Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[OH:11]S(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]([NH2:6])=[O:11]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccc(O)c(Br)c1
Temperature: 80 °C
Yield: 83 %

Procedure:
3-Bromo-4-hydroxy-benzonitrile (495 mg, 2.5 mmol) is dissolved in H2SO4 98%, heat the solution at 80° C. for 1 hour. Cool the mixture at room temperature and pour it into ice-water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4. Eliminate the solvent to obtain the title compound (450 mg, 83%). 1H-NMR (metanol-d4, 200 MHz): 8.04 (d, 1H, J=2.0 Hz), 7.70 (dd, 1H, J=2.0 and 8.4 Hz), 6.93 (d, 1H, J=8.6 Hz)
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[CH:6][O:5][N:4]=1.[Cl:8][C:9]1[CH:10]=[C:11]([OH:30])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([OH:28])([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)[C:17]([F:20])([F:19])[F:18]>>[Cl:8][C:9]1[CH:10]=[C:11]([O:30][CH2:2][C:3]2[N:7]=[CH:6][O:5][N:4]=2)[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)([OH:28])[C:17]([F:18])([F:20])[F:19]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: ClCc1ncon1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3ncon3)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 3-(chloromethyl)-1,2,4-oxadiazole and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=429.3 (MH+).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([OH:12])[CH:4]=1.C([O:16][C:17]([CH3:22])([CH:20]=[CH2:21])[CH2:18]Cl)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([O:12][CH2:18][C:17]([CH3:22])([OH:16])[CH:20]=[CH2:21])=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: C=CC(C)(CCl)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(C)(O)COc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 71.1 %

Procedure:
Into N,N-dimethyl formamide (200 ml) were suspended 11 g (0.27 mol) of 60%-sodium hydride. With stirring under ice cooling, an N,N-dimethyl formamide (150 ml) solution containing 38 g (0.27 mol) of p-nitrophenol was added dropwise therein over three hours. After the resulting solution was continuously stirred for further one hour as it was, the reaction liquid became a homogeneous yellow solution. The reaction liquid was returned to room temperatures, and an N,N-dimethylformamide (100 ml) solution containing 38 g (0.23 mol) of (1-chloro-2-methyl-3-butene-2-yl) acetate was added dropwise therein over three hours. The resulting mixture was stirred for additional one hour as it was. The reaction liquid was dispersed in water (1,000 ml), and 20 g of potassium carbonate were added therein, followed by stirring for one hour. After the extract obtained by extraction therefrom with ethyl acetate (500 ml) was washed with water and dried, it was concentrated under reduced pressure, thereby obtaining a yellowish brown and oily residue. This residue was purified by chromatography on a silica gel column (ethyl acetate:n-hexane system), whereby 36.5 g of the title compound were obtained. (Yield: 70.8%)
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][C:9]1[N:10]=[C:11]([N:14]=[C:15]2[N:19]3[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:27][C@H:18]3[CH2:17][S:16]2)[S:12][CH:13]=1)=[O:7])C.[ClH:28]>C(O)C>[ClH:28].[C:6]([CH2:8][C:9]1[N:10]=[C:11]([N:14]=[C:15]2[N:19]3[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:27][C@H:18]3[CH2:17][S:16]2)[S:12][CH:13]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)Cc1csc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1csc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Temperature: 20 °C

Procedure:
A 4 N aqueous solution of sodium hydroxide (30 cc) is added to a solution of (S)-3-[(4-ethoxycarbonylmethylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinoline (10 g) in ethanol (60 cc). The mixture is heated under reflux for two hours. After cooling to 20° C., it is acidified by adding 12 N hydrochloric acid (d=1.19; 11 cc). The white precipitate which has formed is filtered off, washed with water and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). The resulting solid is crystallised by dissolving it in boiling ethanol (200 cc), cooling and filtering off the crystals formed; the product is then recrystallised by dissolving it in dimethylformamide (60 cc) at 100° C., adding ethanol (120 cc) and cooling to 0° C. The crystals are filtered off, washed with ethanol (20 cc) and then with diethyl ether (20 cc) and dried at 40° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(4-carboxymethylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline hydrochloride (5.6 g), m.p.=206° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[O:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[O:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[OH:9])=[CH:11]1
Reactant: Cc1cccc(Br)c1O
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(-c2ccoc2)c1O
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
2-Bromo-6-methylphenol (800 mg, 4.28 mmol), 3-furan boronic acid (574 mg, 5.13 mmol), sodium carbonate (1400 mg, 12.8 mmol) and Pd2(dppf)2Cl2 (699 mg, 0.82 mmol) were dissolved in dimethoxyethane/water 10 mL/10 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(furan-3-yl)-6-methylphenol (273 mg, 26%).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[CH:1]=[O:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of syringaldehyde (10 g, 55 mmol), p-nitrobenzyl bromide (13 g, 60 mmol) and potassium carbonate (9.0 g, 65 mmol) in 40 ml of acetone was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure. The residue was added with water and then with dichloromethane. The organic layer was thereafter dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was added with ether, followed by stirring at room temperature. The insoluble colorless solid was collected by filtration to give 16.7 g of the title compound (yield: 93%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].[CH3:12][O:13][C:14]1[CH:22]=[CH:21]C(C(Cl)=O)=[CH:16][CH:15]=1.[NH4+].[Cl-]>O>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:5]([C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:4])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
To a liquid mixture consisting of 25 ml of solvent naphtha and 50 ml of water, 19.5 g (0.15 mol) of ethyl acetoacetate were added, followed by cooling to 5° C. A 33% aqueous sodium hydroxide solution (6.5 ml) was added to the resultant liquid mixture, followed by vigorous agitation. A 33% aqueous sodium hydroxide solution (27 ml) and 27.6 g (0.16 mol) of 4-methoxybenzoyl chloride were simultaneously added in small portions over 30 minutes, whereby they were reacted while the internal temperature and pH were maintained below about 10° C. and at about 11, respectively. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 2.5 hours to allow the reaction to proceed further. After completion of the reaction, 8 g (0.15 mol) of NH4Cl were added further and the resulting mixture was allowed to stand overnight. An oil thus formed was extracted with ethyl acetate. The organic layer was washed with water and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=5/1), whereby the title compound was obtained as a colorless oil. Yield: 16.1 g (48%)
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[C:23]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:22]=2)[CH2:17]1)=O)(C)(C)C>ClCCl>[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]2[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[C:23]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:22]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(C(=O)OC(C)(C)C)c(NC3CCOCC3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCN(c2ccc(C(=O)O)c(NC3CCOCC3)c2)C1
Temperature: 25 °C
Reaction time: 30 h
Yield: 137.6 %

Procedure:
19.7 ml (25 eq) of trifluoroacetic acid is added to a solution of 4.72 g (10.23 mmol) of tert-butyl (S)-4-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzoate in 100 ml of dichloromethane. The reaction medium is stirred at room temperature for 30 hours. The solvents are evaporated and the residue is redissolved in diethyl ether and triturated until a solid is obtained. The solid formed is filtered and dried under vacuum to yield 4.3 g (100%) of a yellow powder of (S)-4-(3-aminopyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid in the form of a trifluoroacetic acid salt.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.Cl.[Cl-].[Na+]>O.N>[SH:4][CH2:5][CH:6]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Product: COC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.33 h

Procedure:
2.1 g. of the product from Example 81 is dissolved in a mixture of water (35 ml.) and concentrated ammonia (35 ml.) under a blanket of argon. After 20 minutes, the solution is chilled in an ice bath, made acidic with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to yield 1.1 g. of the named product that is purified by chromatography on silica gel (benzene:acetic acid 75:25) Rf : 0.35 (silica gel-benzene:acetic acid, 75:25).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:12]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>FC(F)(F)C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1NC(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccc3c(c2)OCO3)ccc1C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(4-fluorobenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 39 mg of 4-(benzo[1,3]dioxol-5-yl)-2-(4-fluorobenzamido)benzoic acid as white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[OH-].[Na+].[N+:14]([O-])([OH:16])=[O:15]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=2)[CH2:5][CH2:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC1=NCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: CC1=NCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of 1-methyl-3,4-dihydroisoquinoline was dissolved in 7.0 ml of conc. nitric acid at 0° C., and 14.0 ml of fuming nitric acid was added dropwise to the solution. The solution was stirred for one hour at the same temperature, and overnight at room temperature. The reaction mixture was poured into ice, neutralized with aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. The desiccant was separated by filtration, and the filtrate was purified by silica gel column chromatography to obtain 1.08 g of 1-methyl-7-nitro-3,4-dihydroisoquinoline, which was white crystal (yield: 82%).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([N:18]1[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]3)[CH2:19]1)(=[O:17])=[O:16])=[CH:10]2)(=O)C.O.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([N:18]1[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]3)[CH2:19]1)(=[O:17])=[O:16])=[CH:10]2
Reactant: CC(=O)Oc1cccc2cc(S(=O)(=O)N3CC4CCC(CC4)C3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc2c(O)cccc2c1)N1CC2CCC(CC2)C1
Reaction time: 8 h

Procedure:
The title compound was prepared from 3-(5-Acetoxy-2-naphthylsulfonyl)-3-azabicyclo[3.2.2]nonane, by dissolving the acetoxy compound in 3 ml THF and then adding 2 ml water and 2 ml saturated sodium bicarbonate solution. After stirring overnight, the solvent was evaporated and the product extracted with chloroform. After drying over magnesium sulfate, the solvent was evaporated to give an orange oil. This was purified by chromatotron using 3/1 hexane/ethyl acetate which gave a yellow solid (32 mg, 48% yield): 1H NMR (CDCl3): 8.33 (d, J=8.8, 1 H, H3), 8.25 (d, J=1.6, 1 H, H1), 7.70 (d, J=8.8, 1 H, H4), 7.49 (d, J=8.3, 1 H, H6), 7.40 (t, J=7.8, 1 H, H7), 7.02 (d, J=7.4, 1 H, H8), 6.68 (br s, 1 H, OH), 3.30 (d, J=4.2, 4 H, N(CH2R)2), 2.08 (s, 2 H, N(CH2CHR)2),1.72-1.58 (in, 8 H, alkyl H's).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2([NH2:41])[CH2:40][CH2:39]2)[N:33]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:34]6[N:33]=[N:32][CH:37]=[CH:36][CH:35]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2cccnn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.018, 0.099 mmol, 1 eq) and Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.031 mg (60%). 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.92-7.96 (m, 3H), 7.77-7.69 (m, 4H), 7.65 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.30 (dd, J=1.6, 8.4 Hz, 1H), 7.23-7.19 (m, 2H), 5.94 (bs, 1H), 3.0 (s, 3H), 2.33 (s, 3H), 1.89-1.86 (m, 2H), 1.60-1.57 (m, 2H). 19F NMR (376.47 MHz, CDCl3): δ −75.82 (TFA), −109.29 LCMS: (ES+) m/z=521.0 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C1(C)C=CC=CC=1>[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:12]2[C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:11]2)=[CH:26][CH:25]=1
Reactant: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=c1c2cccnc2c(-c2cccc([N+](=O)[O-])c2)nn1Cc1ccncc1
Temperature: 65 °C
Reaction time: 17 h
Yield: 52.8 %

Procedure:
8-(3-nitrophenyl)-pyrido[2,3-d]pyridazin-5-one (5.12 g, 19.1 moles), sodium hydride (50% in oil, 1 g, 20.1 moles) were mixed in 100 mL of 1-methyl-2-pyrrolidone and the mixture heated to 65° C. In a separatory funnel, 4-picolyl chloride hydrochloride (4.5 g, 27.4 mmoles), 20 mL of saturated potassium carbonate and 75 mL of toluene are mixed. After separation, the toluene solution was added to the reaction mixture dropwise over the period of 1 hour. The reaction mixture was diluted with water (250 mL) and extracted twice with ethyl acetate (200 mL). After concentrating the organic fractions, methanol and hexanes (75 mL each) were added and the mixture allowed to stir at room temperature for 17 hours. The material was filtered and dried to yield 5.2 g of 6-(4-pyridylmethyl)-8-(3-nitro-phenyl)-pyrido[2,3-d]pyridazin-5-one.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH3:18])[C:11]([OH:17])=[CH:12][CH:13]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:5][O:4][CH2:3][CH2:2][O:17][C:11]1[C:10]([CH3:18])=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([CH3:6])=[N:8]2)=[CH:13][CH:12]=1
Reactant: Cc1ccc2ccc(O)c(C)c2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCCOc1ccc2ccc(C)nc2c1C
Yield: 16.9 %

Procedure:
1-Bromo-2-methoxyethane (0.64 g, 4.6 mmol), 2,8-dimethylquinolin-7-ol (1.0 g, 2.3 mmol) and potassium carbonate (0.96 g, 6.9 mmol) in acetone (15 mL) were heated to 70° C. in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-(2-methoxyethoxy)-2,8-dimethylquinoline (90 mg, 17% yield) as an oil
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:12]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)cc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(F)cc(Br)cc1C=O
Temperature: 70 °C
Yield: 94 %

Procedure:
To a solution of 5-Bromo-3-fluoro-2-hydroxy-benzaldehyde (2.0 g, 9.13 mmol), in DMF (10 mL) was added Cs2CO3 (3.56 g, 10.95 mmol) and iodomethane (2.59 g, 18.26 mmol) and heated at 70° C. for 6 h. Reaction mixture was diluted with EtOAc (25 mL) and filtered, filtrate was washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography (EtOAc:Hex, 1:3) gave pure 5-Bromo-3-fluoro-2-methoxy-benzaldehyde (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:40]1([CH2:46][NH2:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:47][CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)NCc4ccccc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added 1-phenylmethanamine (47 mg, 0.44 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH:21]4[CH2:22][CH2:23][CH:17]3[CH2:18][O:19][CH2:20]4)[CH:13]=[C:12]([N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][O:27][CH2:28]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>CC(O)C.ClCCl.[Pd]>[CH:25]12[N:24]([C:12]3[CH:13]=[C:14]([N:16]4[CH:21]5[CH2:22][CH2:23][CH:17]4[CH2:18][O:19][CH2:20]5)[N:15]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[N:11]=3)[CH:29]([CH2:30][CH2:31]1)[CH2:28][O:27][CH2:26]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C4CCC3COC4)cc(N3C4CCC3COC4)n2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1ccc(-c2nc(N3C4CCC3COC4)cc(N3C4CCC3COC4)n2)cc1
Reaction time: 4 h
Yield: 86.1 %

Procedure:
In a 250 mL round-bottomed flask was placed 8,8′-(2-(4-nitrophenyl)pyrimidine-4,6-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane) (37, 246 mg, 0.581 mmol) in 2-propanol (3 mL) and dichloromethane (3 mL) to give a yellow solution. A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 4 hours. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (40-60%). Collected fractions were concentrated to give the title compound (197 mg, 0.5 mmol, 86%) as a light yellow solid. For [M+H]+ mass error=0.2 mDa or 0.46 ppm.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@H:39]([OH:41])[CH3:40]>>[OH:41][C@H:39]([CH3:40])[CH2:38][NH:37][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 86.4 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 48 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.