Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15].Cl.[CH3:18][C:19]1([NH2:22])[CH2:21][CH2:20]1>CS(C)=O>[Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:19]1([CH3:18])[CH2:21][CH2:20]1)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15]
Reactant: CCn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CS(C)=O
Product: CCn1c(NC2(C)CC2)nc2c(Br)c(F)ccc2c1=O
Yield: 81.2 %

Procedure:
A solution of 8-bromo-2-chloro-3-ethyl-7-fluoroquinazolin-4(3H)-one (512c; 200 mg, 0.655 mmol), 1-methylcyclopropanamine hydrochloride (Small Molecules, Inc.; 211 mg, 1.964 mmol), and TEA (0.274 mL, 1.964 mmol) in DMSO (1.5 mL) was heated in a sealed microwave vial at 90° C. for 30 min. The reaction mixture was then partitioned between DCM (60 mL) and water (40 mL). The organic layer was separated and sequentially washed with water (2×40 mL) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-3-ethyl-7-fluoro-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (181.1 mg, 0.532 mmol, 81% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (1H, dd, J=8.8, 6.1 Hz), 6.93 (1H, t, J=8.5 Hz), 4.84-5.23 (1H, m), 4.02 (2H, q, J=6.4 Hz), 1.61 (3H, s), 1.30 (3H, t, J=7.2 Hz), 0.91 (2H, br. s.), 0.81-0.88 (2H, m). 19F NMR (376 MHz, CDCl3) δ ppm −96.57 (1F, br. s.). m/z (ESI, +ve) 339.8/341.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:9][C:3]1[C:2]([NH2:1])=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][N:4]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(N2CCOCC2)cnc1Cl
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-amino-5-bromo-2-chloropyridine (2.0 g, 9.7 mmol), morpholine (1.3 mL, 14.9 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (0.37 g, 0.8 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.36 g, 0.39 mmol) in dry THF (15.0 mL) was degassed by nitrogen. To this mixture was added 1.0M lithium bis(trimethylsilyl)amide in THF (25 mL) dropwise, and the resulting reaction was heated to 60° C. After 2.5 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-20% EtOAc in hexanes) to afford an off-white solid as 2-chloro-5-morpholinopyridin-3-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.35 (1H, d, J=2.7 Hz), 6.67 (1H, d, J=2.7 Hz), 5.33 (2H, s), 3.79 (4H, m), 3.11 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:9]=O)=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([BH3-])#N.[Na+].O>CO>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Reaction time: 18 h
Yield: 11.1 %

Procedure:
To a solution of bis-(4-chloro-phenyl)-acetaldehyde (3.74 mmol) in methanol under a nitrogen atmosphere, N-BOC-piperazine (1.05 g, 5.61 mmol) was added ???, the reaction mixture was stirred for 1 hour before addition of sodium cyanoborohydride (0.28 g, 4.49 mmol). The reaction mixture was stirred for 18 hours, water added (3 ml) and the solvent removed under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer was separated, dried (MgSO4), filtered and concentrated. Purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (3:7) to yield the title compound (0.18 g, 11% yield for steps 30A and 30B combined). LC/MS: (PS-A2) Rt 2.66 [M−BOC+H]+ 335.02.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.CN.Cl.C[CH2:16][N:17](C(C)C)C(C)C>ClCCl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:17][CH3:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(CCl)cc1
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To a solution 4-(chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) and methylamine.HCl (1.0 g, 5.80 mmol) in dichloromethane (40 mL) was added DIPEA (2.01 g, 15.6 mmol) at 0° C. and stirred for 1 h. The reaction mixture was extracted with water (1×50 mL). The organic layer was extracted with brine (1×50 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford 1.0 g (quantitative) of 4-(chloromethyl)-N-methylbenzamide (I-30) as an off white solid. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=3.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 4.80 (s, 2H), 2.78 (d, J=4.4 Hz, 3H); ESI-LC/MS (m/z): [M+H]+ 184.2, RT 2.46 min.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13](Cl)=[N:14][CH:15]=3)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[N-:20]=[N+:21]=[N-:22].[Li+]>CN(C=O)C>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[N:20]=[N+:21]=[N-:22])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: [N-]=[N+]=[N-]
Reactant: OC[C@H]1O[C@@H](n2cnc3cnc(Cl)nc32)[C@@H](O)[C@@H]1O
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.3 %

Procedure:
A solution of 4 (170 mg, 0.63 mmol) in DMF (5 ml) was treated with lithium azide (270 mg, 5.52 mmol) and stirred for two days at room temperature. The solvent was evaporated under reduced pressure at 40° C. and the crude oil was recrystallizd from MeOH to obtain pure 5 (67 mg, 38.4%): mp 185-190° C. (dec.); UVλmax (water) pH 2: 205.0 (15,506), 287.0 (6,496); pH 7: 208.5 nm (12,943), 287.5 nm (6033); pH 11: 222.5 nm (6,730); 1H NMR (DMSO-d6) δ 3.66-3.90 (m, 3H, H-5′, H-4′), 4.16-4.33 (m, 2H, H-2′, H-3′), 5.14 (t, 1H, 5′-OH, exchangeable with D2O), 6.50 (d, 1H, H-1′), 8.75 (s, 1H, H-8), 10.12 (s, 1H, H-2); IR (KBr) 2037, 1649; Anal. (C10H11N7O4.0.65 CH3OH): C, H, N.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.0005 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 0.0025 mol) and allowed to stir r for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.151 g, 0.0012 mol) was added and stirred for further 3 h at 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. to get the desired compound as yellow oil (0.025 g, 16% yield). 2,8-Dimethyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrid[4,3-b]indole (0.025 g, 0.000078 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0098 g, 0.000078 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.015 g, 47% yield).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([O-])=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.O.[NH2:16][NH2:17]>C(O)C>[NH:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH:16][NH2:17])=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: NN
Reactant: O=C([O-])c1ccc(-c2nnn[nH]2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
0.20 g (0.99 mmol) of the 4-(1H-tetrazol-5-yl)benzoate was heated with ethanol (3.2 ml) and 0.84 g (16.8 mmol) of hydrazine monohydrate under reflux for 8.5 hours, and then the reaction solution was cooled to room temperature, and the precipitated pale yellow solid was collected by filtration through a Kiriyama funnel, washed with methanol and dried under reduced pressure to obtain the desired product (0.096 g, yield 47%, purity 99%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:14]([Mg]Br)[CH3:15]>C1COCC1>[NH2:1][C:2]1[C:3]([CH:12]([OH:13])[CH2:14][CH3:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC[Mg]Br
Reactant: Nc1c(C=O)ccc2cccnc12
Solvent: C1CCOC1
Product: CCC(O)c1ccc2cccnc2c1N
Yield: 76.3 %

Procedure:
In a similar fashion using route 27 general procedure 66, 8-amino-quinoline-7-carbaldehyde 404 (1 g, 5.83 mmol), ethyl magnesium bromide (3M in THF; 5.81 ml, 17.44 mmol) and THF (30 ml) gave the title compound (900 mg, 91%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:35]1(=O)[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:35]4[CH2:39][CH2:38][C:37](=[O:40])[CH:36]=4)[CH2:22]3)[C@@H:18]2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: O=C1CCC(=O)C1
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 12.3 mg (0.26 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in ˜2 mL dry toluene was added 2.7 mg (0.028 mmol) cyclopentane-1,3-dione and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 16 hr. The solvent was removed vacuum and the residue was purified by prep TLC eluting with EtOAc/MeOH (95/5) to afford the title compound. 1H-NMR (CDCl3): δ: 7.73 (1H, s), 7.20 (2H, s), 7.03–6.90 (2H, m), 4.98, 4.80 (1H, s), 4.50 (1H, m), 3.62–3.18 (2H, m), 3.30–3.18 (3H, m), 3.15, 2.97 (1H, d, J=11.2 Hz), 2.68 (2H, m), 2.55–2.40 (4H, m), 2.17 (1H, m), 2.20 (1H, m), 2.00 (1H, m), 1.85 (1H, m), 1.62 (1H, m), 1.33 (3H, d, J=6.2 Hz). MS: (MH)+556.0.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:13]=2)[N:3]=1.Cl.O1CCOCC1.O=P(Cl)(Cl)[Cl:30]>C(#N)C>[Cl:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:13]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)NC(=O)Cn1cc(Nc2nccc(O)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(C)NC(=O)Cn1cc(Nc2nccc(Cl)n2)cn1

Procedure:
To a mixture of 2-(4-(4-hydroxypyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-isopropylacetamide (6.0 g, 22 mmol) in acetonitrile (300 mL) was added 4M HCl in dioxane (12 mL, 48 mmol) then POCl3 (10 g). The mixture was heated to reflux for 0.5 h then concentrated in vacuo. The residue was slurried with water and adjusted to pH 9 with aqueous sodium hydrogen carbonate. The remaining solid was collected by filtration and purified by column chromatography (50% v/v DCM/ethyl acetate) to afford 2-(4-(4-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-isopropylacetamide II-1 (2.30 g, 36%) as a white solid. LC-MS (Method A), RT=8.28 min. (ES+) 295.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.O=[CH:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH3:28][C:27]([O:26][C:25]([NH:24][CH2:23][CH2:22][NH:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1)=[O:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: CC(C)(C)OC(=O)NCC=O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCNC(=O)OC(C)(C)C

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and t-butyl N-(2-oxoethyl)carbamate employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=1.4 Hz, 1 H), 7.80 (br, 1 H), 7.13 (dd, J=7.9, 5.8 Hz, 2 H), 6.98-6.93 (m, 3 H), 4.85 (br, 1 H), 4.38 (q, J=7.1 Hz, 2 H), 3.90 (s, 2 H), 3.30 (m, 4 H), 1.43-1.38 (m, 12 H); MS m/z 418 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])=[O:3].C([Li])CCC.[P:14](Cl)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[CH2:17]([O:16][P:14]([CH2:1][S:2]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])=[O:3])([O:19][CH2:20][CH3:21])=[O:15])[CH3:18]
Reactant: CC(C)OS(C)(=O)=O
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OC(C)C)OCC
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a rapidly stirred solution of 8.28 g (60 mmol) of isopropyl methanesulfonate in 150 mL of THF at -73° C. (internal temp.) was added 25 mL (60 mmol) of 2.4M n-butyllithium dropwise over 20 min. The internal temperature was not allowed to rise above -69° C. throughout the course of the addition. After an additional 15 min., 5.17 g (30 mmol) of freshly distilled diethyl chlorophosphate was added at a rate to keep the solution temperature below -69° C. The reaction mixture was stirred for 0.3 h at -73° C. and for 0.5 h at -40° C. when it was quenched with 125 mL of saturated NH4Cl solution. The reaction mass was warmed to room temperature and the THF removed under reduced pressure. The remainder was partitioned between methylene chloride and water (3×75 mL). The extracts were dried (Na2SO4), concentrated, and purified by flash chromatography (350 g silica gel) eluting with 1:1 methylene chloride/ether to provide 5.20 g (67%) of title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:32]2[CH2:31][CH2:30][CH2:29][NH:28][C:27]=2[CH:26]=[N:25]1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:18]4[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=4[F:16])[N:25]=[CH:26][C:27]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Fc1ccc(-n2ncc3c2CCCN3)c(F)c1
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1F
Yield: 70 %

Procedure:
The compound was prepared 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid and 1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The organic layer was concentrated and the residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide the title compound as a white foamy solid (47 mg, 70%). 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.39 (s, 0.8H), 7.64 (s, 0.2H), 7.48 (m, 2H), 7.00 (m, 2H), 5.25 (s, 0.4H), 5.14 (s, 1.6H), 3.92 (m, 0.4H), 3.85 (m, 1.6H), 2.70 (m, 2H), 2.33 (s, 2.4H), 2.32 (s, 0.6H), 2.11 (m, 1.6H), 2.03 (m, 0.4H); MS: (ES) m/z calculated for C19H16ClF5N5O [M+H]+ 460.1, found 460.1.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][C@H:14]1[O:18][C:17](=[O:19])[NH:16][CH2:15]1>>[CH3:13][C@H:14]1[O:18][C:17](=[O:19])[N:16]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH2:15]1
Reactant: C[C@@H]1CNC(=O)O1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: C[C@@H]1CN(c2ccc(C(=O)O)cc2)C(=O)O1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 40 and using ethyl 4-iodobenzoate and (R)-5-methyloxazolidin-2-one, the title compound (2 g) was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[N+:14]([C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[N:4]([CH3:3])[S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (4.0 ml), N-methyl-2,4-dinitroaniline (0.39 g (1.98 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, benzenesulfonyl chloride (0.38 ml (2.98 mmol)) was added dropwise. After two hours' stirring at room temperature, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.52 g (78%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][CH:54]=[O:55])[N:10]=2)[N:5]=1)[CH3:3].N1CC[O:59][CH2:58][CH2:57]1.C([BH3-])#N.[Na+]>C(O)C.CO>[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31]([C:33]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:32]=3)=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][C:54]([O:59][CH2:58][CH3:57])=[O:55])[N:10]=2)[N:5]=1)[CH3:3]
Reactant: C1COCCN1
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCC=O)ccc2n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)COc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Reaction time: 20 h
Yield: 23.9 %

Procedure:
A saturated solution of hydrogen chloride in ethanol (0.1 ml) was added to a solution of compound B (600 mg) and morpholine (450 mg) in methanol (10 ml) containing 3A molecular sieves (1 g). Sodium cyanoborohydride (53 mg) was added and the mixture was stirred for 20 hours. Volatile material was removed by evaporation and the residue purified by flash chromatography, eluting with methanol/ethyl acetate (1:9 v/v). to give 2-ethyl-6-[2-(4-morpholino)ethoxy]-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A) (152 mg), m.p. 135°-137° C. (after trituration with hexane); NMR (d6 -DMSO): 1.3(t, 3H), 2.3-2.45(m, 4H), 2.6-2.8(m, 2H), 2.85(q, 2H), 3.4-3.55(m, 4H), 4.45-4.6(m, 2H), 5.4(s, 2H), 6.8-6.9(m, 6H), 7.1-7.7(complex m, 18H), 7.8(dd, 1H), 8.15(d, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:8]=1[C:9]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:10].[CH2:37]([C@@H:39]1[O:41][CH2:40]1)[Cl:38]>O1CCCC1.C(=O)(O)[O-].[Na+].O>[Cl:6][C:7]1[CH:35]=[CH:34][C:33]([CH2:40][C@H:39]([OH:41])[CH2:37][Cl:38])=[CH:32][C:8]=1[C:9]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:10]
Reactant: COc1ccc(CN(CC23CC4CC(CC(C4)C2)C3)C(=O)c2cc(I)ccc2Cl)cc1
Reactant: ClC[C@H]1CO1
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(CC23CC4CC(CC(C4)C2)C3)C(=O)c2cc(C[C@H](O)CCl)ccc2Cl)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
iso-Propylmagnesium chloride solution (2M in tetrahydrofuran, 72.9 mL) was added to a stirred solution of 2-chloro-5-iodo-N-[(4-methoxyphenyl)methyl]-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)benzamide (Example 15a) (72.87 g) in anhydrous tetrahydrofuran (1 L) at 0° C. under nitrogen. After 30 minutes, copper(I) bromide dimethylsulphide complex (0.68 g) followed by (R)-(−)epichlorohydrin (11.4 mL) were added. The mixture was warmed to 30° C. for 2 hours then diluted with saturated sodium bicarbonate solution (1 L) and water (500 mL) then extracted with ethyl acetate (2×1 L). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residual oil was dissolved in methanol (600 mL), stirred overnight and the precipitated solid filtered and dried in vacuo to give the titled compound (52.25 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=3[F:19])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].NCCC(O)=O>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])=[CH:13][C:12]=3[F:19])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reactant: O=C1CSC(=O)N1
Agent: NCCC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)c(F)c2)S1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-benzaldehyde (which was obtained in Example 59), 2,4 thiazolidinedione and β-alanine according to the procedure of Example 33 as an orange solid; mp 159–160° C.; 1H NMR (300 MHz, CDCl3) δ 7.01 (m, 1H), 7.13–7.22 (m, 2H), 7.71–7.77 (m, 1H); MS (ES) m/z: 363.3 (M−H)−.