Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH3:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[C:22]([CH3:29])[N:21]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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]>[CH2:8]([C:4]1[C:3]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[C:2]([C:24]2[CH:23]=[C:22]([CH3:29])[N:21]=[C:20]([CH3:19])[CH:25]=2)[CH:7]=[CH:6][N:5]=1)[CH3:9]
Reactant: Cc1cc(B(O)O)cc(C)n1
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
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: COCCOC
Product: CCc1nccc(-c2cc(C)nc(C)c2)c1C#Cc1ccc(N)nc1
Temperature: 190 °C
Reaction time: 5 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 100 mg (0.39 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 88 mg (0.58 mmoL) 2,6-dimethyl-pyrid-4-yl boronic acid, 18 mg (0.02 mmol) Pd2(dba)3, 28 mg (0.06 mmol) XPhos and 107 mg (0.47 mmol) K3PO4 in a mixture of 6.0 mL DME. The reaction mixture is stirred twice under microwave irradiation at 190° C. for 300 min. The reaction mixture is concentrated in vaccuo and the crude product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 17 mg (14%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:25])[C@H:11]([NH:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[Li+].[OH-].OS([O-])(=O)=O.[K+].C(OCC)(=O)C>CO.O>[CH:22]([O:21][C:19]([NH:18][C@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:25])=[O:20])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](NC(=O)OC(C)C)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A mixture of 1-[(R)-isopropoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid methyl ester (0.95 g) and 0.13 g of LiOH in 20 mL of methanol and 5 mL of water was stirred for 16 h at ambient temperature. KHSO4 was added, the volatiles were pumped off followed by addition of water, extraction with ethyl acetate and concentration of the organic layer to give 0.76 g (83%) of the title compound as a white solid. (+)-APCI-MS: 335 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22](Cl)[N:21]=1>C(O)CC(C)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:22]3[N:21]=[C:20]([NH2:19])[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=3)[CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: COC(=O)c1ncc(NC2CCNCC2)nc1N
Solvent: CC(C)CCO
Product: COC(=O)c1ncc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1N
Temperature: 120 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
Compound (38) (2.5 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (0.6 g, 2.5 mmol) in isoamyl alcohol (20 mL) at 25° C. The mixture was stirred at 120° C. for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.70 g (65%) of the title compound: TLC (Rf =0.30; 10% CH3OH/CH2Cl2); 1H NMR (DMSO) δ 7.59 (d, 1H, J=7.7), 7.41 (s, 1H), 7.22 (s, 1H), 7.15 (br s, 4H), 6.73 (s, 1H), 4.63 (d, 2H, J=13.2), 4.10 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H), 2.99 (t, 2H, J=9.8), 1.90 (d, 2H, J=10.0), 1.39 (m, 2H); 13C NMR (DMSO) δ 167.0, 31.2; HRMS (FAB) m/z 455.2143 (M+H)+ (C21H26N8O4 requires 455.2155); Anal. (C21H26N8O4 ·1/2H2O·1/2CH3OH) C, H, N.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:16][NH:17][C:18](=[O:23])[C:19]([O:21]C)=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH3:34]CO>O>[CH3:34][N:17]([CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18](=[O:23])[C:19]([OH:21])=[O:20]
Reactant: COC(=O)C(=O)NCC(C#Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(C#Cc2ccccc2)CN(C)C(=O)C(=O)O)cc1OC1CCCC1

Procedure:
A solution of (+,-)-methyl 2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenyl-but-3-ynyloxamate (100 mg, 0.24 mmol) in hot EtOH (3 ml) was treated with 2.5N NaOH (0.5 ml). The reaction was diluted with H2O, acidified with Hcl, and extracted with EtOAc. The extracts were washed with H2O, dried and the solvent evaporated. The residue was recrystallized from MeCN, and gave the titled compound, 42 mg (44%). mp 157-159°. 1H NMR (400 MHz, CDCl3 +DMSO-D6) δ 7.63 (t, 1 H), 7.45 (m, 2 H), 7.30 (m, 4 H), 6.97 (m, 2 H), 6.85 (d, 1 H), 4.79 (m, 1 H), 4.07 (t, 1 H), 3.84 (s, 3 H), 3.74 (m, 1 H), 3.62 (m, 1 H), 1.78-1.98 (m, 6 H), 1.61 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]1.[H-].[Na+].[SH:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(Cl)(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:14]1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: COc1ccc2nccc(N3CCC(OS(C)(=O)=O)C3)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nccc(N3CCC(SCCNC(=O)OC(C)(C)C)C3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
To a solution of methanesulfonic acid 1-(6-methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl ester (650 mg, 2 mmol, prepared as Example 2b) in DMF (3 mL) was added NaH (89 mg, 2.2 mmol, 65% in mineral oil) followed by 1,1-dimethylethyl (2-mercaptoethyl)carbamate (0.373 mL, 2.2 mmol). The resulting mixture was stirred at 25° C. for 12 h and then diluted with brine. Chloroform was used the extracted the aqueous solution. The organic fractions were pooled, concentrated and purified with column chromatography (silica, 10% MeOH in CDCl3 (1% NH4OH)) to afford the title compound as an off-white solid (630 mg, 78%): LC/MS m/z 405 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[C:14]([CH3:15])[N:4]2[N:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>COCCO>[CH3:15][C:14]1[N:4]2[N:3]=[C:2]([NH:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]2=[N:12][N:13]=1
Reactant: NCCN1CCCC1
Reactant: Cc1nnc2c3c(c(Cl)nn12)CCCC3
Solvent: COCCO
Solvent: O
Product: Cc1nnc2c3c(c(NCCN4CCCC4)nn12)CCCC3

Procedure:
A solution of 10.0 g of 6-chloro-3-methyl-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine and 12.8 g of 1-(2-aminoethyl)pyrrolidine in 50 ml of 2-methoxyethanol was heated at reflux for 15 hours. The reaction mixture was poured into 150 ml of cold water and the white precipitate which formed was separated by filtration and air dried to give 3-methyl-6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 184°-186° C.
Reaction SMILES: [H][H].S[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1>CO.[Au]>[C:8]([NH2:10])(=[O:9])[C:7]1[CH:11]=[CH:12][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccc(S)cc1
Reactant: [H][H]
Agent: [Au]
Solvent: CO
Product: NC(=O)c1ccccc1

Procedure:
Gold substrates were annealed in a hydrogen flame to get rid of contamination and form well ordered Au surfaces. 4-Mercaptobenzamide prepared according to Example 4 was dissolved (1 mM) in methanol and degassed using argon to avoid oxidation of thiols. The insulated tips treated substrates were immersed in this solution for >2 hours. This resulted in the formation of monolayers of benzamide on the surface. Extended functionalization times degraded insulation on the probes so treatment of probes was limited to 2 h. Functionalization of gold substrates was carried out for up to 20 hours.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][S:19](=[O:23])(=[O:22])[CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH2:30]([C:32]1[N:33]([C:2]2[N:3]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH:14]([N:16]5[CH2:17][CH2:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21]5)[CH2:15]4)[S:8][C:6]=3[N:7]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: O=S1(=O)CCN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)C2)CC1
Reactant: CCc1nc2ccccc2[nH]1
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: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCS(=O)(=O)CC4)C3)sc2n1
Temperature: 145 °C
Yield: 60.2 %

Procedure:
A mixture of 5-chloro-2-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (150 mg, 0.33 mmol), 2-ethylbenzimidazole (58 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium (15 mg, 0.02 mmol), Xphos (31 mg, 0.07 mmol) and Cs2CO3 (213 mg, 0.65 mmol) in dioxane (3 mL) was purged with argon then heated at 145° C. for 45 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording 436 as a foam (113 mg, 60%). LCMS (Method I): RT 2.59 min, [M+H]+ 569.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.79-7.75 (m, 1 H); 7.33-7.27 (m, 2 H); 4.41 (m, 4 H); 4.02 (s, 2 H); 3.91-3.81 (m, 4 H); 3.72 (m, 2 H); 3.39-3.30 (m, 3 H); 3.16 (m, 2 H); 3.08 (m, 4 H); 2.90-2.85 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([CH2:30]O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:30][CH:27]2[CH2:29][CH2:28]2)=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: OCC1CC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC2CC2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and cyclopropyl-methanol in analogy to Example 9c): MS (ISP): 450.2 and 452.0 (M+H)+, 350.2 and 352.2 ((M-Boc)+H)+ (100%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(Cl)ccc1F
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C1CC(=O)CC(c2cc(Cl)ccc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (7.4 g) was added at room temperature diethyl malonate (3.6 g), and then added little by little 4-(5-chloro-2-fluorophenyl)-3-buten-2-one (4.3 g). The mixture was stirred at room temperature for 30 minutes and then for 2 hours while heating, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (17 ml), and the mixture was refluxed for 1 hour and cooled. To the mixture was added 2.5M sulfuric acid (17 ml) for 10 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-chloro-2-fluorophenyl)cyclohexane-1,3-dione (4.1 g) as pale yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[O:19]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][N:22]([C:30]([C:32]2[N:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[S:35][CH:36]=2)=[O:31])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:27]1[CH2:28][CH2:29][C:24]2([O:19][CH2:20][CH2:21][N:22]([C:30]([C:32]3[N:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[S:35][CH:36]=3)=[O:31])[CH2:23]2)[CH2:25][CH2:26]1
Reactant: OCCc1cccc(CBr)c1
Reactant: O=C(c1csc(C(F)(F)F)n1)N1CCOC2(CCNCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1csc(C(F)(F)F)n1)N1CCOC2(CCN(Cc3cccc(CCO)c3)CC2)C1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.354 g) was added to a solution of 1-oxa-4,9-diazaspiro[5.5]undecan-4-yl(2-(trifluoromethyl)thiazol-4-yl)methanone trifluoroacetate (example 25, step a) (0.74 g) and triethylamine (0.689 mL) in acetonitrile (15 mL) and the mixture stirred at 20° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% triethylamine and 3% methanol in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.640 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:27]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:27]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C1Nc2ccc(Cl)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
N-{[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=4:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([CH:17]([CH2:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[O:42])[NH:34][N:33]=2)[CH:28]=[CH:27][C:26]=1[F:43])=[O:23])[C:18]([OH:20])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[CH2:10]([CH:17]1[CH2:21][C:22](=[O:23])[N:24]([C:25]2[CH:30]=[C:29]([CH2:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35](=[O:42])[NH:34][N:33]=3)[CH:28]=[CH:27][C:26]=2[F:43])[C:18]1=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CC(Cc1ccccc1)C(=O)O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC(Cc2ccccc2)C(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.14 g, 0.44 mmol) and diisopropylethylamine (0.097 g, 0.44 mmol) were added sequentially at ambient temperature to a stirred solution of 2-benzyl-N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]succinamic acid (0.156 g, 0.34 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 3 hours, then it was added dropwise to ice-cold water (10 ml). The mixture was stirred for 30 minutes, then the resulting solid was collected by filtration, washed with water (5 ml) and dried in vacuo to give 3-benzyl-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]pyrrolidine-2,5-dione (0.120 g) as a white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 2.6–3.4 (m 5H) (—CH2CH(CO2H)CH2Ph), 4.5 (s, 2H) (ArCH2—), 7.3–7.6 (m, 7H) (7×ArH), 7.6–7.7 (m, 1H) (ArH), 7.9–8.2 (m, 3H) (3×ArH), 8.4 (m, 1H) (ArH), 12.8 (br s, 1H) (CONH); m/z (M+H)+ 442, 96.8% purity.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([CH:12](CCCC)[C:13]([O-:15])=[O:14])[CH3:11].[Sn+2].C(C(CCCC)C([O-])=[O:25])C>>[CH2:1]([O:9][C:11](=[O:25])[CH2:10][CH2:12][C:13]([OH:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Product: CCCCCCCCOC(=O)CCC(=O)O
Temperature: 140 °C
Reaction time: 2 h
Yield: 5513 %

Procedure:
A mixture containing 4.1 g (31.5 mmol) of 1-octanol, 100 mg of tin(II) 2-ethylhexanoate and 3.0 g (30 mmol) of succinate anhydride was stirred under nitrogen at 140° C. for 2 hours. The mixture was cooled to room temperature and, the crude product was purified by column chromatography on silica gel (40% ethyl acetate in hexane) to provide 3.134 g of succinic acid mono-(1-octyl) ester (45.36%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>O.N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10](/[CH:11]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1cccc(Oc2ccccc2)c1
Temperature: 100 °C
Yield: 84.4 %

Procedure:
A mixture of 3-phenoxybenzaldehyde (214 g), malonic acid (300 g) and pyridine (450 cm3) was heated at 50° C. until all the malonic acid had dissolved, after which piperidine (20 cm3) was added and the mixture heated at 100° C. for 3 hours. The mixture was poured into iced water (3.0 l) and acidified with concentrated hydrochloric acid (600 cm3). The precipitated solid was collected by filtration, washed with water and then dissolved in chloroform. The chloroform solution was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate, after which the solvent was removed by evaporation under reduced pressure to give a solid residue which was recrystallised from a chloroform-hexane mixture to give E-3-(3-phenoxyphenyl)propenoic acid (219 g) as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]#[N:24])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25](I)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.O>[C:9]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]#[N:24])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC1CCCCN1C(=O)c1ccccc1
Reactant: ICCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CCc2ccccc2)CCCCN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 200 ml of a solution of lithium diisopropylamide (140 mmol) in tetrahydrofuran was added 15 g of solid 1-benzoyl-2-piperidinecarbonitrile at -78° C. and the mixture was stirred for 30 minutes. Then, 100 ml of a solution of 33.2 g of phenethyl iodide in tetrahydrofuran was added dropwise at -78° C. After completion of dropwise addition, the temperature of the reaction mixture was gradually increased to 0° C. The reaction mixture was diluted with water and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The pooled organic layer was dried over magnesium sulfate and filtered and the solvent was distilled off. The group was purified by silica gel column chromatography using ethyl acetate-hexane (1:2) as the eluent. The active fraction was concentrated under reduced pressure and the solid group was recrystallized from ethyl acetate-hexane to provide 17.3 g of colorless crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH2:13].[Cl-].[Li+]>C1(C)C=CC=CC=1.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>[CH2:13]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1)[CH:12]=[CH2:11]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(Cl)c1

Procedure:
A mixture of 4-bromo-2-chlorobenzonitrile (22 mg, 1.0 mmol), allyl tri-n-butylstannane (400 mg, 1.2 mmol), lithium chloride (126 mg, 3.0 mmol), and Pd(PPh3)4, (18 mg, 0.04 mmol) in toluene (10 mL), was refluxed overnight. Then the reaction was quenched with aq. KF (10 mL), extracted with ethyl acetate (10 mL×3), dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography to give the title product.
Reaction SMILES: [C:1]1([CH2:7][N:8](CC2C=CC=CC=2)[CH2:9][CH2:10][N:11]([CH2:25][CH2:26][CH3:27])[C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>CO.[Pd]>[ClH:35].[C:1]1([CH2:7][NH:8][CH2:9][CH2:10][N:11]([CH2:25][CH2:26][CH3:27])[C:12](=[O:24])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN(CCN(Cc1ccccc1)Cc1ccccc1)C(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCN(CCNCc1ccccc1)C(=O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 1.25 h

Procedure:
To a solution of 13.09 g (27.3 mmol) N-[2-[bis(phenylmethyl)amino]ethyl]-N-propyl-4-[(methylsulfonyl)amino]benzamide in 75 mL 80% aqueous methanol is added 27.3 mL 1 N HCl and 1.6 g 10% palladium on charcoal. The solution is hydrogenated at 50 psi for 75 minutes. After this time, the reaction mixture is diluted with 100 mL methanol, filtered and the solvents are evaporated to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].Cl>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2,6-dimethyl-3-nitrobenzoic acid (3.09 g) in tetrahydrofuran (5 ml) was added borane-methyl sulfide complex (2.41 g) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature, for 1 hour at ambient temperature, and then for 4 hours under heating. To the mixture was added 1N hydrochloric acid under ice-cooling, and the mixture was allowed to stand overnight. The mixture was extracted with ethyl acetate twice, and the combined organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue was recrystallized with diisopropyl ether to give 2,6-dimethyl-3-nitrobenzyl alcohol (2.296 g) as a pale yellow crystal.