Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1[C:7]#[C:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:8]#[CH:7])(=[O:22])=[O:21]
Reactant: OCCC#Cc1ccccn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCOS(C)(=O)=O
Temperature: 4 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 4-(pyridin-2-yl)but-3-yn-1-ol (3.60 g, 24 mmol) in dry methylene chloride (30 mL) was added triethylamine (4.40 mL, 32 mmol). The mixture was cooled at 4° C. and methanesulfonyl chloride (2.50 mL, 32 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was then poured over ice/water (100 mL) and stirred for 5 min. To this mixture was added saturated aqueous sodium bicarbonate solution (50 mL) chilled to 4° C., and the mixture was stirred for 30 min, then extracted with DCM. The combined organic fractions were dried over MgSO4, filtered and concentrated under pressure to afford 4.60 g of 4-pyridin-2-yl)but-3-ynyl methanesulfonate (Yield: 83%) as a brown oil which can be used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[Na].O.C(O)(=O)C.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1nc(N)nc(Cl)c1[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(N)nc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Amino-4-chloro-6-methyl-5-nitropyrimidine (Boon et al., J. Chem. Soc., 96-102 (1951)) (1.24 g, 6.58 mmol) was added to a solution of sodium (0.21 g, 9.13 mmol) in benzyl alcohol (14 mL) under argon. The solution was heated in a 135° C. oil bath for 3.5 h, and was poured into water (70 mL) with constant stirring for 10 min. After neutralization with glacial acetic acid, a yellow precipitate formed which was collected by filtration and washed with water. This solid was crystallized from benzene to give 5b as a bright yellow crystalline solid: yield, 0.57 g (33%); mp 159°-160° C.; UV (pH 1) λmax 268 nm (ε=0.783×104), 345 (sh) (0.104×104); (pH 6.9) 282 (0.564×104), 345 (sh) (0.338×104); (pH 13) 282 (0.549×104), 345 (sh) (0.332×104); 1H NMR δ2.35 (s, 3H, CH3), 5.44 (s, 2 H, ArCH2), 7.34-7.46 (m, 5H, ArH), 7.64 (b s, 2H, NH2, exchange with D2O); MS (EI) calcd. m/z for C12H12N4O3 260.0908, found 260.0913; Anal.(C12H12N4O3) C, H, N.
Reaction SMILES: Cl[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:13][C:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)([CH3:17])[CH2:15][OH:16]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].O>[CH3:17][C:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)([CH3:13])[CH2:15][OH:16]
Reactant: CC(C)(CO)Oc1ccc(-c2ccccc2)cc1
Reactant: ClN1CCCCC1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)(CO)Oc1ccc(-c2ccc(N3CCCCC3)cc2)cc1
Reaction time: 0.25 h

Procedure:
Under agitation, a solution of 12 g. of N-chloropiperidine in 15 ml. of concentrated sulfuric acid is added dropwise within 10 minutes to a mixture of 24.2 g. of 2-methyl-2-(4-phenylphenoxy)-propanol (obtainable from 4-hydroxy-diphenyl and 2-bromo-2-methylpropanol), 7 g. of iron(II) sulfate heptahydrate, 8 ml. of concentrated sulfuric acid, and 3 ml. of water. The mixture is agitated for 15 minutes at 20°, then poured on ice water, washed with ether, made alkaline with sodium hydroxide solution, and extracted with chloroform. From the extract, after evaporation, one obtains 2-methyl-2-[4-(4-piperidinophenyl)-phenoxy]-propanol, m.p. 158°-160°.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[Br:20]C1C(OC)=C(C=CC=1)C=O>>[Br:20][C:4]1[C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:2][CH:3]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1c(Br)cccc1C=O
Product: COc1c(Br)cccc1C(O)C#Cc1ccccc1
Yield: 92 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 3-bromo-2-methoxy-benzaldehyde was reacted to give the title compound as an oil (3.70 g, 92%).
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C@@H:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12].Br[CH2:15][C:16]([OH:18])=[O:17]>C1COCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]([CH2:9][CH2:10][CH2:11][CH3:12])[O:13][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCC[C@H](O)c1ccco1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(OCC(=O)O)c1ccco1
Temperature: 0 °C

Procedure:
NaH (16.3 g, 680.9 mmol) and freshly distilled THF (170 mL) were stirred at room temperature as (S)-1-(2-furyl)-1-pentanol ([α]25D -17.2°, 30.0 g, 46.0 mmol) in THF (170 mL) was added dropwise. After the addition was complete, the mixture was stirred for 15 m before cautiously heating to reflux for 1 h. The mixture was cooled to 0° C. before adding dropwise a solution of bromoacetic acid (27.3 g, 196.5 mmol) in THF (40 mL). The mixture was refluxed 2 days before cooling and carefully pouring into 600 mL ice water. The aqueous was washed with ether and acidified with HCl to pH 4, and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to give a quantitative yield of crude product which was used in the next step without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:15][C@@H:14]2[CH2:16][N:17]([C:19]3[N:24]=[N:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:32]=[N:33][NH:34][CH:35]=5)=[CH:27][C:26]=4[OH:36])=[CH:21][CH:20]=3)[CH2:18][C@@H:13]2[CH2:12]1)(C(C)(C)C)(C)C.Cl.N>O1CCOCC1.CO>[OH:8][CH2:9][CH2:10][N:11]1[CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[N:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:35]=[N:34][NH:33][CH:32]=5)=[CH:27][C:26]=4[OH:36])=[CH:21][CH:20]=3)[CH2:16][C@@H:14]2[CH2:15]1
Reactant: CC(C)(C)[Si](C)(C)OCCN1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: OCCN1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 2-(6-((3aR,6aS)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (20 mg, 0.039 mmol) in dioxane (2 mL) was added 4N HCl in dioxane (1 mL, 4.00 mmol). The reaction mixture was stirred at RT overnight, then basified with 2N NH3 in MeOH and concentrated. The crude product was purified via preparative HPLC to give an off-white solid 2-(6-((3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (6.5 mg, 0.016 mmol, 41% yield). LCMS Rt=0.87 min [Method Q]; MS (M+1)=393.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.01 (d, J=9.60 Hz, 1H), 7.93 (s, 2H), 7.69 (d, J=8.08 Hz, 1H), 7.08-7.19 (m, 3H), 3.67-3.77 (m, 4H), 3.56 (d, J=11.12 Hz, 2H), 3.11 (br. s., 2H), 2.97-3.05 (m, 2H), 2.72 (t, J=5.81 Hz, 2H), 2.63-2.70 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[NH2:24])[CH:18]=[CH:19][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:24][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=3)[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: CN(C)Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I

Procedure:
3-Iodo-4-methylbenzoyl chloride (2.2 g, 7.88 mmol), dissolved in anhydrous THF (13 mL), was added dropwise to a solution of 3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.5 g, 5.5 mmol), DIPEA (2.1 mL, 11.8 mmol) in THF (30 mL) at ˜5° C. The resultant solution was stirred at ambient temperature overnight. The solvent was removed in vacuo and the crude residue was redissolved in CH2Cl2 and washed with 1N NaOH. The organic layer was then washed with water, and brine then dried over NaSO4 before being concentrated in vacuo. The brown colored residue was then triturated in a mixture of hexanes/DCM to precipitate 1.4 g of the desired product as an off-white powder: 529 m/z (M+H).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(=[O:19])C.[K+].C(O)(=O)C>O>[CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:19])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCc1ccc(CCl)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(CO)cc1
Yield: 53.4 %

Procedure:
A mixture of 16.2 g (68 mMols) of 4-octylbenzyl chloride, 41,8 g (0.43 mols) of potassium acetate and 200 ml of glacial acetic acid was heated for 20 h to 130° C. After cooling, the mixture was poured into approximately 1 liter of water and the aqueous phase was extracted with tert.-butyl methyl ether. The organic phase was washed twice with water, repeatedly with potassium hydrogen carbonate solution (2N) and then with saturated sodium chloride solution. After the solvent had been distilled off, the residue was taken up in 160 ml of 1,2-dimethoxyethane and, after the addition of 64 g of sodium hydroxide in 130 ml of water, the solution was heated for 45 h to boiling point. After the solvent had been distilled off, the residue was extracted with tert.-butyl methyl ether, the ether phase was washed with water, the solvent was distilled off, the residue was taken up in petroleum ether and the solution was reconcentrated by evaporation after treatment with active carbon and fuller's earth. Fractionation under reduced pressure produced 8 g (54% of theoretical) of 4-octylbenzyl alcohol boiling at 128° C./0.11 mbar and having a refractive index n of 1.5033.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O1CCCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 200 ml tetrahydrofuran were added dropwise 35 ml (315 mmol) 1-methylpiperazine within 10 min. The reaction mixture was refluxed for additional 1.5 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 27.9 g (quantitative) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:41]=[CH:40][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:7][CH:6]=1)(O)=O.[NH:42]1[CH2:45][CH2:44][CH2:43]1>>[N:42]1([CH2:1][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=3[C@@H:23]3[CH2:32][CH2:31][C:30]4[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=4[CH2:24]3)=[CH:40][CH:41]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: C1CNC1
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Product: COc1cc(NCCCc2ccc(CCN3CCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 19.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and azetidine (10 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.3 mg) was obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][C@@H:21]1[CH3:27])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]([N:20]1[CH2:25][CH2:24][C@@H:23]([O:26][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:39][CH:38]=2)[CH2:22][C@@H:21]1[CH3:27])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C

Procedure:
With stirring, a solution of 2 ml (0.012 mol) of diethyl azodicarboxylate (93%) in 10 ml of toluene is added dropwise at 5°-10° C. to a suspension of 2.15 g (0.01 mol) of cis-N-BOC-2-methyl-4-hydroxypiperidine (cf. Example 1b), 2.0 g (0.012 mol) of 4-nitrobenzoic acid and 3.15 g (0.012 mol) of triphenylphosphine in 30 ml of toluene. The reaction mixture is further stirred for 15 hours at room temperature and then filtered to remove precipitated diethyl hydrazinedicarboxylate. The filtrate is then concentrated under vacuum and the oily residue is purified by flash chromatography over silica gel using ethyl acetate:hexane (1:5). Concentration of the fractions containing the product gives the title compound as a crystalline residue which melts at 106°-108° C.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([Cl:20])=[N:15][N:14]=[C:13]3Cl)=[O:9])[CH:2]=1.[OH-].[Na+].[O:25]1CCOCC1.Cl>O>[C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([Cl:20])=[N:15][NH:14][C:13]3=[O:25])=[O:9])[CH:2]=1
Reactant: Cc1cccc(NC(=O)c2ccc3c(Cl)nnc(Cl)c3c2)c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(NC(=O)c2ccc3c(Cl)n[nH]c(=O)c3c2)c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid m-tolylamide (350 mg, 0.87 mmol), 2N NaOH (4.4 mL, 8.70 mmol) and dioxane (4 mL) was heated to 50° C. for 3 h. The reaction was diluted with water, acidified with conc. HCl to ˜pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid m-tolylamide (8 mg) as a pale yellow solid, 1H NMR (400 MHz, d6-DMSO) δ: 2.32 (s, 3H), 7.96 (d, 1H), 7.26 (t, 1H), 7.60 (d, 1H), 7.65 (s, 1H), 8.14 (d, 1H), 8.52 (dd, 1H), 8.87 (s, 1H), 10.67 (s, 1H), 13.00 (bs, 1H) ppm; m/z (M−1) 312.13; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid m-tolylamide (23 mg) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ: 2.11 (s, 3H), 6.76 (m, 1H), 7.05 (m, 1H), 7.40 (m, 2H), 8.25 (m, 3H), 10.42 (s, 1H), 12.80 (s, 1H) ppm; m/z (M−1) 312.13.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CO[CH2:29][CH2:30]OC>O.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>[CH:29]([C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:16]=1[N:15]=[C:14]([O:17][CH3:18])[CH:13]=[CH:12]2)=[CH2:30]
Reactant: COCCOC
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
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: [K+]
Solvent: O
Product: C=Cc1ccnc2ccc(OC)nc12
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate (from Prep. 2b) (5.0 g, 16.23 mmol) in DME (80 mL) and H2O (40 mL) was added trivinyl boronate (1.96 g, 8.1 mmol), K2CO3 (2.23 g, 16.23 mmol) and Pd(PPh3)4 (0.19 g, 0.16 mmol). After 3 h at 90° C. under N2, the reaction solution was concentrated under vacuum and purified on silica (hexane/EtOAc, 4:1) to give the title compound as a yellow oil (2.44 g, 81%): LC/MS (m/z) (ES) 187 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:25])=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2C)cc1

Procedure:
The title compound was prepared from 2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylic acid (D13) by stirring a DMF solution together with iodomethane and potassium carbonate for 3 hours, followed by dilution with water and extraction into ethyl acetate.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33])=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C(Cl)Cl.Cl>[CH3:2][N:3]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1)[OH:4]
Reactant: CCCCCCOc1ccc(CCCCCCCCC(=O)Cl)cc1
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCOc1ccc(CCCCCCCCC(=O)N(C)O)cc1
Yield: 48.5 %

Procedure:
To a cold, stirring suspension of 0.6 gm of N-methyl hydroxylamine hydrochloride and 0.7 gms sodium carbonate in 15 ml CH2Cl2 was added dropwise 2 gms 9(4-hexyloxyphenyl)nonanoyl chloride. The resulting mixture was stirred in the cold for 1/2 hr, then 0.9 ml water was added and the reaction stirred at room temperature for 22 hr. 100 ml CH2Cl2 and 40 ml water was added, and the pH of the aqueous layer was adjusted to 3-4 with a few drops of conc. HCl. The organic layers were separated and the aqueous layer was 3×20 ml CH2Cl2 extracted. The combined organic extracts were washed with water and NaCl solution, and dried over MgSO4. The drying agent was filtered off, the solvent was evaporated in vacuo, and the residue was purified by column chromatography on silica gel in chloroform. The major component had R=0.2. The fractions containing product (as determined by thin layer chromatography) were combined, evaporated in vacuo and the resulting solid recrystallized from hexanes to give 1.0 gm product of m.p. 59°-61°. Elemental analysis calculated C 72.69, H 10.26, N 3.85, O 13.2% found C 72.54, N 10.46, N 3.98%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C)[C:11](Cl)=[CH:10][C:9]=1[NH:16][C:17](=[O:42])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[C:31]([CH2:33][O:34]C3CCCCO3)[N:30]=[C:29]([CH3:41])[CH:28]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[CH2:51]([Cl:53])Cl>>[Cl:53][C:51]1[C:12]([CH3:11])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[C:29]([CH3:41])[N:30]=[C:31]([CH2:33][OH:34])[CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:42])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-methyl-2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M297) (0.45 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (200 mg, 67%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].O>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Cl)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A mixture of 2-bromo-4-chloro-1-methoxybenzene (1 g, 4.5 mmol), CuI (43 mg, 0.23 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.23 mmol) in NEt3 (10 mL) was degassed, Then ethynyltrimethylsilane (0.5 g, 5 mmol) was added to the solution, the mixture was stirred at 80° C. for 6 hours. Then the mixture was cooled to 25° C., and added to H2O (50 mL). The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=10:1) to provide the product of ((5-chloro-2-methoxyphenyl)ethynyl)trimethylsilane (1 g, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 7.40 (s, 1H), 7.21˜7.23 (m, 1H), 6.76˜6.78 (d, J=9.2 Hz, 1H), 3.86 (s, 3H), 0.26 (s, 9H). MS (M+H)+: 239/241
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH2:17][CH3:18]
Reactant: CCCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added bromopropane (7.2 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-propoxybenzene (10.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:11][CH:10]=3.[O:29]1[CH2:34][CH:33]=[C:32](B(O)O)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[O:29]1[CH2:30][CH:31]=[C:32]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@:15]5([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:22]2[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:11][CH:10]=4)[CH2:33][CH2:34]1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)C1=CCOCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(C3=CCOCC3)cc12
Temperature: 110 °C
Yield: 92.9 %

Procedure:
A vial was charged with and (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (79.05 mg, 0.199 mmol), 3,6-dihydro-2H-pyran-4-ylboronic acid (76 mg, 0.598 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.05 mg, 9.96 μmol), and potassium phosphate (127 mg, 0.598 mmol). Dioxane (747 μL) and water (249 μL) were added, and the vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (82.18 mg) as a yellow solid.