Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[NH2:28][C:24]1[CH:23]=[C:22]([C:2]2[S:10][C:9]3[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=3[CH:3]=2)[CH:27]=[CH:26][N:25]=1
Reactant: CC1(C)OB(c2ccnc(N)c2)OC1(C)C
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2sc(-c3ccnc(N)c3)cc2N1

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.039 g, 0.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.022 g, 0.10 mmol), 2 M sodium carbonate (0.075 mL, 0.15 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.024 g, 0.030 mmol) in 1,4-dioxane (0.5 mL) was microwave-irradiated at 140° C. for 1 h. Reactions were repeated on 0.10 mmol and 0.20 mmol scales (based on the boronic ester). The reaction mixtures were combined, and concentrated with silica gel (10 mL), and the residue was purified by flash chromatography (silica gel, ethyl acetate to 90:10 ethyl acetate/methanol) to give a crude product as a yellow solid, which was further purified by preparative HPLC. Preparative HPLC was carried out on a Varian Prostar 210 HPLC system using a Phenomenex Luna C18(2) column with UV detection at 254 nm and a solvent gradient of 95:5 solvent A/solvent B to 5:95 solvent A/solvent B (solvent A=water with 0.1% v/v trifluoroacetic acid; solvent B=acetonitrile with 0.1% v/v trifluoroacetic acid). Upon concentration, a TFA salt was obtained, which was dissolved in methanol (10 mL), and the solution was concentrated with NaHCO3 (0.2 g) and silica gel (1 mL). Flash chromatography (silica gel, dichloromethane to 85:15 dichloromethane/methanol) gave the title compound (0.012 g, 11%) as a yellow solid:
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:7][CH:6]=1.[C:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[C:23]([CH3:25])=[CH2:24].N12CCCN=C1CCCCC2>CN(C=O)C>[C:28]([O:27][C:22](=[O:26])[CH:23]([CH3:25])[CH2:24][N:13]1[CH2:14][CH2:15][O:16][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:2]=3[CH3:1])=[CH:10][CH:9]=2)[CH2:12]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: Cc1cccc(Oc2ccc(C3CNCCO3)cc2)c1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc(C3CN(CC(C)C(=O)OC(C)(C)C)CCO3)cc2)c1C
Temperature: 140 °C
Yield: 33.4 %

Procedure:
A mixture of 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine (0.60 g; 1.9 mmol), tert-butyl methacrylate (0.61 ml; 3.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.84 ml; 5.6 mmol), and DMF (10 mL) was heated at 140° C., overnight, in a closed vessel. After cooling to room temperature, the mixture was partitioned between 5% aqueous NaHCO3 and EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:9) to afford 3-{2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholin-4-yl}-2-methyl-propionic acid tert-butyl ester (0.27 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:12]([C:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1noc(C)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1CO
Yield: 95.7 %

Procedure:
To a stirred solution of 3-butyl-5-methyl-isoxazole-4-carboxylic acid ethyl ester (9.8 g, 46.3 mmol) in THF (100 mL) under argon and at 0° C. was added lithiumaluminiumhydride (2.03 g, 53.4 mmol) in five portions. After 1 h the reaction mixture was quenched dropwise with Seignette salt solution. The reaction mixture was filtered and the filtrate extracted with ethyl acetate. The combined organic extracts were washed with Seignette salt solution then dried, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 4:6) afforded the title compound (7.5 g, 95%) as a yellow liquid. MS: m/e=170.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:25]=4[F:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(c2ccc(CS(C)(=O)=O)cc2F)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4F)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-(2-fluoro-4-methanesulfonylmethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane following a procedure analogous to that described for Intermediate 7. LC (method 6): tR=1.61 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C>CN(C)C=O>[C:13]([O:17][C:18]([NH:20][C@@H:21]1[C:22](=[O:23])[NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][CH2:25]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reaction time: 18 h
Yield: 71.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.54 g, 44.5 mmol) was added to a cooled (0° C.) solution of 2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid (11.95 g, 40.5 mmol) in 100 ml of dimethylformamide and stirred for 18 hours. The reaction was poured into 700 ml of ethyl acetate and washed four times with 100 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a brown solid that was purified by flash chromatography eluting with 3:7 ethyl acetate/hexane to give 8 g (71%) of the title compound: 1H NMR (CDCl3) δ7.78 (1H, s), 7.02-6.95 (1H, m), 6.88-6.82 (1H, m), 6.82-6.78 (1H, m), 6.75-6.70 (1H, m), 5.8-5.7 (1H, d), 4.55-4.45 (1H, m), 3.95 (1H, s), 3.9-3.82 (1H, m), 3.48-3.40 (1H,m), 1.45 (9H,s).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14])([O-:9])=[O:8]>O1CCCC1>[C:2]([O:4][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)([CH3:5])([CH3:3])[CH3:1]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 63.5 %

Procedure:
Potassium t-butoxide solid (3.82 g, 32.30 mmol) was added to a solution of 3-nitrobenzoyl chloride (5.00 g, 26.94 mmol) in dry tetrahydrofuran (70 mL) and stirred under nitrogen for 2 hrs. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. After separating the phases, the aqueous layer was back-extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo. The crude product was purified on flash grade silica gel using 0-5% gradient of ethyl acetate in n-hexane. Fractions containing the product were combined, concentrated in vacuo, and then dried under high vacuum to provide 3.82 g of the title compound as an oil. 1H NMR (300 MHz, CDCl3) d 8.79 (m, 1H), 8.35 (m, 2H), 7.62 (m, 1H), 1.63 (s, 9H); low resolution MS (Cl) m/e 224 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:32])/[CH:5]=[C:6](\[CH3:31])/[CH:7]=[CH:8]/[C:9](/[F:30])=[C:10](\[C:12]1[CH:13]=[C:14]([CH:27]([CH3:29])[CH3:28])[CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:18][C:17]2([CH3:26])[CH3:25])/[CH3:11])C.[OH-].[Na+]>>[F:30]/[C:9](=[C:10](/[C:12]1[CH:13]=[C:14]([CH:27]([CH3:28])[CH3:29])[CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:18][C:17]2([CH3:26])[CH3:25])\[CH3:11])/[CH:8]=[CH:7]/[C:6](/[CH3:31])=[CH:5]/[C:4]([OH:32])=[O:3]
Reactant: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)c21
Agent: [Na+]
Agent: [OH-]
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(F)\C=C\C(C)=C\C(=O)O)c21

Procedure:
Following General Procedure I, (2E,4E,6E)-7-(1-n-propyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Compound 26, 830 mg, 1.88 mmol) was hydrolyzed with NaOH to yield the title compound as a yellow solid after purification by column chromatography (silica, first using 100% hexane, followed by 5:95 ethyl acetate:hexane, then 1:1 ethyl acetate:hexane) to yield a yellow oil. The resulting yellow oil was recrystallized from acetonitrile.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:35](Cl)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Reactant: CC(C)CC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)CC(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3-(isovaleryloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[S:12](=[O:22])(=[O:21])[C:11]=2[CH:23]=1)#[N:6].[N-:24]=[N+:25]=[N-:26].[Na+].Cl>O1CCCC1>[NH:24]1[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:16][CH2:15][C:14]4[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=4[S:12](=[O:21])(=[O:22])[C:11]=3[CH:23]=2)=[N:6][N:26]=[N:25]1
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1CC2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=S1(=O)c2ccccc2CCc2ccc(-c3nnn[nH]3)cc21

Procedure:
To 9 cc. tetrahydrofuran, cooled in an ice bath, is added in the following order 862 mg. aluminum chloride, 792 mg. 3-cyano-10,11-dihydrodibenzo[b,f]thiepin-5,5-dioxide, and 839 mg. sodium azide. The mixture is refluxed for six hours, cooled down, treated with 3 cc. 15% aqueous hydrochloric acid. The organic solvent is decanted and the residue triturated several times with ethyl acetate. The combined organic phases are washed with water, then extracted with aqueous sodium bicarbonate solution. The aqueous layer is acidified with hydrochloric acid and the precipitated tetrazole is filtered, washed with water, and dried, yield 580 mg. (63%), m.p. 233° C. dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[F:13][C:14]([F:28])([F:27])[C:15]1[N:20]=[CH:19][C:18]([C:21]2([CH:25]=[O:26])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.CCOC(C)=O>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:25]([C:21]1([C:18]2[CH:19]=[N:20][C:15]([C:14]([F:28])([F:13])[F:27])=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22]1)[OH:26]
Reactant: Brc1ccccn1
Reactant: O=CC1(c2ccc(C(F)(F)F)nc2)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccccn1)C1(c2ccc(C(F)(F)F)nc2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 4.6 %

Procedure:
To solution of 2-bromopyridine (506 mg, 3.2 mmol) in THF (10 mL) was added dropwise n-BuLi (2.4 mL, 3.84 mmol, 1.6 M) at −78° C. under nitrogen. After stirring for 30 minutes at −78° C., a solution of Example 85F (733 mg, 3.2 mmol) was added and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was allowed to warm up to room temperature, quenched with water (20 mL), extracted with dichloromethane (30 mL×2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC eluting with petroleum ether:EtOAc=2:1 to provide the title compound (45 mg, 4.6% yield) as a white solid. LC-MS: m/z 309.1 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J=4.4 Hz, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.57-7.61 (m, 1H), 7.46-7.49 (d, J=8.0 Hz, 1H), 7.34-7.39 (m, 1H), 7.14-7.17 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 5.05 (s, 1H), 4.51 (brs, 1H), 2.70-2.814 (m, 2H), 2.34-2.43 (m, 2H), 1.90-2.16 (m, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1cc(F)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Product: O=C(O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 185, Step 1, using the following starting materials: 3-fluoro-5-(trifluoromethyl)phenylacetic acid and benzyl alcohol.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CO.C[O-].[Na+].[C:11]([NH:14][C:15]1[S:16][C:17]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[C:18]([CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=2)[N:19]=1)(=[O:13])[CH3:12]>CN(C=O)C>[C:11]([NH:14][C:15]1[S:16][C:17]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[C:18]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:4][C:3]([NH2:5])=[NH:2])=[O:27])=[CH:30][CH:31]=2)[N:19]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)c1ccc(CCc2nc(NC(C)=O)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(C(=O)NC(=N)N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
Guanidine hydrochloride (152 mg) was dissolved in DMF (3 ml), and then 28% sodium methoxide methanol solution (0.3 ml) was added to the solution at r.t. The suspension was stirred at r.t. for 15 minutes, and methyl 4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)benzoate (150 mg) was added to the mixture at r.t. The reaction mixture was stirred at r.t. for 14 hours, and concentrated in vacuo. The residue was dissolved in water, and neutralized with 1N—HCl. The precipitate was collected through filtration, and purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The solid was washed with ethyl ether to give 4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)-N-[amino(imino)methyl]benzamide (36.6 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)=[N:15][CH:16]=1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Reactant: Nc1ccc(Cl)cn1
Product: Cc1ccc2ccnc(Nc3ccc(Cl)cn3)c2n1

Procedure:
The title compound, MS: m/e=271.3 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 2-amino-5-chloropyridine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:23](OCC)[O:24]CC)=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:23]=[O:24])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1cccs1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccs1
Temperature: 25 °C

Procedure:
To a solution of diethyl 2-methyl-4-(2-thienyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (424 mg) in acetone (15 ml) was added 6N-hydrochloric acid (0.2 ml) and this solution was stirred at room temperature for an hour. The resultant solution was concentrated and the residue was extracted with diethyl ether. The extract was washed with water and dried and then the solvent was removed to give yellowish oil of diethyl 2-methyl-4-(2-thienyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate, which was soon crystallized. The product was recrystallized from a mixture of n-hexane and diethyl ether to give the pure product (247.7 mg), m.p. 67° to 68.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1.BrC[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:1][O:2][C:3](=[O:13])[C:4]2[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=2)=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(C(=O)OCC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 25 ml round flask, 2.0 g (11.1 mmol) of isophtalic acid monomethyl ester and 2.6 g (11.1 mmol) 2-bromo-1-(4-chloro-phenyl)-ethanone are dissolved in 10 ml of DMF followed by addition of 3.1 g (22.2 mmol, 2.0 eq.) of K2CO3. After stirring the suspension 2 h at room temperature, the solvent is removed in vacuo and the residue taken up in CH2Cl2. The organic phase is washed with aqueous NaHCO3 (5%) and the phases separated. The organic layer is dried (Na2SO4) and concentrated to yield the title compound which is used for the next step without further purification. Mass spectrum: m/z (M+H+NH3)+: 198.0
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([O:22][CH3:23])=[N:16][C:17](F)=[CH:18]3)[N:13]=2)(=[O:11])=[O:10])=[C:6]([O:24][CH3:25])[CH:5]=[CH:4][N:3]=1.C[O-].[K+].[C:29](O)(=[O:31])C>CS(C)=O.CO.ClCCl>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([O:22][CH3:23])=[N:16][C:17]([O:31][CH3:29])=[CH:18]3)[N:13]=2)(=[O:11])=[O:10])=[C:6]([O:24][CH3:25])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)O
Reactant: COc1ccnc(Cl)c1NS(=O)(=O)c1nc2cc(F)nc(OC)n2n1
Agent: C[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc2nc(S(=O)(=O)Nc3c(OC)ccnc3Cl)nn2c(OC)n1

Procedure:
To a solution of 0.60 g (1.5 mmol) of N-(2-chloro-4-methoxy-3-pyridinyl)-7-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine-2-sulfonamide in 20 mL of dimethyl sulfoxide was added with stirring 0.24 g (3.4 mmol) of potassium methoxide in 2.4 mL of dry methanol. After 1 hour 5 mL of acetic acid was added and the solution taken up in 400 mL of dichloromethane. The resulting solution was washed with water (6×150 mL), dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 270 mg (20 percent of theory) of the title compound as a white solid melting at 197°-199° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.P.[CH2:16]([O:18][C:19](=[O:22])[CH:20]=[CH2:21])[CH3:17]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:16]([O:18][C:19](=[O:22])[CH:20]=[CH:21][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[CH3:17]
Reactant: Fc1ccc(-c2ccc(Br)cn2)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(-c2ccc(F)cc2)nc1
Temperature: 90 °C

Procedure:
9.30 g (36.9 mmol) of 5-bromo-2-(4-fluoro-phenyl)-pyridine were mixed with 100 ml of triethylamine, 2.06 g (9.2 mmol) of palladium acetate, 2.80 g (9.2 mmol) of tri)ortho-tolyl)phosphine and 6.47 g (64.6 mmol) of acrylic acid ethyl ester and heated to 90° C. for 2 h. The reaction mixture was evaporated, taken up in water and extracted with ethyl acetate. The combined organic phases were dried and evaporated, and the residue was subjected to column chromatography (silica gel, n-heptane/ethyl acetate 3:1). Yield: 7.7 g.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Cl.[H][H]>[Ru].C(O)C>[OH:4][C@H:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C)=O
Agent: [Ru]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C[C@@H](C)O
Temperature: 80 °C
Reaction time: 19 h

Procedure:
30 g of ethyl acetoacetate, 5 ml of degassed ethanol and 0.9 ml of 1 N HCl are introduced in succession into a Schlenk vessel filled with argon. This solution and the catalyst solution from Example C1 are then transferred in succession by means of a steel capillary into a 50 ml steel autoclave filled with argon. The s/c (substrate/catalyst) ratio is 75 000. The autoclave is closed and a pressure of 50 bar is set using 4 flushing cycles (pressurization with 20 bar of hydrogen). The autoclave is then heated to 80° C., and after 30 minutes the reaction pressure is set to 80 bar. The autoclave is stirred for 19 hours. The heating is subsequently switched off and the autoclave is cooled to room temperature. After depressurization, a reddish reaction solution is isolated. The conversion is >98% (determined by means of GC and 1H-NMR). Removal of the solvent on a rotary evaporator gives a quantitative yield of ethyl (R)-3-hydroxybutyrate having an enantiomeric purity of 97.1% ee. (determined by means of GC after reaction with trifluoroacetic anhydride; column: Lipodex E, 50 m).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[C:28]([O-:31])(=[O:30])[CH3:29].[Na+].C(OCC)(=O)C>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:28]([O:31][CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])(=[O:30])[CH3:29]
Reactant: CC(=O)[O-]
Reactant: COc1ccccc1CN(C(=O)CCl)c1ccccc1Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccccc1CN(C(=O)COC(C)=O)c1ccccc1Oc1ccccc1
Yield: 96 %

Procedure:
In 10 ml of benzene were stirred 1.01 g of N-chloroacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline, 1.30 g of sodium acetate and 170 mg of tetra-n-butyl ammonium bromide at 80° C. for 5 hours. The reaction mixture was poured into ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:3) to give 1.03 g of N-acetoxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.