Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]#[C:11][Si](C)(C)C)[NH:6]1)=[O:4].O[Li].O.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O1CCCC1>[Cl:19][CH2:20][C:21]([N:6]1[C@H:7]([C:10]#[CH:11])[CH2:8][CH2:9][C@H:5]1[C:3]([OH:2])=[O:4])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@@H]1CC[C@@H](C#C[Si](C)(C)C)N1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
A solution of the product from Example 19 (11.9 kg total, 308.1 g active, 1.37 mol) was concentrated to about 1240 grams and transferred to a 5-L flask. Tetrahydrofuran (1800 mL) was added and the mixture was cooled to less than 10° C. LiOH—H2O (127 g, 3.03 mol) was added over 5 minutes. After 1 hour the mixture was cooled to 0° C. and chloroacetyl chloride (339.8 g, 3.01 mol) was added over about 60 minutes. After 1.5 hours, the reaction was quenched by the addition of a 1/9 mixture of 6 M HCl and 25% aq NaCl (1.8 kg) and isopropyl acetate (1.9 L). The layers were separated and the organic layer was washed with a 1/9 mixture of 6 M HCl and 25% aq NaCl (1.1 kg). The combined aqueous layers were extracted with isopropyl acetate (2×2 L). The combined organic layers were concentrated several times from isopropyl acetate to dry and then to about 800 grams total weight. Solids had come out of solution during the concentration. Heptane (200 mL) was added slowly, causing more solid to precipitate. After stirring for 2-3 h, the mixture was filtered and the solids were washed with 1:1 isopropyl acetate/heptane (250 mL) and dried at 40° C. in a vacuum oven to give 255 g (86% yield) of white solid. The 1H NMR spectrum of the product exhibited 2 rotomers. Rotomer (a) was the major rotomer and rotomer (U) was the minor rotomer. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.07 (m, 2H) 2.08-2.30 (m, 2H) rotomer b: 3.13 (d, J=2.20 Hz, 1H) rotomer a: 3.46 (d, J=2.20 Hz, 1H) rotomer b: 4.09 (d, J=14.13 Hz, 1H) rotomer a: 4.32 (d, J=14.41 Hz, 1H) 4.21 (t, J=741 Hz, 7H) rotomer b; 4.40 (d, J=14.00 Hz, 1H) rotomer a: 4.59 (d, J=14.27 Hz, 1H) rotomer b; 4.61-467 (m, 1H) rotomer a: 4.77-4.85 (m, 1H) 12.53-12.85 (m, 1H)
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:38]([O:40][C:41](=[O:65])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[C:55](=[O:56])[CH:54]=[CH:53][C:52]([C:57]3[CH:62]=[CH:61][C:60]([CH2:63][NH2:64])=[CH:59][CH:58]=3)=[N:51]2)[CH:44]=1)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:65])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[C:55](=[O:56])[CH:54]=[CH:53][C:52]([C:57]3[CH:58]=[CH:59][C:60]([CH2:63][NH:64][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:61][CH:62]=3)=[N:51]2)[CH:44]=1)[CH3:39]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CN)cc3)ccc2=O)c1
Reactant: CC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CNC(=O)CNC(C)=O)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
61 mg (0.52 mmol) of N-acetylglycine are suspended in 2 ml of DMF, 106 μl (0.95 mmol) of 4-methylmorpholine, 66 mg (0.47 mmol) of 1-hydroxybenzotriazole and 184 mg (0.95 mmol) of N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 10 min, 180 mg (0.48 mmol) of ethyl{3-[3-(4-aminomethylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}carbamate are subsequently added, and the mixture is stirred at room temperature for 24 h.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][CH:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1cccc(C#N)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4cccc(C#N)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(3-cyano-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH2:13])[CH:6]=[CH:5]2.CCN(CC)CC.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH:13][C:21](=[O:23])[CH3:22])[CH:6]=[CH:5]2
Reactant: NCc1ccc2cc(Br)ccc2n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc2cc(Br)ccc2n1

Procedure:
To a slurry of 4b (401 mg, 1.7 mmol) in CH2Cl2 at room temperature was added NEt3 (0.47 mL, 3.4 mmol), followed by acetyl chloride (0.18 mL, 2.6 mmol). Once the reaction was complete by LCMS analysis, the mixture was concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes, followed by 10% MeOH in EtOAc) to give the desired product, 4c.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([CH2:8][NH:9]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:9][CH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:3][C@@H:2]1[OH:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CNCc2ccccc2)[C@@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@@H](O)C1

Procedure:
A mixture of intermediate (60) (0.016 mol) in methanol (150 ml) was hydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst at a temperature of 50° C. After uptake of hydrogen (1 equivalent) the catalyst was filtered off and the filtrate was evaporated, yielding 1,1-dimethylethyl(3R-trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate 61).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[OH-].[Na+].I[CH3:20]>C(O)C>[CH3:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: CI
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccc(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2

Procedure:
A suspension of 3,4-dihydro-6-hydroxy-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (prepared as described in Example 3--2.5 g.) in ethanol (125 ml.) was stirred, ethanolic sodium hydroxide (32 ml. of a 0.36 M solution) was added, and the mixture was stirred for 30 minutes. Iodomethane (1.5 ml.) was added, and the solution was heated on a steam-bath for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in a mixture of diethyl ether (100 ml.) and N sodium hydroxide solution (50 ml.). The ether layer was separated, the aqueous layer was re-extracted with ether (100 ml.), and the ether extracts were combined and dried. The solvent was evaporated, and the sticky residue was stirred for 15 minutes with petroleum ether (b.p. 60°-80°, 100 ml.). then filtered and washed with more petroleum ether to yield 3,4-dihydro-6-methoxy-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 162°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[C:37]([CH2:39][CH2:40][N:41]([CH3:51])[C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)#[N:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][C:42]([N:41]([CH2:40][CH2:39][C:37]#[N:38])[CH3:51])=[O:50])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(CCC#N)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)CCC#N)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-cyano-ethyl)-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 16d) in an analogous manner as described in example 25. LR-MS: 714.3 [(M+H)+]
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>ClCCl>[Si:16]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.3 %

Procedure:
A solution of 4-hydroxyindole (13.31 g, 75 mmol) in dry dichloromethane (400 mL) was treated with imidazole (8.17 g, 120 mmol) and t-butyldimethylsilyl chloride (18.09 g, 120 mmol) and the mixture was stirred at room temperature under nitrogen overnight. The precipitated white solid was filtered off and washed with dichloromethane and the combined filtrates were washed successively with 0.5 M aq. hydrochloric acid, 0.5 M aq. sodium hydroxide and brine, dried and evaporated to give 9 as white crystals (21.03 g, 85%), mp 80-81° C. (from hexanes); 1H NMR (500 MHz) δ 8.06 (br s, 1H), 7.08 (dd, J=3.1, 2.4 Hz, 1H), 6.99-7.05 (m, 2H), 6.58-6.59 (m, 1H), 6.52 (dd, J=7, 1.5 Hz, 1H, 1.06 (s, 9H), 0.23 (s, 6H). Anal. Calcd. for C14H21NOSi: C, 67.97; H, 8.56; N, 5.66. Found: C, 67.60; H, 8.80; N, 5.57.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][F:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH2:25][F:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: NC[C@@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CCF)C(=O)O1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CCF)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.022 ml, 0.282 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-7-fluoro-1-(2-fluoro-ethyl)-1,3-dihydro-iridol-2-one (0.080 g, 0.188 mmol) and diisopropylethylamine (0.137 ml, 0.752 mmol) in dichloromethane (2 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as an off white solid. HPLC r.t. 3.93 min; 1H NMR (300 MHz, CDCl3) 7.32 (m, 1H), 7.25 (m, 1H), 5.15 (m, 1H), 4.77 (m, 1H), 4.75 (t, J=5.1 Hz, 1H), 4.57 (t, J=4.8 Hz, 1H), 4.22 (t, J=5.1 Hz, 1H), 4.14 (t, J=4.8 Hz, 1H), 4.02 (t, J=9 Hz, 2H), 3.80 (dd, J=6.6, 9 Hz, 1H), 3.69 (s, 3H), 3.61 (s, 2H), 3.50-3.69 (m, 2H); MS for C16H17F2N3O5 m/z 370.0 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][N:22]2[C:31]3[C:26](=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[NH:25][C:24](=O)[C:23]2=[O:37])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:3][C:24]1[C:23](=[O:37])[N:22]([CH2:21][C:20]2[CH:38]=[CH:39][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:31]2[C:26]([N:25]=1)=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c(=O)n2Cc1ccc(OC)cc1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)nc(Cl)c(=O)n2Cc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
POCl3 (2 g, 13.25 mmol) and N,N-dimethylbenzenamine (2.13 g, 17.60 mmol,) were added to a solution of methyl 1-(4-methoxybenzyl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (3 g, 8.81 mmol) in toluene (100 ml). The resulting reaction was stirred overnight at 110° C. and concentrated in vacuo. The residue was triturated with methanol (50 ml) and collected by filtration to afford methyl 3-chloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a green solid (2.27 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH3:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=O)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[NH:8][C:7]3[C:6]([O:9][CH3:10])=[CH:5][CH:4]=[C:3]([CH3:11])[C:2]=3[N:1]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C)c(N)c1N
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C)c2nc(Cc3ccc(Cl)cc3)[nH]c12
Yield: 40.7 %

Procedure:
A mixture of 2,3-diamino-4-methoxytoluene [prepared by hydrogenation of 4-methoxy-2,3-dinitrotoluene (7.5 g) over 10% palladium-carbon (2.5 g) in ethanol] and 4-chlorophenylacetic acid (23 g) was heated at 130°-150° C. for 4.5 h under nitrogen. The mixture was cooled, dissolved in chloroform, washed with 10% sodium carbonate solution, then with water, dried (Na2SO4) and evaporated to dryness in vacuo. The product was recrystallized from chloroform-pentane to afford the title compound, (5.75 g), m.p. 195°-197° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17]CC)=[O:16])[C:7]([C:10]([O:12]CC)=[O:11])=[N:8][CH:9]=1)[CH:2]=[CH2:3].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:4]1[CH:5]=[C:6]([C:15]([OH:17])=[O:16])[C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cnc(C(=O)OCC)c(C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCc1cnc(C(=O)O)c(C(=O)O)c1

Procedure:
To a solution of 6.07 g of diethyl 5-allylpyridine-2,3-dicarboxylate in 20 mL of methanol, stirred under nitrogen, is added slowly a solution of 3.3 g of sodium hydroxide in 13 mL water. After diluting the reaction mixture with 10 mL each of water and methanol, it is heated at reflux for 13/4 hours. The reaction is cooled in an ice bath, acidified to pH 3 with concentrated hydrochloric acid, and concentrated in vacuo to a damp solid. This solid is reevaporated from pyridine to afford the product as a brown solid, mp>250°(dec).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)C.Cl>C(OCC)(=O)C>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH2:5][CH:4]=[O:3])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(CCc1ccc2ncccc2c1)OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: O=CCCc1ccc2ncccc2c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 6-(3,3-diethoxypropyl)quinoline (23, Method A of Example 16, 520 g , 2.08 mol, 1.0 equiv) in ethyl acetate (EtOAc, 2.2 L) was cooled to 0° C. before a 2 N aqueous hydrochloric acid (HCl) solution (2.2 L) was added over 1 h while keeping the reaction temperature below 5° C. The resulting reaction mixture was stirred for an additional 2 h at 0-5° C. When TLC and HPLC/MS indicated the reaction was complete, the reaction was quenched with an ice cold 3 N aqueous sodium hydroxide (NaOH) solution at 0° C. until the pH was between 8 to 9. The layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc, 2 L). The combined organic layers were washed with brine (2 L), dried with sodium sulfate (Na2SO4), and concentrated under the reduced pressure to afford crude 3-(quinolin-6-yl)propanal (9, 385.3 g, 385.3 g theoretical, 100%) as a yellow oil, which was found to be identical to the material obtained from Method 1 in every comparable aspect. Since this crude material was found to be sufficiently pure, it was used directly in subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
In 20 ml of methylene chloride was dissolved 1.1 g of 4-benzyloxybenzoic acid chloride, and to the solution was slowly added a solution of 0.74 g of (R)-(+)-1,1,1-trifluoro-2-octanol ([α]D20 =+25.2°), 0 4 g of triethylamine, and a catalytic amount of dimethylaminopyridine in 10 ml of methylene chloride under ice-cooling. After warming to room temperature, the solution was stirred for 12 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride phase was successively washed with diluted hydrochloric acid, water, an aqueous 1N sodium carbonate solution, and water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residual crude product was purified by silica gel column chromatography to obtain 1.0 g of 1,1,1-trifluoro-2-octyl 4-benzyloxybenzoate.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH2:15][N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1cccnc1
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: O=c1c(Br)cc(-c2ccccn2)cn1C1=CCCN(Cc2ccccc2)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
718 mg of 3-bromo-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 40 ml of acetonitrile. 383 mg of benzyl bromide was added thereto, followed by stirring at 70° C. overnight. Further, 383 mg of benzyl bromide was added thereto, followed by stirring at 70° C. for 2 nights. After cooling to room temperature, the mixture was evaporated. The residue was dissolved in 30 ml of methanol, followed by cooling to 0° C. under stirring. 265 mg of sodium borohydride was added thereto, followed by stirring overnight under heating from 0° C. to room temperature. Water was added thereto, the solvent was evaporated, and then the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 550 mg of 3-bromo-5-(2-pyridyl)-1-(1-benzyl-1,2,3,6-tetrahydropyridin-5-yl)-1,2-dihydropyridin-2-one. 270 mg of the product was dissolved in 20 ml of dimethylformamide. 179 mg of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 313 mg of cesium carbonate and 15 mg of tetrakistriphenylphosphine palladium were added thereto, followed by stirring at 120° C. for 1 hour. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 174 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C:14]#[CH:15]>O1CCOCC1>[Cl:8][C:7]1[C:2]([NH:12][CH2:13][C:14]#[CH:15])=[N:3][CH:4]=[C:5]([C:9]([OH:11])=[O:10])[N:6]=1
Reactant: C#CCN
Reactant: O=C(O)c1cnc(Cl)c(Cl)n1
Solvent: C1COCCO1
Product: C#CCNc1ncc(C(=O)O)nc1Cl

Procedure:
A mixture of 2,3-dichloropyrazine-5-carboxylic acid (19.3 g, 0.100 mole) and 3-amino-1-propyne (1.10 g, 0.20 mole) in 100 ml dioxane is refluxed for 24 hours, cooled and concentrated under vacuum. The residue is partitioned between aqueous sodium bicarbonate and chloroform and the aqueous extract neutralized with acetic acid to give a precipitate of 3-chloro-2-(2-propyn-1-ylamino)pyrazine-5-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7][C:6]=1[NH2:12])C.C(O)(=O)C.[CH:18](N)=[NH:19]>C(OCCO)C>[Cl:11][C:9]1[CH:8]=[N:7][C:6]2[N:12]=[CH:18][N:19]=[C:4]([OH:3])[C:5]=2[CH:10]=1
Reactant: CCOC(=O)c1cc(Cl)cnc1N
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCOCCO
Product: Oc1ncnc2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of 2-amino-5-chloro-nicotinic acid ethyl ester (1.5 g, 7.38 mMol) and formamidine acetate (3.1 g, 29.51 mMol) in 2-ethoxyethanol (50 mL) was heated at reflux overnight. The solution was cooled to room temperature, and allowed to stand for 2 hours. The resulting precipitate was collected by filtration, rinsed with a small amount of 2-ethoxyethanol followed by diethyl ether (10 mL), and allowed to air dry. The filtrate was concentrated in-vacuo, and the residue was triturated with methylene chloride. The resulting solids were combined with the solids from the earlier filtration, and this material was crystallized from methanol to yield 475 mg of tan needles as product, in three crops. MS (ES+)=182 (M+H)+. Yield=37%.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[C:17]1(/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CC(=O)OCCCC
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
0.38 g (2.9 mmol) of butyl acrylate and 0.30 g (2.2 mmol) of K2CO3 are added to a solution of 0.32 g (2.0 mmol) of bromobenzene in 20 ml of dimethylformamide. After the mixture has been stirred at room temperature for 5 minutes, 0.08 g (0.05 mmol) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is added, and the reaction mixture is heated under reflux for 20 hours. After cooling and addition of 100 ml of water, the reaction mixture is extracted with 100 ml of diethyl ether. The organic phase is washed with water and dried using MgSO4. After filtration and removal of the solvent (in vacuo), 0.26 g of butyl (E)-3-(phenyl)acrylate is isolated as a colourless oil. The yield is 64%, based on the bromobenzene employed.