Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][CH2:12]2)=O)(C)(C)C.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1.C(O)(C(F)(F)F)=O>>[C:24]1([C:21]2[N:20]=[N:19][C:18]([N:11]3[CH2:12][CH:13]4[NH:8][CH:9]([CH2:16][CH2:15][CH2:14]4)[CH2:10]3)=[CH:23][CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccc(N3CC4CCCC(C3)N4)nn2)cc1

Procedure:
Was prepared according to reaction-conditions of Method A from 9-tert-butoxycarbonyl-3,9-diazabicyclo[3.3.1]nonane and 3-chloro-6-phenylpyridazine at 130° C. for 3 days, followed by treatment with TFA. Workup procedure was done according to Method A. LC-ESI-HRMS of [M+H]+ shows 281.1761 Da. Calc. 281.176621 Da, dev. −1.9 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:36])=O>>[Cl:36][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1cncn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCn1cncn1
Yield: 65 %

Procedure:
A solution of 6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.11 g, 3.86 mmol) and DMF (0.6 ml) in thionyl chloride (15 ml) was heated at reflux for 1 hour. The mixture was allowed to cool, toluene was added and the volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH8.5 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified solid was triturated with ether, collected by filtration, washed with water and then ether, and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline (756 mg, 65%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C@@H:30]([NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH3:33]
Reactant: C[C@H](N)CO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](C)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (S)-2-aminopropan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=433.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].CO.[OH-].[Li+].Cl>O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3]([OH:4])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (7.5 g, 25 mmol) was suspended in 2:1 methanol:water. Lithium hydroxide (2.1 g, 50 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was acidified to pH 1 with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[CH3:24].[Li+].[OH-].C1COCC1.Cl>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:24]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(C)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.6 %

Procedure:
Methyl 5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinate (example BI; 4.8 g, 13.3 mmol) and LiOH (0.96 g, 40.0 mmol) were combined with THF (70 mL), water (14 mL) and methanol (7 mL) to give a yellow suspension. The reaction mixture was stirred for 22 h at room temperature, 15 mL water was added and the reaction mixture was heated to 45° C. and stirred for 3 h. After cooling to room temperature the reaction mixture was poured into 150 mL of 1 M HCl with ice (pH=1) and extracted with ethyl acetate (2×150 mL). The organic layers were combined, dried with Na2SO4, filtrated and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 100% EtOAc in heptane to give 3.8 g (82%) of the title compound as a white crystalline solid; MS (ESI): 346.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1.[C:18]([O:22]C)(=O)[CH:19]=[CH2:20].O>CS(C)=O>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]3([CH2:20][CH2:19][C:18](=[O:22])[CH2:2][CH2:1]3)[C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 828.7 %

Procedure:
Potassium tert-butoxide (0.085 g, 0.80 mmol) was added to a suspension of 6-bromoindolin-2-one (preparation 1, 3.00 g, 14.2 mmol) in dimethylsulphoxide (7 mL) and, after stirring for 10 minutes at ambient temperature, the mixture was heated to 40-45° C. and methyl acrylate (4.00 mL, 44.40 mmol) was added dropwise over 70 minutes. After the addition, the mixture was stirred for 1 hour and then further potassium tert-butoxide (3.82 g, 34.00 mmol) was added portionwise over 30 minutes keeping the temperature below 50° C. The mixture was then heated to 100° C. and stirred for 1.5 hours. Water (45 mL) was added and heating was continued at 85° C. for 4 hours and then the mixture was left to cool overnight. The resultant precipitate was filtered and the solid washed with water and hexanes to give the crude product. Recrystallization from ethyl alcohol gave the title compound (1.95 g, 42%) as a white solid.
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]=[N:20]O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N12CCCN=C1CCCCC2.O>ClCCl>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]#[N:20])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: ON=C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: N#C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde oxime (37.4 mg, 0.132 mmol) in dichloromethane (3 mL) was mixed with trifluoromethanesulfonic anhydride (24.0 μL, 0.145 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (43.0 μL, 0.289 mmol) and stirred at room temperature for 18 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2 (v/v)) and washed with hexane/ethyl acetate (5/1 (v/v)) to give the title compound as a colorless solid (20.7 mg, yield 59%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8](O)([OH:13])[C:9]([F:12])([F:11])[F:10]>>[F:10][C:9]([F:12])([F:11])[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[OH:13]
Reactant: OC(O)C(F)(F)F
Reactant: Oc1ccccc1
Product: Oc1ccccc1C(O)C(F)(F)F
Temperature: 100 °C
Yield: 88 %

Procedure:
9.3 g (100 mmol) of phenol and 3.9 g (25 mmol) of 75% fluoral hydrate are introduced into a 100 ml reactor. 5.0 g of hydrotalcite Mg6Al2(O4)16.4H2O are added. The mixture is heated at 100° C. for 5 hours. After treating the reaction medium according to the protocol described in Example 1, a yield of 88% of the corresponding alcohol is obtained with an ortho/para ratio equal to 1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[K].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[OH:20]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [K]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1Cl

Procedure:
A stirred solution of 2,4-dichlorobenzonitrile (51.6 g., 0.03 mole) and the potassium salt of 2,4-dichlorophenol (60.3 g., 0.03 mole) in 250 ml. of dimethyl acetamide was heated for 24 hours at 120° C. The cooled reaction mixture was diluted with 1000 ml. of water and the resultant oil was extracted with ether. Evaporation of the ether solution gave 88.0 g. of brown oil. Analysis by v.p.c. showed a 2:1 mixture of the desired compound and the isomeric 4-chloro-2-(2',4'-dichlorophenoxy) benzonitrile. A series of fractional crystallizations from 60°-110° C. petroleum ether gave the desired 2-chloro-4-(2',4'-dichlorophenoxy)benzonitrile with a melting point of 69°-74° C. The minor isomeric by-product melted at 110°-113° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11]O)[CH:2]=1.O=S(Cl)[Cl:15]>C(Cl)Cl>[ClH:15].[Cl:15][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: OCc1cnc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of quinolin-3-ylmethanol MDE 32002 (0.26 g, 1.63 mmol) in dry CH2Cl2 (10 mL) at 0° C. under N2 in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (2.4 mL, 33.1 mmol) and the mixture was stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)quinoline hydrochloride MDE 32004 as an off-white solid (301 mg, 85% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(O)C.Cl[CH:13]([CH:19]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCOC(=O)C(Cl)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(Br)ccn12
Temperature: 60 °C

Procedure:
4-Bromopyridin-2-amine (10.0 g, 0.06 mol) was mixed with ethanol (50 mL) in a reaction flask, under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene; 222 mL; Commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 5 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (500 mL) and sodium bicarbonate solution (200 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (100 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica, eluting with ethyl acetate. Fractions containing the product were concentrated under reduced pressure to give ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (15 g) as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[CH3:15][O:16][CH2:17][CH:18]1[O:20][CH2:19]1>>[CH3:15][O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCC1CO1
Product: COCC(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 98 °C
Yield: 108.4 %

Procedure:
A mixture of 4-pyrazoleboronic acid pinacol ester (4.24 g, 21.9 mmol) and glycidyl methyl ether (7.94 g, 76.6 mmol) was heated to 98° C. for 4 h. It was cooled to r.t. and concentrated in vacuo to give the title compound (6.7 g, quantitative) as a yellow oil. δH (CDCl3) 1.32 (12H, s), 3.37 (3H, s), 3.12-3.54 (3H, m), 4.08-4.37 (3H, m), 7.73 (1H, s), 7.80 (1H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:14][C@H:13]2[CH3:26])=[N:4][N:3]=1.[C:27]1([CH3:36])[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.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>[CH3:26][C@H:13]1[N:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:30]3[CH:31]=[CH:32][C:27]([CH3:36])=[CH:28][CH:29]=3)=[N:3][N:4]=2)[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ccccc12
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nnc(N3CCN(C(=O)c4ccccc4)C[C@H]3C)c3ccccc23)cc1
Temperature: 100 °C
Yield: 86.3 %

Procedure:
Compound 20 was prepared as described generally in synthetic Method D. Substrate JK-5 was prepared as described in detail in Example 11. To a reaction flask was added (R)-(4-(4-chlorophthalazin-1-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (JK-5) (200 mg, 0.54 mmol), p-tolyl boronic acid (111 mg, 0.82 mmol, 1.5 eq), and Pd(PPh3)4 (31 mg, 0.027 mmol, 0.05 eq). The flask was fitted with a reflux condenser and purged with nitrogen. Toluene (5.4 mL) and aqueous Na2CO3 (2 M, 0.54 mL, 2 eq) were added and the reaction was heated to 100° C. overnight. The reaction was then cooled to rt and diluted with 75 mL of ethyl acetate. The organic phase was washed with 1×10 mL of sat. NaHCO3 solution, 1×10 mL of H2O, and 1×10 mL of sat. NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (60% ethyl acetate in hexanes) afforded 197 mg (86%) of (R)-(3-methyl-4-(4-p-tolylphthalazin-1-yl)piperazin-1-yl)(phenyl)methanone 20 MS (M+H)+=423.3.
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:5]([C:2]4([OH:1])[CH2:4][CH2:3]4)=[O:7])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(O)C1(O)CC1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3(O)CC3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-hydroxycyclopropanecarboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (53.4% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 8.03, 7.01, 3.98-3.73, 3.58, 1.53, 1.16, 1.02, 0.76, 0.48, 0.10. MS (ES+) m/z 360 (M+1).
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][CH2:19]I)([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].S(=O)(=O)(O)[OH:22]>>[C:1]([CH2:14][C:15]([CH2:18][CH2:19][OH:22])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(=O)(O)O
Reactant: FC(F)(CCI)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: OCCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
Ethylene (25 g) was introduced to an autoclave charged with C4F9CH2CF2I (217 g) and d-(+)-limonene (1 g), and the reactor heated at 240° C. for 12 hours. The product was isolated by vacuum distillation to provide C4F9CH2CF2CH2CH2I. Fuming sulfuric acid (70 mL) was added slowly to 50 g of C4F9CH2CF2CH2CH2I and mixture was stirred at 60° C. for 1.5 hours. The reaction was quenched with ice-cold 1.5 wt % Na2SO3 aqueous solution and heated at 95° C. for 0.5 hours. The bottom layer was separated and washed with 10 wt % aqueous sodium acetate and distilled to provide C4F9CH2CF2CH2CH2OH: bp 54-57° C. at 2 mmHg (267 Pa).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C@@H:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:16])=[CH:10][CH:11]=1)=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[C@H](C)COC(=O)c1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@H](C)COC(=O)c1ccc(CBr)cc1

Procedure:
20.63 g (0.1 mole) of the 4-methylbenzoic acid[(S)-2-methylbutyl]ester obtained in Step A-1, 17.80 g (0.1 mole) of N-bromosuccinimide, and 1.32 g (0.005 moles) of benzoyl peroxide were dissolved in 120 ml of dry carbon tetrachloride and allowed to react under reflux for three hours. On completion of the reaction, the reaction mixture was filtered while hot to remove the succinimide, which is a by-product of the reaction, and 27.70 g of a crude form of the objective 4-((S)-2-methyl butoxycarbonyl)benzylbromide was obtained from the filtrate by evaporating off the carbon tetrachloride.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@H:5]([OH:30])[CH2:4]1)[CH3:2].[C:31](Cl)(=[O:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)O[C@H]1C[C@H](C2N3C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=CC3=NN=2)[C@H](CC)C1>[C:31](=[O:42])([O:32][C:33]1[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)[O:30][CH:5]1[CH2:6][CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@H]1C[C@@H](O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: CC[C@@H]1C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCC1CC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (1.20 g, 2.82 mmol) in pyridine (10 mL) was added DMAP (0.103 g, 0.846 mmol) and 4-nitrophenyl carbonochloridate (0.853 g, 4.23 mmol). The resulting mixture was stirred at ambient temperature for about 1 h. The reaction mixture was purified using silica gel chromatography eluting with 0-30% EtOAc in DCM to give a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.72 g. 43%): LC/MS (Table 1, Method b) Rt=2.64 min; MS m/z: 591 (M+H)+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:3][CH:2]=1.[I:19][CH3:20]>C(OCC)(=O)C>[I-:19].[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([N:14]2[CH:18]=[N+:17]([CH3:20])[CH:16]=[N:15]2)=[CH:3][CH:2]=1
Reactant: CI
Reactant: c1ccc2c(c1)oc1c(-n3cncn3)cccc12
Solvent: CCOC(C)=O
Product: C[n+]1cnn(-c2cccc3c2oc2ccccc23)c1
Product: [I-]
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A solution of 1-(dibenzo[b,d]furan-4-yl)-1H-1,2,4-triazole (2.3 g, 9.78 mmol) and iodomethane (3.0 mL, 49 mmol) in ethyl acetate (20 mL) was heated at 55° C. for 60 h. After cooling to room temperature, the precipitate was collected by filtration to yield 1-(dibenzo[b,d]furan-4-yl)-4-methyl-1H-1,2,4-triazol-4-ium iodide (1.6 g, 43%) as a white solid.
Reaction SMILES: COC1N=C(C2CCC3C(=CC=C(OC)C=3)C2)C(N)=CC=1.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27](O)=O.FC1C=[C:45](C=CC=1OCCN1CCCCC1)[CH2:46][NH:47][C:48]1[C:49]([CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1>>[CH2:46]([N:47]([CH2:27][C:26]1[CH:30]=[CH:31][C:32]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:24]([F:23])[CH:25]=1)[C:48]1[C:49]([CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1)[CH3:45]
Reactant: COc1ccc2c(c1)CCC(c1nc(OC)ccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc2c(c1)CCC(c1nc(OC)ccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccc(OC)nc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 6-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-3-ylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 282, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]-[6-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-3-yl]amine (548 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][6-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-3-yl]amine (454 mg). This compound (452 mg) was used according to an analogous synthetic method to Example 111 to provide 6-{3-{ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-6-methoxypyridin-2-yl}-5,6,7,8-tetrahydronaphthalen-2-ol (140 mg) and 5-{ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-6-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-2-ol (60 mg).