Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[C:6]([NH:21][C:22]([C:24]2[S:25][CH:26]=[CH:27][C:28]=2[CH3:29])=[O:23])[CH:5]=1.[OH-].[Na+].Cl>CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][C:6]=2[NH:21][C:22]([C:24]2[S:25][CH:26]=[CH:27][C:28]=2[CH3:29])=[O:23])=[N:13]1
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2sccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccsc1C(=O)Nc1cc(C(=O)O)ccc1/C=C/c1n[nH]c2ccccc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Compound 97 (740 mg, 1.77 mmol) was dissolved in methanol (5.00 mL) and the solution was added with 2 mol/L aqueous sodium hydroxide solution (5.00 mL), followed by stirring at 40° C. for 1 hour. The reaction mixture was acidified by hydrochloric acid (6 mol/L) and the precipitated crystal was collected by filtration to obtain Compound 98 (603 mg, 85%).
Reaction SMILES: [C:1]([C:4]1[C:5](=O)[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9]=1[O:10]C)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=2)=[CH:18][CH:17]=1>C(O)C>[C:1]([C:4]1[C:9](=[O:10])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=2)=[CH:18][CH:17]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: COC1=C(C(C)=O)C(=O)CC(C)(C)C1
Solvent: CCO
Product: CC(=O)C1=C(Nc2ccc(C3=NNC(=O)CC3)cc2)CC(C)(C)CC1=O
Yield: 94.2 %

Procedure:
230 mg of 2-acetyl-5,5-dimethyl-3-methoxy-2-cyclohexene-1-one and 284 mg of 4,5-dihydro-6-(4-aminophenyl)-3(2H)-pyridazinone was suspended in 2 ml of ethanol, and the resulting mixture was heated to reflux for an hour. After cooled, crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform:methanol=30:1). 390 mg of the title compound was obtained. m.p. 212.0°-213.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[N:17]=[C:16]1S(C)(=O)=O.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[N:15]([CH2:14][CH2:13][O:12][CH3:11])[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(Oc2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred solution of 4-bromophenol (149 mg) in DMF (4 mL) was added NaH (60% in oil, 36.0 mg) at room temperature. The mixture was stirred at room temperature for 30 min. To the mixture was added 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (200 mg). The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (243 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[CH2:20]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[CH2:20][Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(OC(F)(F)F)ccc1OCc1ccccc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Benzyloxy-5-trifluoromethoxy-phenyl)-methanol (510 mg) is dissolved in methylene chloride (5 ml) and thereto is added thionyl chloride (198 μl) and the mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→4:1) to give 1-benzyloxy-2-chloromethyl-4-trifluoromethoxy-benzene (360 mg). 1H-NMR (CDCl3): δ 4.67 (2H, s), 5.14 (2H, s), 6.91 (1H, d), 7.10-7.45 (7H, m)
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:10]([C:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:11][C:3]=12.[F:32][C:33]1[CH:34]=[CH:35][C:36]([O:42][CH3:43])=[C:37](B(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[F:8][C:7]1[C:2]([C:35]2[CH:34]=[C:33]([F:32])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])=[C:3]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:9]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:4]2=[N:5][CH:6]=1
Reactant: CCOC(=O)C1CC=C(c2cc3c(Cl)c(F)cnc3n2S(=O)(=O)c2ccccc2)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CC=C(c2cc3c(-c4cc(F)ccc4OC)c(F)cnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 75 °C

Procedure:
To a solution of Example 279A (1250 mg, 2.86 mmol) in 13.3 mL tetrahydrofuran/water (3:1) was added 5-fluoro-2-methoxyphenylboronic acid (1043 mg, 3.72 mmol), sodium carbonate (1214 mg, 11.45 mmol) and phenylallylchloro[1,3-bix(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (60.3 mg, 0.086 mmol) and the mixture was heated at 75° C. for 2 hours. The mixture was cooled to room temperature, and diluted with ethyl acetate, and the organics washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography (Analogix280, SF 40-80 column, 10-60% ethyl acetate/hexane gradient) gave the title compound. MS (ESI): 553.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:25]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([CH2:12][C@@H:11]([C:22]([O:24][CH2:13][C:21]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])=[CH:14]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Yield: 77 %

Procedure:
The same procedures as in Example 137 were carried out from sodium hydroxide (4.6 g), methylene chloride (160 mL), N-tert-butoxycarbonyl-L-tryptophan (10.0 g), benzyl bromide (20 mL), and tetra-n-butylammonium hydrogensulfate (1.1 g), to give the captioned compound (12.2 g, 77%) as an oily product.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([NH2:23])=[O:22])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([NH2:23])=[O:22])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:8]
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 84.8 %

Procedure:
4.02 g (8 mmoles) of Z-Glp-Ser(tBu)-Pro-NH2 are dissolved in 160 ml of methanol, 0.8 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for 30 minutes. The catalyst is filtered off, the filtrate is evaporated, and the residue is covered with ether and allowed to crystallize. The crystals are filtered off to obtain 2.50 g (85%) of Glp-Ser(tBu)-Pro-NH2 ; m.p.: 186°-187° C., Rf4 =0.45, [α]D25 =-60.8° (c=1%, in acetic acid). Amino acid analysis: Glu: 1.03 (1.0), Ser: 1.00 (1.0), Pro: 1.00 (1.0).
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(CO)C=2)C1)(OC(C)(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][C:39]=1[CH3:46]>>[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[C:39]([CH3:46])[CH:40]=2)[C:31]1=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1COCCN1Cc1ccccc1
Reactant: Cc1cc(CBr)ccc1F
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Product: Cc1cc(CC2OCCN(Cc3ccccc3)C2=O)ccc1F

Procedure:
N-Benzyl-2-(4-fluoro-3-methylbenzyl)-morpholin-3-one was prepared as described for example 70, intermediate (b), but using 4-benzylmorpholine-3-one and 4-fluoro-3-methylbenzyl bromide and was isolated as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[S:10](Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:9][C:3]1[C:2]2=[N:1][S:10][N:8]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cccc2nsnc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2,3-diaminotoluene (5.0g, 40.9 mmol) in pyridine (40 mL) at 0° C. was added thionyl chloride (7.0 mL, 98.2 mmol) dropwise. The reaction mixture was stirred at 0° C. for 30 mins, then water (200 mL) was added. The solution was extracted with dicholomethane (2×250 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give compound 839A (5.57g) as a dark brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22](C2C=NC=CC=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(Cc2ccccc2)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 144-145° C.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9][CH:8]([NH:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:7]1=[O:24])([OH:4])=[O:3].C(O)C.[OH-].[Na+].Cl>O>[ClH:1].[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9][CH:8]([NH:17][CH2:18][C:19]([OH:21])=[O:20])[C:7]1=[O:24])([OH:4])=[O:3]
Reactant: CCOC(=O)CNC1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CNC1CSc2ccccc2N(CC(=O)O)C1=O
Yield: 90.1 %

Procedure:
420 mg of the 5-carboxymethyl-3-ethoxycarbonylmethylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride obtained in Example 15 was dissolved in 5 ml of water, 3 ml of ethanol and 3.5 ml of a 1N aqueous solution of sodium hydroxide and then reacted for 2 hours. Thereafter, the solution was adjusted to pH 1-2 with hydrochloric acid and concentrated to dryness under reduced pressure. Ethanol was added to the residue and the insoluble matter was filtered off. After the filtrate was concentrated, ether was added thereto so as to cause crystallization. Thus, there was obtained 350 mg of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:3]=1.C(O)(=O)C.C(O)=O.O>C(N(CC)CC)C.[Pd]>[OH:20][CH2:19][CH2:18][CH2:17][NH:16][C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1c(NCCCO)cc(Cl)cc1NCCCO
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(NCCCO)cccc1NCCCO

Procedure:
340 mg of palladium at a concentration of 10% on calcium carbonate are added to 0.017 mole (5.2 g) of 4-chloro-2-(γ-hydroxypropyl)amino-6-(γ-hydroxypropyl)amino-nitrobenzene in 11.7 ml of triethylamine. 0.9 ml of acetic acid and 2.3 ml of formic acid are then run in dropwise. A high exothermicity is noted. The reaction mixture is heated under reflux for 3 hours. 10 ml of water are added. The reaction mixture diluted in this manner is filtered hot to remove the catalyst. The expected product precipitates from the filtrate as it cools. It is filtered off, washed with water and then dried under vacuum in the presence of phosphorus pentoxide. Recrystallized from ethyl acetate, it melts at 90° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)=[O:15])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: CCN1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Ni]
Solvent: CCO
Product: CCN1CCN(C(=O)c2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
Hydrogenation of (3-nitro-5-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (16.5 g, 50 mmol) in ethanol (300 ml) In the presence of Raney-Nickel (3 g), filtration through celite, concentration of the filtrate and crystallization from hexane gives the title compound: m.p.: 104° C.; MS: [M+1]+=302; 1H-NMR (CDCl3): 6.96 (s, 1H), 6.91 (s, 1H), 6.83 (s, 1H), 3.99 (sb, H2N), 3.80 (m, 2H), 3.44 (m, 2H), 2.53 (m, 2H), 2.46 (q, 2H), 2.40 (m, 2H), 1.12 (t, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1)=O.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[CH2:17]([NH:21][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: CCOC(=O)COc1ccc(C=O)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of ethyl (4-formyl-2-methylphenoxy)acetate (3 g, 13.5 mmol) in anhydrous ethanol (50 mL) at room temperature, was added n-butylamine (1.6 mL, 16.2 mmol) and 4A molecular sieves. The resultant mixture was stirred at room temperature for 18 h under nitrogen, prior to portion wise addition of sodium triacetoxyborohydride (3.43 g, 16.2 mmol). After a further 3 h stirring at room temperature, the reaction was quenched by cautious addition of sat. sodium bicarbonate solution (40 mL) and then diluted with water (50 mL), before extracting with EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as brown oil (2.6 g).
Reaction SMILES: [OH-].[Na+].C([NH:6][C@@:7]1([C:20]([O:22]CC)=[O:21])[CH2:14][C:11]2([CH2:13][CH2:12]2)[C@@H:10]2[C@H:8]1[C@H:9]2[C:15]([O:17]CC)=[O:16])(=O)C>>[NH2:6][C@@:7]1([C:20]([OH:22])=[O:21])[CH2:14][C:11]2([CH2:13][CH2:12]2)[C@@H:10]2[C@H:8]1[C@H:9]2[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(C)=O)(C(=O)OCC)CC21CC1
Agent: [Na+]
Agent: [OH-]
Product: N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Yield: 100 %

Procedure:
Add 2M sodium hydroxide (11.5 mL, 23.1 mmol) with diethyl (1S,2S,5R,6S)-2-acetamidospiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate (1.19 g, 3.8 mmol). Upon addition heat the reaction mixture to reflux under a blanket of nitrogen. After 21 hours add excess 2M sodium hydroxide (5.8 mL, 11.5 mmol) and resume heating for 120 hours. Purify by cation exchange chromatography (Dowex™ 50X8-100) as follows. Filter any insoluble particles and rinse with HPLC grade water. Concentrate the solution by half. Load the solution onto the resin, allowing to flow through the column at a drip rate of about 1 drop every 1-2 seconds. After the initial loading volume has dropped to the resin surface, rinse the resin with HPLC grade water (˜1 to 2 column volumes) and repeat 3 times. Monitor the pH of the effluent and pursue rinsing with HPLC grade water until application complete (return of pH back to pH=7.). Once the complete pH cycle has been observed and the effluent has returned to pH=7, wash the column with at least one column volume each of HPLC grade water, HPLC grade water: tetrahydrofuran (1:1), then HPLC grade water. Displace the product from the resin with 10% pyridine: HPLC grade water and continue elution with 10% pyridine: HPLC grade water until no additional product was detected by TLC. Combine the fractions containing the desired material, concentrate to dryness to give a white solid. Freeze-dry to yield the title compound (795 mg, 3.8 mmol). MS (m/z): 212 (M+1). 1H NMR (D2O+5% d5-pyridine) δ: 0.38 (m, 1H), 0.45 (m, 1H), 0.55 (m, 1H), 0.69 (m, 1H), 1.50 (dd, J=2.9 Hz, 1H), 1.62 (d, J=13.7 Hz, 1H), 1.78 (m, 2H), 2.11 (dd, J=2.9 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1([OH:17])[CH2:8][CH2:7][CH:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1)[CH3:2].[ClH:18].O1CCOCC1>O1CCOCC1>[ClH:18].[NH2:9][CH:6]1[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([OH:17])[CH2:4][CH2:5]1
Reactant: CCC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC1(O)CCC(N)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 248) (0.256 g) and dioxane (2 mL), 26% hydrogen chloride-dioxane (1.4 mL) was added under ice cooling and stirred at room temperature for 17 hours. The precipitated solid was collected by filtration to give 4-amino-1-ethylcyclohexanol hydrochloride (0.152 g) as a white solid.
Reaction SMILES: [CH3:1][C:2](C)(O)[C:3]#[N:4].[S:7](=[O:11])(=[O:10])([OH:9])[OH:8]>O>[S:7]([OH:11])([OH:10])(=[O:9])=[O:8].[C:3]([NH2:4])(=[O:8])[CH:2]=[CH2:1].[S:7](=[O:9])(=[O:8])([OH:11])[OH:10]
Reactant: CC(C)(O)C#N
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CC(N)=O

Procedure:
In Chemical Abstracts 91:158321U acetone cyanohydrin is reacted in aqueous solution with more than 1 mole sulphuric acid to form acrylamide sulphate in the presence of unreacted sulphuric acid, and further water is added and the mixture hydrolysed to form methacrylic acid. In Chemical Abstracts 83:44010W a similar process is described starting from methacrylonitrile, with the final product being subjected to phase separation and recycling of the small amount of distillate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[CH3:25][O:24][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:26][CH3:27])[N:14]=[C:13]([N:7]1[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[CH2:2][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:8]1)[NH:22][C:21]2=[O:23]
Reactant: COc1cc2nc(N3CCc4c(CBr)cccc4C3)[nH]c(=O)c2cc1OC
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nc(N3CCc4c(CN5CCOCC5)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(5-bromomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 23a (54 mg, 0.12 mmol), morpholine (12 mg, 0.13 mmol) and sodium bicarbonate (16 mg, 0.18 mmol) in dimethyl sulfoxide (0.5 mL) was heated to 80° C. with stirring for 18 h. After cooling to room temperature, water (2 mL) was added and the precipitated product was separated by filtration, rinsed with water and dried. 6,7-Dimethoxy-2-(5-morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-3H-quinazolin-4-one 701 was purified by flash chromatography eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide. The product was converted to the hydrochloric acid salt. Yield 15 mg, mp. 227.9–229.6° C., [M+H]+=437.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Nc1cc(F)ccc1F
Agent: Br
Product: CC(Nc1cc(F)ccc1F)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 66.8 %

Procedure:
2,5-difluoroaniline (0.074 mL, 0.73 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.09 g, 0.18 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(2,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.055 g, 66%) as a white solid. Mass Spectrum: M+H+ 458. NMR Spectrum (DMSOd6): 1.57 (d, 3H), 2.72 (bs, 3H), 2.94 (bs, 3H), 3.51-3.64 (m, 4H), 3.71-3.78 (m, 4H), 5.02-5.11 (m, 1H), 5.61 (s, 1H), 6.19-1.33 (m, 2H), 6.43 (d, 1H), 7.01-7.09 (m, 1H), 7.60 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:6][CH:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:7]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:6][CH:5]=1
Reactant: COCCOc1ncc(C(=O)OC)cc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOc1ncc(C(=O)OC)cc1-c1ccc(Cl)cc1
Temperature: 90 °C
Yield: 56.8 %

Procedure:
5-Bromo-6-(2-methoxy-ethoxy)-nicotinic acid methyl ester (8.7 g, 29 mmol) was dissolved in toluene (85 mL). To this solution was added with stirring [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CH2Cl2 (1.2 g, 1.4 mmol), 4-chlorophenylboronic acid (4.9 g, 29 mmol) and sodium carbonate solution (2M, 30 mL). This mixture was heated to 90° C. for 1.5 h and cooled to room temperature. Water (150 mL) was added, the phases were separated and the water mixture was extracted with ethylacetate. Organic phases were pooled, dried with MgSO4 and the volatiles removed in vacuo. The residue was purified by flash chromatography on silica (heptane/ethylacetate, 1:3) to give the title compound (5.3 g) as a pinkish solid; MS (ISP) 322.1 (M+H)+.