residue and solid materials were combined and chromatographed (2 M NH3 in MeOH/EtOAc) to provide 2.02 g of product as a white solid (51%). MS (ESI): mass calcd. for: C8H11N3O2, 181.1; m/z found, 182.2 [M+H]+. 1H NMR (CD3OD): 5.66 (br s, 1H), 3.93-4.01 (m, 2H), 3.75-3.85 (m, 2H), 3.28-3.31 (m, 2H), 3.16-3.24 (m, 1H), 2.18-2.27 (m, 1H), 2.05-2.15 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:16](=[O:17])[N:15]([CH3:14])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(N2CCOCC2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(N2CCOCC2)cc1)c1ccccc1

Procedure:
The title product was prepared from and 4-morpholin-4-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was extracted with dichloromethane from citric acid (5%). The combined organic phases were evaporated and the product crystallized from ethanol (22%, crystals). HPLC-MS: m/z=313.2 (M+1); Rt: 3.75 min.