Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=S)=[C:5]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:4]=1)#[N:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=[C:5]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH:4]=1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1NC(=S)Nc1ccccc1Br
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Reaction time: 0.42 h
Yield: 104.1 %

Procedure:
To a solution of N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)thio urea (3.4 g, 7.4 mmol) in methylene chloride (40 mL) at 0° C. was added triethylamine (3.1 mL, 22 mmol), DMAP (20 mg) and methane sulfonyl chloride (1.1 mL, 15 mmol). After 25 min, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3.3 g (100%) of N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide as a yellow solid which required no further purification. 1H NMR (400 MHz, DMSO) δ 7.7 (d, 1H), 7.45 (d, 1H), 7.4 (m, 4H), 7.15 (t, 1H).
Reaction SMILES: C([O:4][CH:5]([C:8]1[C:13]([S:14]([NH:17][C:18]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)=[O:19])(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:6][F:7])(=O)C.O.[OH-].[Li+]>CO>[F:7][CH2:6][CH:5]([C:8]1[C:13]([S:14]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=2)=[O:19])(=[O:15])=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)[OH:4]
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2C(CF)OC(C)=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2C(O)CF)n1

Procedure:
To 0.88 g of 2-(1-acetoxy-2-fluoroethyl)-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-3-pyridinesulfonamide in 20 ml of methanol is added 0.25 g of lithium hydroxide monohydrate. The mixture is heated to reflux for 1 hour, then allowed to cool and the methanol is evaporated.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5][C:6]([F:9])([F:8])[F:7].[Li+].[OH-]>C1COCC1.O>[CH2:14]([O:13][C:11]([NH:10][C@@H:4]([CH2:5][C:6]([F:7])([F:9])[F:8])[C:3]([OH:21])=[O:2])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CC(F)(F)F)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](CC(F)(F)F)C(=O)O)OCc1ccccc1

Procedure:
To a solution of 250 mg (S)-2-Benzyloxycarbonylamino-4,4,4-trifluoro-butyric acid methyl ester in 2 ml THF and 0.5 ml water were added 20 mg LiOH at 0° C. The reaction mixture was brought to pH 3 by using Amberlite IR-120 ion exchange resin before being filtered and concentrated to give the crude title compound. Yield: 236 mg.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[NH2:38][CH2:39][CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1.Cl>CS(C)=O.C(OCC)(=O)C.CO>[ClH:1].[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:38][CH2:39][CH2:40][C:41]3[N:45]=[CH:44][NH:43][CH:42]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCc1c[nH]cn1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCc4c[nH]cn4)nc32)[C@H](O)[C@@H]1O
Yield: 79.9 %

Procedure:
A solution of 1-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-1-deoxy-N-ethyl-β-D-ribofuranuronamide (0.155 g, 0.296 mmol) and histamine (0.22 g) in dimethylsulphoxide (1.5 ml) was heated at 120° C. for 16 h. The mixture was cooled and diluted with ethyl acetate (50 ml) then washed with water (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml) and the combined organic phase was washed with water (50 ml), dried (MgSO4) and evaporated to leave a solid which was treated with 2N hydrochloric acid (2 ml) in methanol (30 ml) and the solution was evaporated to leave the title compound (0.15 g, 80%) as a solid. MH+ =598, nmr(δ,DMSO-d6) includes 1.02(t,3H), 3.0(m,2H), 3.13(m,2H), 3.7(m,2H), 4.2(m,2H), 4.85(s,1H), 4.55(m,3H), 5.9(d,1H), 7.1-7.6(m,12H), 8.45(s,1H), 9.05(s,1H), 14.3(m,1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:6][S:7]([C:10]1[S:14][C:13]([NH:15]C(=O)C)=[N:12][C:11]=1[CH3:19])(=[O:9])=[O:8])[CH2:4][OH:5]>Cl>[OH:1][CH2:2][CH:3]([NH:6][S:7]([C:10]1[S:14][C:13]([NH2:15])=[N:12][C:11]=1[CH3:19])(=[O:9])=[O:8])[CH2:4][OH:5]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(CO)CO)s1
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)NC(CO)CO
Temperature: 80 °C
Yield: 43.9 %

Procedure:
A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (1.45 g, 4.69 mmol) in 6N hydrochloric acid (22 ml) was heated for 2 h at 80° C., evaporated, and saturated NaHCO3 solution (50 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization (dichloromethane/MeOH/hexane) to yield the title compound (0.55 g, 44%) as an off-white solid. MS (ISP) 266.0 [(M−H)−].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[N:14]=1>>[CH3:26][O:25][C:18]1[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[C:15]([NH:27][C:28]1[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=1)[N:14]=[C:13]2[O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: CC(=O)Nc1ccc(O)cc1
Product: COc1ccc2c(Oc3ccc(NC(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[5,6-dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 434(MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:7])[OH:6].C(=O)(O)[O-].[Na+].[C:20]([O:25][CH:26]([O:28][C:29](OC1CC(=O)NC1=O)=[O:30])[CH3:27])(=[O:24])[CH:21]([CH3:23])[CH3:22]>O.C(#N)C.C(OCC)C>[C:20]([O:25][CH:26]([O:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:6])[OH:7])=[O:30])[CH3:27])(=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: NCCCP(=O)(O)CC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: CC(OC(=O)NCCCP(=O)(O)CC1CCCCC1)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-aminopropyl(cyclohexylmethyl)phosphinic acid (10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) is added a solution of compound (17) (10 mmol) in acetonitrile (20 mL) over 1 min. The reaction is stirred at ambient temperature for 16 h. The reaction mixture is diluted with diethyl ether (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 mL). The organic phase is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (91) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:34])[NH:28][C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:34])[NH:28][C@@H:29]1[CH2:33][CH2:32][N:31]([CH2:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:7]3[N:8]([CH3:11])[C:9]4[C:5]([C:6]=3[C:20]#[N:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:17]=2)[CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CN3CC[C@@H](NC(=O)OC(C)(C)C)C3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester are processed according to the method described in Example 170 to give {(R)-1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. MS (ESI) m/z 466.17 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=O)[CH:14]=[C:9]12)[CH3:3].O=P(Cl)(Cl)Cl.[CH3:26][O:27][C@@H:28]([C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[CH3:29].N1C=CC=CC=1>ClCCCl.C(Cl)Cl>[CH3:26][O:27][C@@H:28]([C:30]1[N:31]=[CH:32][N:33]([C:15]2[CH:14]=[C:9]3[C:10]4[C:5]([CH2:6][CH2:7][N:8]3[C:18](=[O:19])[CH2:17][N:16]=2)=[C:4]([C:2]([CH3:3])=[CH2:1])[CH:13]=[CH:12][CH:11]=4)[CH:34]=1)[CH3:29]
Reactant: C=C(C)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Reactant: CO[C@H](C)c1c[nH]cn1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)c1cccc2c1CCN1C(=O)CN=C(n3cnc([C@@H](C)OC)c3)C=C21
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 15.5 %

Procedure:
Example 118. A solution of 9-(prop-1-en-2-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (275 mg, 1.03 mmol) in DCE (20 mL) was treated with POCl3 (0.29 mL, 3.07 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, diluted with DCM and washed with H2O. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (20 mL) and (R)-4-(1-methoxyethyl)-1H-imidazole (200 mg, 1.59 mmol) and pyridine (0.17 mL, 2.05 mmol) were then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, diluted with DCM and washed with H2O. The org. layer was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) and SFC (column: 4-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: 6% MeOH/CO2 for 1 min, then from 6% MeOH/CO2 to 11% MeOH/CO2 in 6 min; then from 11% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) gave the title compound (60 mg). UPLC-MS: MS 377.2 (M+H+); UPLC rt 1.02 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.35 (d, J=5.87 Hz, 3 H); 2.01 (s, 3 H); 2.90 (t, J=5.87 Hz, 2 H); 3.14 (s, 3 H); 3.75 (t, J=6.06 Hz, 2 H); 4.16-4.33 (m, 3 H); 4.85 (s, 1 H); 5.29 (s, 1 H); 7.12 (s, 1 H); 7.27-7.40 (m, 2 H); 7.57 (s, 1 H); 7.90 (d, J=7.82 Hz, 1 H); 8.18 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(F)nc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(F)nc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 124.6 %

Procedure:
To a solution of 6-fluoro-3-pyridinecarboxylic acid (9.5 g, 67.3 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (12.0 g, 74.1 mmol), and the mixture was stirred at 80° C. for 10 min. The reaction solution was cooled to room temperature and monoethyl malonate magnesium salt (10.6 g, 37.0 mmol) was added. The mixture was stirred at room temperature for 2 hrs. To the reaction solution were added ethyl acetate (100 ml) and water (100 ml). Then, conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(6-fluoropyridin-3-yl)-3-oxopropionate (9.74 g, 68%) as a brown oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.CO[C:25](=[O:40])[CH:26]([OH:39])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[Br:38])([CH3:30])[CH3:29].S(Cl)(Cl)=O.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]2[C:54](=[O:55])[O:53][N:52]=[C:51]([CH3:56])[C:50]=2[CH:57]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CC(OC)(C)C.CC(N(C)C)=O>[Br:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[C:28]([CH3:29])([CH3:30])[CH2:27][C:26](=[O:39])[C:25]([NH:45][C:46]1[CH:47]=[CH:48][C:49]2[C:54](=[O:55])[O:53][N:52]=[C:51]([CH3:56])[C:50]=2[CH:57]=1)=[O:40]
Reactant: Cc1noc(=O)c2ccc(N)cc12
Reactant: COC(=O)C(O)CC(C)(C)c1cc(F)ccc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3cc(F)ccc3Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.6 %

Procedure:
663 mg (1.56 mol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin-periodinane, cf. D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277) is added to a solution of 250 mg (0.78 mmol) of 4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methylvaleric acid-methyl ester in 10 ml of dichloromethane. After 1.5 hours at room temperature, the batch is diluted with 150 ml of MTBE, washed with a solution of 1.2 g of NaHCO3 and 4.0 g of Na2SO3 in 50 ml of water, saturated NaHCO3 and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue (250 mg) is taken up in 16 ml of THF-EtOH (1:1) and mixed with 3.9 ml (3.9 mmol) of a 1 M sodium hydroxide solution. After 30 minutes, the batch is concentrated in a vacuum, diluted with 20 ml of water and washed with MTBE. The aqueous phase is acidified with 10% sulfuric acid (pH 2) and extracted with 100 ml of ethyl acetate and 100 ml of dichloromethane. The combined extracts are dried (NaSO4) and concentrated by evaporation in a vacuum. 0.06 ml (0.92 mmol) of thionyl chloride is added in drops at −6° C. to the solution of the residue (230 mg) in 5 ml of dimethyl acetamide. After 20 minutes at −6° C., 201 mg (1.14 mmol) of 6-amino-4-methyl-2,3-benzoxazin-1-one is added to it. The batch is stirred for 15 hours at room temperature, acidified with 50 ml of 10% citric acid and shaken out with 150 ml of MTBE. The organic phase is washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 290 mg of product.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]([OH:13])[C:5]1[CH:10]=[CH:9][C:8](OC)=[CH:7][CH:6]=1.Br[C:19]1C=C(C)C=CC=1C=O.C1([Mg]Br)C=CC=CC=1>>[Br:1][C:2]1[CH:17]=[C:16]([CH3:19])[CH:15]=[CH:14][C:3]=1[CH:4]([OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1ccc(C(O)c2ccccc2Br)cc1
Reactant: Cc1ccc(C=O)c(Br)c1
Agent: Br[Mg]c1ccccc1
Product: Cc1ccc(C(O)c2ccccc2)c(Br)c1

Procedure:
Friedel-Crafts acylation of m-bromoanisole with benzoyl chloride and p-fluorobenzoyl chloride provides 2-bromo-4-methoxybenzophenone, m.p. 83°-84°, and 2-bromo-4'-fluoro-4-methoxybenzophenone, m.p. 79°-81°, respectively, which are reduced with sodium borohydride to 2-bromo-4-methoxybenzhydrol, b.p. 160° (0.05 mm.), and 2-bromo-4'-fluoro-4-methoxybenzhydrol, a liquid. Acylation of benzene with 2-bromo-5-chlorobenzoyl chloride, 2-bromo-4,5-methylene dioxybenzoyl chloride, and 2-bromo-4,5-dimethoxybenzoyl chloride provides 2-bromo-5-chlorobenzophenone, 2-bromo-4,5-methylene-dioxybenzophenone, and 2-bromo-4,5-dimethoxybenzophenone, m.p. 76°-77°, which are reduced with sodium borohydride to 2-bromo-5-chlorobenzhydrol, 2-bromo-4,5-methylenedioxybenzhydrol, and 2-bromo-4,5dimethoxybenzhydrol, m.p. 83°-85°. Acylation of anisole with 2-bromobenzoyl chloride provides 2-bromo-4'-methoxybenzophenone, m.p. 93°-95°, which is reduced to 2-bromo-4'-methoxybenzhydrol, m.p. 64°-65°. Reaction of 2-bromo-4-methylbenzaldehyde and phenylmagnesium bromide provides 2-bromo-4-methylbenzhydrol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:4]([OH:5])[C:3]=1O.CC(C)CC(=[O:16])C>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[CH:6]=[C:7]([CH3:9])[C:8]=1[OH:16]
Reactant: Cc1cc(C)c(O)c(O)c1
Reactant: CC(=O)CC(C)C
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 53, except that 0.25 g. (2.5 m. moles) of 4-methyl-2-pentanone was used instead of 3.61 g. (26.1 m. moles) of it, 3.09 g. (22.4 m. moles) of 3,5-dimethylcatechol and 2.07 g. (15 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 73.6 percent.
Reaction SMILES: [NH2:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14].O=[C:16]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([OH:19])=[O:18].[OH-].[Na+].[Na]>O>[C:17]([CH:16]([NH:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:19])=[O:18]
Reactant: NC1CN2CCCC(C(=O)O)N2C1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCc1ccccc1)NC1CN2CCCC(C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.4 %

Procedure:
0.51 g of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate B) was dissolved in 4 ml of water. 1.37 g of 2-oxo-4-phenylbutyric acid were added and the mixture was adjusted to pH 6 using 2N aqueous sodium hydroxide solution. 0.33 g of sodium cyanoborohydrde was then added and the mixture was left to stir at room temperature for 22 hours. The product was absorbed on to a strong acidic ion-exchange resin and eluted with water containing 2% pyridine to give 0.62 g of crude product. Crystallization from water gave 0.3 g (32%) of 2-(1-carboxy-3-phenylpropylamino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (2 racemates: racemates C and D) in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[S:16])[NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:16][CH:21]=[C:19]([CH2:18][Cl:17])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)N1CCCC(C(N)=S)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2nc(CCl)cs2)C1

Procedure:
To a solution of 3-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2.2 g, 9.02 mmol) in acetone (45 mL) was added 1,3-dichloroacetone (1.49 g, 11.7 mmol), MgSO4 (1.63 g, 13.5 mmol) and MgCO3 (0.76 g, 9.02 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (20 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].O.[CH:13](O)=[O:14]>>[CH:13]([NH:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[Br:1])=[O:14]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: O=CO
Solvent: O
Product: O=CNc1cc([N+](=O)[O-])ccc1Br
Yield: 98 %

Procedure:
A solution of 2-bromo-5-nitroaniline (5.27 g, 24.3 mmol) in 98% formic acid (30 ml) was heated to reflux for 90 min under nitrogen. The cooled reaction mixture was then poured into cold water (600 ml) which afforded a yellow precipitate. The solid was isolated by filtration and the cake washed with cold water (2×200 ml). Subsequent drying overnight under vacuum overnight afforded N-formyl-2-bromo-5-nitroaniline (5.84 g, 98%) as a yellow solid: 1H NMR (DMSO-d6) δ 10.14 (br s, 1H), 9.01 (d, J=2.4 Hz, 1H), 8.46 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.91 (dd, J=8.8, 2.5 Hz, 1H); 13C NMR (DMSO-d6) δ 161.2, 146.9, 136.6, 134.0, 120.6, 119.8, 116.7.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].Br[CH2:8][CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)C>[CH:9]1([CH2:8][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: c1c[nH]cn1
Reactant: BrCC1CCCCCCC1
Agent: [Na]
Solvent: CCO
Product: c1cn(CC2CCCCCCC2)cn1
Reaction time: 15 h

Procedure:
Imidazole (2.0 g, 0.03 mol) was added to a solution of sodium (0.7 g, 0.03 mol) in dry ethanol (50 ml). The mixture was stirred and heated to boiling when bromomethylcyclooctane (5.5 g, 0.027 mol) was added dropwise. Following the addition, the reaction mixture was stirred and boiled for 15 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridyl)benzoic acid (40 mg, 0.1017 mmol) and morpholine (18 mg, 0.2608 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (49 mg, 0.2556 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to give the title compound (32 mg, 0.0692 mmol, 68%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH:19]([CH3:32])[C:20]([O:22]CC1C=CC(OC)=CC=1)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH:19]([CH3:32])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(COC(=O)C(C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxybenzyl 2-(N-CBZ-L-valyloxy)-propionate (7.8 g, 17.5 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml) and the solution was stirred for one hour at room temperature. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography. Yield: 5.0 g