Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:22])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1.C(Cl)Cl>[C:23]([O:1][C@@H:2]1[C@H:7]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C:4](=[O:22])[CH2:3]1)[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:25])[CH3:24]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3[C@@H](O)CC(=O)[C@@]3(C)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@H]12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
168 g of 15α-hydroxy-4-androstene-3,17-dione in 250 ml of pyridine and 125 ml of acetic anhydride are heated on a steam bath. After 90 minutes, the reaction mixture is stirred into ice/water. The thus-precipitated product is suctioned off, taken up in methylene chloride, washed with water, and dried over sodium sulfate. After recrystallization from ethyl acetate, 120 g of 15α-acetoxy-4-androstene-3,17-dione is obtained, mp 145° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-])=O)=[CH:7][CH:8]=2)[NH:3]1.CCO>[Pd].CCOC(C)=O>[NH2:12][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][C:2]([CH3:15])([CH3:1])[NH:3]2)=[CH:8][CH:7]=1
Reactant: CC1(C)CCc2ccc([N+](=O)[O-])cc2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CCc2ccc(N)cc2N1
Reaction time: 6 h
Yield: 99.6 %

Procedure:
In a 200-mL r.b. flask, a solution of 1,2,3,4-tetrahydro-2,2-dimethyl-7-nitroquinoline (1.00 g, 4.84 mmol) in 1:1 EtOH:EtOAc (40 mL) was treated with 10% Pd/C (0.20 g). The reaction mixture was de-gassed and fitted with a balloon of H2. The reaction mixture was stirred for 6 h, de-gassed, and filtered through a pad of Celite. The pad was rinsed with EtOAc (300 mL). The filtrate was concentrated to afford 0.85 g (99%) of the crude aniline as a reddish oil. Data for 7-amino-1,2,3,4-tetrahydro-2,2-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 6.77 (d, J=7.9, 1H), 6.00 (dd, J=7.9, 2.2, 1H), 5.81 (d, J=2.2, 1H), 3.47 (bs, 1H), 3.40 (bs, 2H), 2.66 (t, J=6.7, 2H), 1.65 (t, J=6.7, 2H), 1.18 (s, 6H).
Reaction SMILES: C([O:8][C:9]([C@H:11]([CH3:38])[CH2:12][C@H:13]([NH:27][C:28]([N:30]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[N:31]1)=[O:29])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:10])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@@H:13]([NH:27][C:28]([N:30]2[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[N:31]2)=[O:29])[CH2:12][C@H:11]([C:9]([OH:10])=[O:8])[CH3:38])=[CH:16][CH:17]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1)C(=O)O

Procedure:
Next, a solution of 1-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid (60 mg, 0.117 mmol) in EtOAc (10 mL) is hydrogenated over 10% Pd/C (40 mg) at 1 atm for 5 hours. The catalyst is filtered through Celite and the filtrate evaporated under reduced pressure. The residue is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes 1-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid. HPLC Retention time 0.96 minutes (condition F); MS 422.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07 Hz, 3H), 1.78 (m, 1H), 1.88 (m, 1H), 2.45 (m, 1H), 2.86 (m, 1H), 2.98 (m, 1H), 4.14 (m, 1H), 6.84 (d, J=2.65 Hz, 1H), 7.28 (d, J=8.34 Hz, 2H), 7.33 (t, 1H), 7.43 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.63 (d, J=7.07 Hz, 2H), 8.29 (d, J=2.78 Hz, 1H), 8.58 (d, J=9.09 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.C1C[O:20][CH2:19]C1.CN(C=O)C.Cl>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:19]=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C1CCOC1
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1c(C=O)ccc(C#N)c1Cl
Temperature: -32 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-4-iodo-3-methylbenzonitrile (150 g, 0.54 mol) and THF (1200 ml) was cooled down to −32° C. A 2 M i-PrMgCl-THF-solution (541 ml, 1.08 mol) was added slowly during 1 h and the mixture was stirred at −32° C. for 2 h. DMF (83 ml, 1.08 mol) was added at −32° C. and the reaction mixture was allowed to warm to RT. After stirring overnight 10% HCl solution (1000 ml) was added at 0° C. The layers were separated and the aqueous layer was extracted with diethyl ether (2×900 ml). The combined organic layers were washed with saturated NaHCO3 solution (900 ml) and brine (750 ml). The organic layer was dried with Na2CO4, filtered and evaporated. The dried crude product (95 g) was treated with hot n-heptane and activated carbon. The title compound was obtained as a yellow solid and used without further purification. 1H-NMR (400 MHz; CDCl3): δ 2.78 (s, 3H), 7.71 (d, 1H), 7.84 (d, 1H), 10.36 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:22]([CH:23]3[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]3=[O:30])[C:15]([CH3:16])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: c1c[nH]cn1
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc2cc(Br)ccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a stirred mixture of 2-amino-4-bromobenzoic acid (2.0 g, 9.3 mmol) and imidazole (0.8 g, 11 mmol) in acetonitrile (20 mL), was added acetyl chloride (0.8 mL, 11 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1.5 g, 9.3 mmol), imidazole (1.4 g, 20 mmol) and triphenyl phosphite (2.9 mL, 11 mmol) and heated to reflux for 22 hours. To the mixture, was added water (30 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give 3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (2.4 g, 75% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 18.65 min (98.9%); mp: 315-317° C.; 1HNMR (DMSO-d6) δ 2.08-2.22 (m, 1H, CHH), 2.62-2.79 (m, 5H, CH3, 2CHH), 2.80-2.91 (m, 1H, CHH), 5.28 (dd, J=6, 11 Hz, 1H, NCH), 7.66 (dd, J=2, 8 Hz, 1H, Ar), 7.84 (d, J=2 Hz 2H, Ar), 7.95 (d, J=8 Hz, 1H, Ar), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.83, 23.53, 24.02, 30.58, 56.67, 119.36, 128.06, 128.29, 128.80, 129.67, 147.93, 156.69, 160.02, 169.33, 172.57; LCMS: MH=350, 352; Anal Calcd for C14H12N3O3Br: C, 48.02; H, 3.45; N, 12.00; Br, 22.82. Found: C, 47.94; H, 3.17; N, 11.85; Br, 20.65.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:21])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:20])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:24]I>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([CH3:21])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:20])[N:10]2[CH3:24])=[CH:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: COC(=O)CN1C(=O)N[C@@](C)(c2ccc(C#N)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)N(C)[C@@](C)(c2ccc(C#N)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3 g of methyl (S)-(4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate (10.4 mmol) were dissolved in 15 ml of anhydrous dimethylformamide under argon. 11.4 mmol of sodium hydride in the form of a dispersion in mineral oil were added in an argon countercurrent. The reaction mixture was stirred at room temperature for 15 minutes. It was then treated with 721 μl of methyl iodide (11.4 mmol). The mixture was stirred at room temperature for 4 hours and then allowed to stand at room temperature overnight. The solution was concentrated. For purification, the substance was chromatographed on silica gel using methylene chloride/ethyl acetate (9.5:0.5). The fractions containing the pure substance were concentrated.
Reaction SMILES: [CH3:1][C:2]1([CH:8]=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:17][C:18]([NH:20][CH:21](P(OC)(OC)=O)[C:22]([O:24][CH3:25])=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C(N(C)C)=N>O1CCCC1>[CH2:10]([O:17][C:18]([NH:20]/[C:21](=[CH:1]\[C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)/[C:22]([O:24][CH3:25])=[O:23])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC1(C=O)CCCCC1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1(C)CCCCC1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 96 h

Procedure:
1-Methylcyclohexanecarbaldehyde (2.66 g, 21.08 mmol) and methyl {[(benzyloxy)carbonyl]amino}(dimethoxyphosphoryl)acetate (6.63 g, 20.02 mmol, 0.95 equivalent) are dissolved in 75 ml of tetrahydrofuran and cooled to −78° C. At −78° C., N,N,N′,N′-tetramethylguanidine (27.92 g, 0.24 mol, 11.5 equivalents) is added dropwise and then stirred at −78° C. for 15 min and subsequently at room temperature for 4 days. The mixture is then extracted by shaking with ethyl acetate (twice 100 ml) and water, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. After concentration, the crude product is chromatographed (Biotage 40M, cyclohexane/ethyl acetate 6/1, 27.5 ml/min). 0.91 g (13% of theory) of the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2ncc(Br)cc2N)cn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5-bromo-6′-methoxy-3-nitro-2,3′-bipyridine (776.9 mg, 2.50 mmol) in EtOAc (25 mL) was added tin(II) chloride dihydrate (2.83 g, 12.56 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 2 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the light tan solid was identified as 5-bromo-6′-methoxy-2,3′-bipyridin-3-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.42 (1H, dd, J=2.4, 0.7 Hz), 7.98 (2H, m), 7.34 (1H, d, J=2.0 Hz), 6.90 (1H, dd, J=8.6, 0.7 Hz), 5.49 (2H, s), 3.90 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>>[C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Agent: [H-]
Agent: [Li+]
Product: COC(=O)CN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)C1c1ccccc1C
Yield: 31.9 %

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (1.02 g, 1.86 mmol) prepared in example 24b was reacted with LiH (86 mg, 10.9 mmol) (Aldrich) and methyl bromoacetate (0.57 g, 3.72 mmol) (Aldrich) to give racemic 2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white solid (Yield: 0.37 g, 32%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCCC1.C1C=CC=CC=1.C(O)(=O)C>>[Br:1][C:2]1[S:6][C:5]([C:7](/[C:8](=[CH:19]/[C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)/[C:9]([O:11][CH3:12])=[O:10])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)c1ccc(Br)s1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)/C(=C\c1ccc(Cl)cc1)C(=O)c1ccc(Br)s1
Temperature: 92 °C
Yield: 97 %

Procedure:
To a 500 mL round bottom flask was added a solution of methyl 3-(5-bromo-2-thienyl)-3-oxopropanoate (4.402 g, 16.73 mmol), 4-chlorobenzaldehyde (2.822 g, 20.08 mmol) and piperidine (0.165 mL, 1.673 mmol) in anhydrous benzene (200.0 mL, 2238 mmol). Acetic acid (0.665 mL, 11.712 mmol) was added and the reaction mixture was fitted with a Dean-Stark trap and the bath was heated to 92° C. and allowed to reflux for 18 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude material was split in half and dry loaded onto silica gel and then purified using a ISCO (40 g cartridge, gradient hexanes to 40% EtOAc over 30 min) to afford the title compound (6.26 g, 92%) as a yellow solid. LC/MS (AA) ES− 385, 387, 389(dmso-d6, 400 MHz): δ 7.89 (s, 1H), 7.34-7.24 (m, 5H), 7.00 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CCc1nc(-c2ccc(Cl)cc2)co1)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g) in dichloromethane (20 ml) was added diphenyldiazomethane (0.425 g). After stirring for 4 hours at room temperature, acetic acid (0.5 ml) was added to the mixture. The reaction mixture was washed with a saturated sodium hydrogen carbonate aqueous solution and water, and then dried over MgSO4. The solvent was distilled off and then the oily residue was subjected to a silica gel column chromatography. Crystals of diphenylmethyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.759 g, 91%) were obtained from the fraction eluted with ether-hexane (1:3, V/V). Recrystallization from ether-hexane gave colorless prism crystals of mp 94°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:12]([C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[N:17]=[CH:16][CH:15]=1)[CH3:13]>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:12]([C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[N:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1cccc(Cl)c1)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 3-chlorophenol (1.28 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature, filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by flash chromatography using as eluent a mixture of ethyl acetate and petroleum ether to give 7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.11 g, (mp 124°-126° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:19][CH2:20][CH2:21][C@H:22]([CH2:24][CH2:25][CH2:26]/[C:27](=[CH:29]/[CH2:30][OH:31])/[CH3:28])[CH3:23])[CH3:18])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C:27]([CH2:26][CH2:25][CH2:24][CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH:17]([CH3:18])[CH2:16][CH2:15][CH2:14][CH:12]([CH3:13])[CH3:11])=[CH:29][CH:30]=[O:31]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=CC=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 17.4 mL (202 mmol) of oxalyl chloride was dissolved in methylene chloride (300 mL). 36 mL (0.51 mol) of dimethyl sulfoxide was slowly added dropwise to the mixture at −78° C. After the mixture was stirred for 15 min, 50 g (0.17 mol) of phytol was added, followed by stirring for 1 hour at the same temperature. After addition of 94 mL (0.68 mol) of triethylamine, the reaction mixture was allowed to warm up to room temperature. The mixture was concentrated with methylene chloride, and the residue was diluted with diethylether, and the solution was washed saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 3,7,11,15-tetramethylhexadec-2-en-1-al as a crude product.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[O:15]([C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[CH:25]=[CH:26][C:27](O)=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:27](/[CH:26]=[CH:25]/[C:24]3[CH:30]=[CH:31][CH:32]=[C:22]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc(Oc2ccccc2)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Oc4ccccc4)c3)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.00 g (16.7 mmol) of 3-phenoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.82 g (yield of Compound 191 as pale yellow needles.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C:19]([CH3:32])([C:23]([NH:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.Cl>O1CCCC1>[OH:18][C:19]([CH3:32])([C:23]([NH:25][CH2:26][CH2:27][C:28]([F:29])([F:30])[F:31])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(C(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A solution of 210 mg (0.94 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 215 mg (0.94 mmol) (RS)-2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid in 50 ml tetrahydrofuran were cooled to 0° C. and 129 mg (0.94 mmol) 1-hydroxy-benzotriazole hydrate, 327 μl (1.87 mmol) diisopropylethylamine and 183 mg (0.94 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. The mixture was poured on ice/water and 1 N aqueous hydrochloric acid was added until pH=1 was reached. Extraction with first diethylether and second with ethylacetate, washing with saturated aqueous sodium hydrogen carbonate solution and brine and chromatography on silicagel with ethylacetate/heptane 2/1 yielded 150 mg (41%) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(3,3,3-trifluoro-propyl)-malonamide as a white solid, MS (m/e): 436.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[H][H]>CO.C(O)(=O)C.CN1CCCC1=O.[OH-].[Pd+2].[OH-]>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3]
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCc2ccccc2N1

Procedure:
A carbostyril of Formula 14 is hydrogenated, e.g., in a mixture of methanol/acetic acid, or preferably in N-methylpyrrolidinone, with a palladium hydroxide catalyst at elevated temperature (e.g., 40° to 80° C.) and under a source of hydrogen for 24 to 48 hours, preferably about 36 hours. The catalyst is removed to give the 3,4-dihydrocarbostyril compound of Formula 5c.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[C:20](Br)=[N:21][CH:22]=[C:23]([Br:24])[N:18]2[N:17]=1)(=[O:15])=[O:14].[CH3:27][O-:28].[Na+]>C(#N)C.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[C:20]([O:28][CH3:27])=[N:21][CH:22]=[C:23]([Br:24])[N:18]2[N:17]=1)(=[O:15])=[O:14]
Reactant: C[O-]
Reactant: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(Br)ncc(Br)n2n1
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(OC)ncc(Br)n2n1

Procedure:
A solution of 686 mg (1.35 mmol) of N-(2-fluoro-6-methoxycarbonylphenyl)-5,8-dibromo[1,2,4]triazolo-[1,5-a]pyrazine-2-sulfonamide in 10 mL dry acetonitrile was treated with 3.0 mL (3.0 mmol) of a 1M solution of 15 sodium methoxide in dry methanol at 0° C. with stirring. The reaction was quenched after 5min with 0.5mL of glacial acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue was triturated with water and the resulting light brown solid was collected by filtration and dried in a vacuum oven. This crude material was purified by flash column chromatography on silica gel using a 0.5 to 2percent ethanol/dichloromethane gradient as eluent to obtain 538 mg (87 percent of theory) of the title compound as a white glassy foam solid melting at 201°-202° C.