Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].CO.[NH2:6][C:7]([NH2:9])=[S:8].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15]>C(O)C>[OH:15][C:14]1[CH:13]=[C:12]([C:11]([F:21])([F:20])[F:10])[N:9]=[C:7]([SH:8])[N:6]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Oc1cc(C(F)(F)F)nc(S)n1
Temperature: 22 °C

Procedure:
To a solution of 25% NaOMe/MeOH (23 ml, 0.10 mol) and ethanol (27 ml) are added thiourea (5.33 g, 0.70 mol) and ethyl 4,4,4-trifluoroacetoacetate (7.3 ml, 50 mmol), then the reaction is heated to reflux for 16 hrs. The mixture is cooled to 22° C., concentrated in vacuo, and the residue dissolved in water (50 ml), acidified with HCl (7 ml), and filtered. The solid is collected, washed with water, and dried: 6.58 g (32.5 mmol, 65%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[N:21]=[C:20]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[CH:19]=[CH:18][CH:17]=1.CO.C1COCC1.NN.O>O>[NH2:3][CH2:12][CH2:13][CH2:14][O:15][C:16]1[N:21]=[C:20]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OCCCN4C(=O)c5ccccc5C4=O)n3)nc12
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OCCCN)n3)nc12
Temperature: 50 °C
Yield: 85.3 %

Procedure:
To a solution of (R)-ethyl 5-(2-(6-(3-(1,3-dioxoisoindolin-2-yl)prop oxy)pyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.11 g, 0.20 mmol) in 1:1 MeOH/THF (12 mL) was added hydrazine-H2O (0.10 g, 2.0 mmol). The reaction mixture was heated at 50° C. for 24 hours. After cooling, the reaction mixture was poured into water then extracted with DCM (3×20 mL). The combined organics were dried (MgSO4), filtered, and concentrated to afford the desired product (70 mg, 84% yield). MS (apci) m/z=441.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(C)C>[F:8][C:4]1[CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Fc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
12.27 g (70.2 mmol, 1 eq.) of 1-bromo-3-fluorobenzene and 44.7 g (210.5 mmol, 3 eq.) of K3PO4 are added to a solution of 12.83 g (105.3 mmol, 1.5 eq.) of phenylboronic acid in 200 ml of isopropanol. The mixture is stirred at room temperature for 4 hours. 0.0021 g (14.8 μmol, 0.0021 mol %) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is subsequently added, and the reaction mixture is stirred at room temperature for 20 hours, giving 3-fluorobiphenyl quantitatively.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[C:20]([CH2:23][C:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1)(O)=[O:21]>CO>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:1]3[C:20](=[O:21])[CH2:23][C:24]4([CH2:28][CH2:27][CH2:26][CH2:25]4)[C:29]3=[O:30])[CH:19]=[CH:18][CH:17]=2)=[N:7][NH:8]1
Reactant: O=C(O)CC1(C(=O)O)CCCC1
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Solvent: CO
Product: O=C1CC2(CCCC2)C(=O)N1c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 200 °C

Procedure:
A stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (0.1 g, 0.4 mmol; prepared in a manner similar to that described in Example 1) and 1-(carboxymethyl)cyclopentanecarboxylic acid (0.0685 g, 0.4 mmol) was heated at 200° C. for 2.5 hours then it was allowed to cool to ambient temperature. Methanol (1 ml) was added and the mixture was heated under reflux for 5 minutes. No solid precipitated, so the mixture was concentrated in vacuo and the residue was triturated with water (5 ml). The resulting solid was collected by filtration and dried in vacuo to give 2-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-azaspiro[4.4]nonane-1,3-dione (0.108 g) as a brown solid, m/z (M+H)+. 388, 89.1% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.[H][H]>C(O)C.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(Cl)ncc1N
Yield: 79.1 %

Procedure:
2-Chloro-4-methyl-5-nitropyridine (173 mg) was dissolved in ethanol (5 mL). To the solution, a catalytic amount of Raney nickel was added, and the resultant mixture was stirred in a hydrogen atmosphere at room temperature for 9 hours. The catalyst was removed through filtration, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2), to thereby give the title compound (113 mg).
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:21]2[N:22]=[C:23]([NH2:26])[NH:24][CH:25]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1COCC1>[NH2:26][C:23]1[NH:24][C:25]([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[OH:34])=[C:21]([C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:1][CH3:2])=[CH:4][CH:5]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[N:22]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc([C@H](Cc2ccc(C(F)(F)F)cc2)c2c[nH]c(N)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@H](Cc2ccc(C(F)(F)F)cc2)c2nc(N)[nH]c2C(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.3 %

Procedure:
To a solution of 4-{(1S)-1-(4-methoxylphenyl)-2-[4-(trifluoromethyl)phenyl]ethyl}-1H-imidazole-2-amine (0.05 g, 0.14 mmol) in H2O (1 mL) and THF (0.5 mL) was added benzaldehyde (0.018 g, 0.17 mmol) and sodium carbonate (0.01 g, 0.08 mmol). The reaction was stirred at room temperature for 12 h. The reaction was concentrated and purified by RP HPLC to provide (2-amino-4-{(1S)-1-(4-methoxyphenyl)-2-[4-(trifluoromethyl)phenyl]ethyl}-1H-imidazole-5-yl) (phenyl)methanol (0.01 g, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH:12]=[CH:16][N:17]([CH3:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: COC(OC)N(C)C
Product: COc1ccc(C(=O)C=CN(C)C)cc1OC

Procedure:
A mixture of 50.0 g. of 3',4'-dimethyoxyacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. On cooling the desired compound crystallizes from solution. Hexane is added and the material is recovered by filtration, m.p. 124°-125° C.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][C:10]=1[OH:23])C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][C:10]=1[OH:23]
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1CC(=O)NN=C1c1ccc(N)c(O)c1

Procedure:
43.0 g (139 mmol) 6-(4-benzylamino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 2.2 g of 10% palladium/charcoal and 400 ml of methanol are hydrogenated together for 24 h at RT and 3.45 bar of hydrogen pressure. The catalyst is filtered off and the filtrate is concentrated by rotary evaporation i. V., the residue is triturated with ethyl acetate, suction filtered and then dried at 50° C. in the vacuum dryer.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCOCC>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[C:1]([Br:5])[Br:2])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL methylene chloride was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL methylene chloride in a 1-L rb flask with ice bath cooling over 1.75 h. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formylpiperidine (from Step B2 above) in 100 mL methylene chloride was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL methylene chloride and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes until the total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% sodium bicarbonate, 300 mL water (2×), and 150 mL brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to give 53.5 g crude product as a yellowish solid. Flash chromatography (FC) on 250 g silica gel (0˜15% ethyl acetate in hexanes) gave 21.595 g title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])[C:6]=1[F:27])[CH:2]=[CH2:3].[Cl-].[NH4+].O>CO.O1CCOCC1.[Fe]>[CH2:1]([NH:4][C:5]1[C:14]([NH2:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])[C:6]=1[F:27])[CH:2]=[CH2:3]
Reactant: C=CCNc1c([N+](=O)[O-])cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: C=CCNc1c(N)cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F

Procedure:
A suspension of methyl 4-(allylamino)-3-fluoro-2-(2-fluoro-4-iodophenylamino)-5-nitrobenzoate and ammonium chloride (4.42 g, 79 mmoles) in a mixture of MeOH (20 ml) and dioxane (20 ml) is heated until it became a clear solution. Iron powder (4.42 g, 79 mmoles) is added and the resulting mixture is heated under reflux overnight. Water is added and the reaction mixture is filtered through celite. The solvent is removed under reduced pressure and the crude material is purified by flash chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN.[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:18][CH3:17])=[O:8]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (0.550 g, 2.97 mmol), methylamine hydrochloride (0.241 g, 3.56 mmol), TBTU (0.954 g, 2.97 mmol), and DIPEA (1.15 g, 8.91 mmol) in DCM (10.0 mL) was stirred at rt for 30 minutes. The reaction was quenched with saturated NaHCO3 (10 mL) and extracted with DCM (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a yellow semi-solid. 1H NMR (CDCl3, 400 MHz): δ=3.06 (d, J=5.05 Hz, 3H), 7.20-7.26 (m, 1H), 8.16 (dd, J=8.84, 4.55 Hz, 1H). MS (ES+): m/z 199.05 [MH+] (TOF, polar).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([CH3:20])=[CH:17][CH2:18]Br>O1CCCC1>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH:17]1[C:16]([CH3:20])=[CH2:15])#[N:2]
Reactant: CC(=CCBr)CBr
Reactant: COC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C1CC1(C#N)C(=O)OC
Yield: 102.3 %

Procedure:
A mixture of 65.3 g of methyl cyanoacetate, 228 g of freshly pulverized potassium carbonate and 800 ml of anhydrous tetrahydrofuran was heated at reflux under nitrogen for 2 hours. A solution of 150.5 g of 1,4-dibromo-2-methyl-2-butene in 500 ml of anhydrous tetrahydrofuran was added slowly dropwise to the refluxing reaction mixture over a period of two days. The solids were removed from the cooled reaction mixture by filtration through a bed of celite. The filtrate was concentrated in vacuo to leave 111.4 g of yellow oil. Distillation of the oil gave 81.3 g of the desired product as a colorless oil: b.p. 95°-105° C. (0.05 mm Hg) consisting of two isomers in a ratio of 2:1 by GLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:38])[C:6]=1[C:7]1[N:12]=[C:11]2[CH2:13][N:14]([C@@H:17]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:15](=[O:16])[C:10]2=[CH:9][CH:8]=1.NN>CO>[NH2:19][CH2:18][C@@H:17]([N:14]1[C:15](=[O:16])[C:10]2[C:11](=[N:12][C:7]([C:6]3[N:5]([CH3:38])[N:4]=[CH:3][C:2]=3[Cl:1])=[CH:8][CH:9]=2)[CH2:13]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: Cn1ncc(Cl)c1-c1ccc2c(n1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: NN
Solvent: CO
Product: Cn1ncc(Cl)c1-c1ccc2c(n1)CN([C@H](CN)Cc1cccc(F)c1)C2=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-[(2S)-2-[2-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (0.050 g, 0.094 mmol) was dissolved in methanol (2 mL), and hydrazine (0.06 g, 2 mmol) was added. The reaction was stirred at 60° C. for 2 hr. After concentration, the residue was purified by pH=10 Prep.—HPLC to give the desired product as white powder. LC-MS found: 400.1 (M+H)+.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
1.0 g. of 1-benzyloxy-2-[(2,6-dichlorophenyl)-imino]imidazolidine is dissolved in 10 ml. of methylene chloride, and 1 ml. of boron tribromide is added carefully at room temperature. After 1 hour, the solution is evaporated in vacuo. The residue is dissolved in water and the solution is adjusted to pH 10 with caustic soda solution and extracted, first with methylene chloride and then with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from acetonitrile, whereupon 2-[(2,6-dichlorophenyl)imino-1-hydroxyimidazolidine, m.p. 211° (decomp.), is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>C1COCC1>[CH2:11]([O:18][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Br:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2ccccc2)c(Br)c1
Yield: 90 %

Procedure:
3-Bromo-4-flurobenzonitrile (3.00 g, 15 mmol), benzyl alcohol (1.71 ml, 16.5 mmol) and THF (40 ml) are combined and treated with 60% sodium hydride in oil (0.66 g, 16.5 mmol). The reaction mixture is heated to reflux under nitrogen for 3 hours. Aqueous workup and chromatographic purification (cyclohexane:dichloromethane, 3:1) yields 4-benzyloxy-3-bromobenzonitrile as a white solid (3.88 g, 13.5 mmol). A portion of this material (2.64 g, 9.16 mmol) in THF (25 ml) is treated with a 1 M solution of borane in THF (18.3 ml, 18.3 mmol). After the exotherm subsides the reaction is refluxed a couple of days under nitrogen. The excess borane is destroyed by the addition of methanol and 4-benzyloxy-3-bromobenzylamine is precipitated as the hydrochloride salt (1.58 g, 4.8 mmol). This material is suspended in dichloromethane (30 ml) and treated successively with triethyl amine (1.68 ml, 12.02 mmol) and di-tert-butyl dicarbonate (1.26 g, 5.77 mmol). The reaction mixture is stirred under nitrogen four hours; aqueous workup and chromatographic purification (ethyl acetate:cyclohexane, 3:7) yields the title compound as a white solid (1.69 g, 4.3 mmol). MS(EI): 394(M+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14](=[O:35])[CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:23]=[CH:22][N:21]=[C:20]2Cl)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:35])[CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:23]=[CH:22][N:21]=[C:20]2[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCOC(=O)COc1cc2ncnc(Cl)c2cc1OCC(=O)OCC
Product: CCOC(=O)COc1cc2ncnc(N3CCCc4ccccc43)c2cc1OCC(=O)OCC
Yield: 19 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 19% yield from 1,2,3,4-tetrahydroquinoline and (4-chloro-7-ethoxycarbonylmethoxy-quinazolin-6-yloxy)-acetic acid ethyl ester. (film; LC-MS: 465 (MH+)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.O>CS(C)=O>[O:13]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncccc1-c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A mixture of potassium carbonate (3287 mg), phenol (821 mg) and 6′-fluoro-3,3′-bipyridin-2-amine (1500 mg) in DMSO (15 mL) was stirred for 1 hr at 150° C. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (1750 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][O:19][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(CO)ccc2C1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(COc3ccc(Cl)c(C(F)(F)F)c3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 6-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (85 mg, 0.323 mmol) in CH2Cl2 (1.5 mL) is added a solution of 4-chloro-3-trifluoromethyl-phenol (76 mg, 1.23 eq.) in CH2Cl2 (0.5 mL), PPh3 (127 mg, 1.5 eq.), and 1,1′-(azodicarbonyl)-dipiperidine (122 mg, 1.5 eq.). The mixture is stirred at room temperature overnight. All the solvent is removed under reduced pressure and the mixture is purified by column chromatography (silica gel, EtOAc/Hexane, gradient) to give 70 mg of 6-(4-chloro-3-trifluoromethyl-phenoxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:16]([CH3:18])[CH3:17])([C:14]#N)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(Cl)(Cl)Cl.[NH4+].[Cl-].[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][CH2:28][CH2:27][CH3:31])([N:16]([CH3:17])[CH3:18])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CN(C)C1(C#N)CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCC1(N(C)C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
A little iodine was added to a mixture of 17.7 g (6 eq) magnesium and 50 ml dry ether, followed over a period of 1 h by 100 g (6 eq) bromobutane dissolved in 100 ml dry ether. This reaction mixture was stirred for 1 h at room temperature. The Grignard reagent produced in the preceding step was added over a period of 20 min to a solution of 30 g (1 eq) 1-benzyl-4-(dimethylamino)piperidine-4-carbonitrile dissolved in 210 ml dry THF and the reaction mixture obtained was then stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the reaction solution was cooled to 0° C., mixed with saturated NH4Cl solution, filtered over celite, extracted with ethyl acetate (3×200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (aluminium oxide neutral; hexane). 18.2 g (53%) of product were obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([O-])=O.[K+].IC1[CH:14]=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:18][C:17]=2[CH:31]=1>C1(C)C=CC=CC=1.CN(C=O)C.[Cu]I>[F:7][C:3]([F:8])([C:4]1[CH:14]=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:23])[F:24])[C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:18][C:17]=2[CH:31]=1)[C:2]([F:10])([F:9])[F:1]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2OC1C(F)(F)F
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Temperature: 120 °C

Procedure:
Potassium pentafluoropropionate (0.476 g, 2.35 mmol) was dissolved in toluene (6 mL) and DMF (6 mL). The vessel was fitted with a distilling head, and CuI (0.471 g, 2.474 mmol) was added with stirring. The reaction was heated to 120° C., removing the toluene by distillation. Ethyl 6-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 72, Step 3) (0.469 g, 1.178 mmol) was added and the reaction was heated to 150° C. for 2 hours. The reaction was allowed to cool to room temperature and was partitioned between diethyl ether and H2O. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel 60, eluant: hexanes-ethyl acetate, 8:1) yielding, upon concentration of the solution, the desired ester (0.096 g, 21%) as a tan solid mass of suitable purity to use without further purification: 1H NMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.91 (d, 1H, J=2.2 Hz), 7.74 (dd, 1H, J=8.7, 2.2 Hz), 6.00 (q, 1H, J=7.1 Hz), 4.42−4.24 (m, 2H), 1.34 (t, 3H, J=7.3 Hz).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]([OH:5])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>>[Br:1][CH:2]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:5]
Reactant: COCCOCCC(Br)C(=O)O
Reactant: Cc1ccc(N)nc1
Product: COCCOCCC(Br)C(=O)Nc1ccc(C)cn1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A16 (Step 5) starting from 2-bromo-4-(2-methoxyethoxy)butanoic acid and 2-amino-5-picoline.