Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[Cl:6][CH:7]1[CH2:12][NH:11][CH:10]([OH:13])[CH:9]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36](Cl)=[O:37]>C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:12]=[N:11][C:10]2[O:13][CH2:35][C:36](=[O:37])[N:14]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC(Cl)CNC2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ncc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an N,N-dimethylformamide suspension (60 ml) of tert-butyl 4-[(5-chloro-2-hydroxypiperidin-3-yl)amino]piperidine-1-carboxylate (3.00 g) and potassium carbonate (3.79 g) was added chloroacetyl chloride (1.09 ml), followed by stirring at room temperature for 30 minutes, and at 140° C. for 4 hours. After the reaction solution was brought back to room temperature, water and ethyl acetate were added, and the solution was separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (1.33 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[C:22]([O:23]C)=[CH:21][CH:20]=[CH:19][C:15]=1C(O)=O>>[OH:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][C:1]([C:21]3[CH:20]=[CH:19][CH:15]=[C:14]([OH:13])[C:22]=3[OH:23])=[N:5][C:4]=2[CH:6]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1cccc(C(=O)O)c1OC
Product: Oc1ccc2oc(-c3cccc(O)c3O)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 2,3-dimethoxybenzoic acid. The product was obtained as a tan solid, m.p. 239-241° C.; MS m/e 244 (M+H)+
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:11]([CH2:12][CH2:13][C@@:14]([OH:18])([CH:16]=C)C)[C@@:10](O)([CH3:19])[CH2:9][CH2:8][C@H:7]1[C:6]([CH3:22])([CH3:21])[CH2:5][CH2:4][CH2:3]2.O=[O+][O-].[OH-].[K+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[CH3:16][C:14]1[O:18][C@@:2]2([CH3:1])[C@@H:11]([C@:10]3([CH3:19])[C@@H:5]([CH2:4][CH2:3]2)[C:6]([CH3:21])([CH3:22])[CH2:7][CH2:8][CH2:9]3)[CH2:12][CH:13]=1
Reactant: C=C[C@](C)(O)CC[C@@H]1[C@@]2(C)CCCC(C)(C)[C@@H]2CC[C@@]1(C)O
Agent: O=S([O-])([O-])=S
Agent: O=[O+][O-]
Agent: OO
Solvent: CO
Solvent: O
Product: CC1=CC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O1
Reaction time: 3 h
Yield: 97 %

Procedure:
40.6 g of sclareol (0.132 mol) in 300 ml methanol was ozonolysed at 20°-25° C. using a Gebr. Herrmann LAB-50-1 lab ozoniser operating at 130V, with flow rate at 61/hr, under which conditions 0.05 mol/hr of ozone was generated. The reaction was complete in 3 hrs whereafter the reaction mixture was poured into a mixture of 19 g KOH and 38 ml H2O2 in 500 ml of water and stirred for 30 min. The suspension was extracted three times with 100 ml toluene. the organic layer was washed with 100 ml 0.1 mol sodium thiosulphate solution and dried over Mg sulphate. Thereafter toluene was removed at 55° C. under reduced pressure. 33.6 g (97.4% yield) of pure sclareol oxide was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:16][CH2:17][C:18]([O:20]CC)=O)=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[Sn]>Cl>[C:10]1([C:8]2[CH:7]=[N:6][C:5]3[O:16][CH2:17][C:18](=[O:20])[NH:1][C:4]=3[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ncc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Product: O=C1COc2ncc(-c3ccccc3)cc2N1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml round-bottomed flask was added ethyl 2-(3-nitro-5-phenylpyridin-2-yloxy)acetate (4.6 g, 15.22 mmol) in hydrochloric acid, 37% (40 ml) to give a yellow suspension. The mixture was cooled to 0-5° C. followed by the portion wise addition of tin powder (9.94 g, 84 mmol). The addition proved to be exothermic. Caution should be taken while adding. The mixture was then stirred at room temperature for further 30 minutes until all foaming ceased. The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 3 hours.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: OCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
3-(Tritylamino)-1-propanol was prepared according to the literature procedure (J.Heterocycl.Chem.; 1993, 30, 1197). To a solution of 3-amino-1-propanol (15.0 g/200 mmol) in THF (100 ml) was added a solution of tritylchloride (23.2 g/83.3 mmol) in THF (100 ml) dropwise at 0° C., and then the resulting solution was stirred at room temperature for 4 days. The solution was evaporated. The resulting residue was dissolved in water (100 ml) and dichloromethane (100 ml). The organic layer was separated. The aqueous layer was extracted with dichloromethane (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by recrystallization from toluene/hexane to afford a white crystal. (21.0 g/80%).
Reaction SMILES: [F:1][C:2]1([F:13])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[O:11])[NH:4][CH:3]1[CH3:12].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:13][C:2]1([F:1])[C:8]([CH3:9])([CH3:10])[O:7][CH2:6][C:5](=[O:11])[NH:4][C@@:3]1([C:16]1[CH:17]=[C:18]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[CH:20]=[CH:21][C:15]=1[F:14])[CH3:12]
Reactant: CC1NC(=O)COC(C)(C)C1(F)F
Reactant: Nc1ccc(F)cc1
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Nc3ccc(F)cc3)ccc2F)C1(F)F
Yield: 55.7 %

Procedure:
Prepared in an analogous manner as described for intermediate A9A or A13A from (R)-545-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate A16B) (300 mg, 819 μmol) and commercially available 4-fluoroaniline [CAS no 371-40-4] 4-fluoroaniline (157 μL, 1.64 mmol). The (R)-6,6-difluoro-5-(2-fluoro-5-(4-fluorophenylamino)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (181 mg, 55.7%) was obtained as a light yellow foam. MS (ISP): m/z=397.0 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C[Al](C)C.C([O:19][C:20]([C:22]1[C:26]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)=[CH:30][C:25]=2[O:24][N:23]=1)=O)C>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([C:22]2[C:26]3[CH:27]=[CH:28][C:29]([O:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)=[CH:30][C:25]=3[O:24][N:23]=2)=[O:19])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)c1noc2cc(Oc3ccncn3)ccc12
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1noc2cc(Oc3ccncn3)ccc12
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 46 μl (0.35 mMol) 4-fluoro-3-trifluoromethyl-aniline are dissolved in 6 ml toluene and cooled to 10° C. Then 550 μl Me3Al (2 M in toluene; 1.1 mMol) are added via syringe. After 1 h at rt, a solution of 101 mg (0.35 mMol) 6-(pyrimidin-4-yloxy)-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 1.25 ml THF is added and the reaction mixture stirred for 25 min in an oil bath at 110° C. Work up as described in step 1.2 gives the title compound: MS: [M−1]=419; Anal.: C,H,N,F.
Reaction SMILES: [C:1]1([CH3:29])[C:2]([S:7]([O:10][C:11]2[CH2:17][CH:16]3[N:13]([C:14](=[O:18])[CH2:15]3)[C:12]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([N-]C(C)C)(C)C.[Li+].[CH:38](=[O:40])[CH3:39].[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[OH:40][CH:38]([CH:15]1[C:14](=[O:18])[N:13]2[CH:16]1[CH2:17][C:11]([O:10][S:7]([C:2]1[C:1]([CH3:29])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:9])=[O:8])=[C:12]2[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[CH3:39]
Reactant: CC=O
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzyl 3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (41 mg) in anhydrous THF (0.5 ml) is added dropwise over 5 mins to a stirring solution of lithium diisopropylamide (from 15.5 μl of diisopropylamine and 0.07 ml of 1.6 N BuLi) in anhydrous THF (1.5 ml) at -78°. The resulting solution is stirred at -78° for 10 mins and then treated with acetaldehyde (56 μl). After 5 more mins, saturated aqueous NH4Cl solution (1.5 ml) is added and the mixture is allowed to warm to room temperature. The mixture is diluted with ethyl acetate (20 ml), washed with H2O and brine, dried with MgSO4, filtered, and evaporated in vacuo to provide benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate as a mixture of diastereomers.
Reaction SMILES: C([O:8][C:9](=O)[NH:10][C@@H:11]([CH3:28])[CH:12]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)[OH:13])C1C=CC=CC=1.[OH-].[K+].C1COCC1.CO>CCOC(C)=O.[Cl-].[Na+].O>[F:26][C:24]([F:25])([F:27])[C:16]1[CH:15]=[C:14]([C@H:12]2[O:13][C:9](=[O:8])[NH:10][C@H:11]2[CH3:28])[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To [(S)-2-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-1-methyl-ethyl]-carbamic acid benzyl ester (11.9 mmol) was added 7.5N aqueous KOH:THF:MeOH (1:4:2; 60 mL), and the reaction was stirred at room temperature for 3 hours. Once no starting material was seen by analytical LCMS, the mixture was diluted with EtOAc and brine, and the organic layer was separated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([OH:38])[C:30]=2[CH2:39][CH2:40][CH3:41])[C:10]=1[CH2:42][CH2:43][CH3:44])C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH-].[Na+].CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])=[C:10]([CH2:42][CH2:43][CH3:44])[C:11]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([OH:38])[C:30]=1[CH2:39][CH2:40][CH3:41])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 89.6 %

Procedure:
A solution of 2.71 g of 4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoic acid ethyl ester in 20 ml of 1.0N sodium hydroxide and 90 ml of methanol was stirred at reflux for 6.5 hours. The methanol was removed in vacuo and the residue was acidified. The product was extracted with ether and the dried (magnesium sulfate) extract was concentrated in vacuo to an oil. Chromatography on 150 g of silica gel and elution with a solvent mixture of 5% acetic acid: 70% toluene: 25% ethyl acetate gave 2.32 g (90% yield) of 4-[4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]butanoic acid as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:6]=2[N:7]=1.[CH2:21]([NH2:23])[CH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:21][CH3:22])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1F
Reactant: CCN
Product: CCNc1nc(Cl)nc2c1COCC2c1ccc(F)c(F)c1

Procedure:
2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation Y) was reacted as described in Preparation Xa with ethanamine to give 2-chloro-8-(3,4-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Ya). LC-MS (M+H)+=326.1.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].[CH3:24]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O.[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6]([O:9][CH3:24])=[CH:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC1=CCC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CC1
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.3 g, 0.96 mmol) in dimethylformamide (3 mL) at 0° C. under an argon atmosphere was added potassium t-butoxide (0.11 g, 0.96 retool) and, 0.5h later, dimethyl sulfate (0.09 mL, 0.96 mmol). After 5 min, ammonium chloride was added, the mixture was extracted three times with ether, the organic extract was washed three times with water, once with brine, was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 9:1 hexanes/ethyl acetate, provided a white solid (0.06 g, 19%): m.p. 123°-125° C. Analysis Calc. for C20H25NO3 ·0.35 H2O:C 71.98, H 7.76, N 4.20; found: C 71.98, H 7.66, N 3.95
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]([CH3:32])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[C:24]([O:30][CH3:31])[CH:23]=1>>[CH3:32][N:21]([CH3:20])[C:22]1[CH:29]=[CH:28][C:25]([C:26]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N(C)C)ccc1C=O
Product: COc1cc(N(C)C)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)ccnc2[nH]1
Yield: 24.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-dimethylamino-2-methoxy-benzaldehyde (38.0 mg, 0.212 mmol) were reacted to produce 20 mg (29%) of the title compound. mp: 185-190° C., 1H NMR (300 MHz, DMSO-d6): 11.78 (s, 1H), 8.00 (d, J=8 Hz, 1H), 7.85 (d, J=5 Hz, 1H), 7.65 (s, 1H), 7.14 (s, 1H), 6.69 (d, J=8 Hz, 2H), 6.46 (d, J=8 Hz, 1H), 6.36 (d, J=8 Hz, 1H), 6.32 (br s, 3H), 3.96 (s, 3H), 3.01 (s, 6H), 2.86 (s, 1H), 2.75 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 419 (M+H), HPLC: 2.09 min (G method).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([OH:27])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:27])[N:29]([CH3:28])[CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: CNCc1cccnc1
Product: COc1cc2c(CC(=O)N(C)Cc3cccnc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with methyl-pyridin-3-ylmethyl-amine to give {6,7-dimethoxy-4-[(methyl-pyridin-3-ylmethyl-carbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C26H32N4O5+H 481.6; found 481.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][O:18][CH2:19][CH2:20]Br>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:20][CH2:19][O:18][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Amine preparation: To 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.5 g) in dry DMF (15 mL) was added sodium hydride (447 mg). After stirring for 2 hrs at room temperature, 2-bromoethyl methyl ether (0.7 mL) was added. The reaction mixture was heated to 40° C. overnight, and then diluted with ethyl acetate, washed with water and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4-(2-methoxy-ethoxy)-piperidine-1-carboxylic acid tert-butyl ester (447 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)([OH:3])=O.C(Cl)(=O)OCC(C)C.[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32])[CH3:25]>C(N(CC)CC)C>[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)=[O:3])[CH3:25]
Reactant: CCN1CCCC1CN
Reactant: O=C(O)c1ccc2c(c1)C(=O)C1(CC1)O2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Yield: 49.9 %

Procedure:
5-Carboxyspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (2.04 g.), triethylamine (1.4 ml.), isobutyl chlorocarbonate (1.5 g.) and N-ethyl-2-aminomethylpyrrolidine (1.4 g.) were allowed to react in the same manner as Example 58. The product was converted to oxalate by a known procedure and recrystallization from ethanol gave colorless prisms of 5-(1-ethyl-2-pyrrolidinyl)methylcarbamoylspiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one (1.567 g.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]1[CH2:16][N:15]([C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:20])[CH3:19])[C:14]1=[O:25].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:5]([O:4][C:2]([NH:12][CH:13]1[CH2:16][N:15]([C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:19])[CH3:20])[C:14]1=[O:25])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(=C(C)C)N1CC(N)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=C(C)C)N1CC(NC(=O)OCc2ccccc2)C1=O
Yield: 80.6 %

Procedure:
Benzyl chloroformate (7.9 g.) was dissolved in methylene chloride (50 ml.). A methylene chloride (20 ml.) solution containing 3-amino-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone (2.42 g.) and triethylamine (3.7 g.) was added dropwise to the solution at -15° to -10° C. in the course of 1.33 hours with stirring, whereafter the mixture was stirred at the same temperature for 1.25 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a residue, which was dissolved in ethyl acetate (150 ml.). The solution was washed three times with 5% hydrochloric acid and once with an aqueous sodium chloride, and then dried over magnesium sulfate. The solvent was removed by distillation and a residue (7.3 g.) was treated with n-hexane to give crude object compound, 3-benzyloxycarbonylamino-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone (3.27 g.). The compound (3.71 g.) thus obtained was subjected to column chromatography on silica gel (60 g.), and elution was carried out with chloroform and a mixture of chloroform and methanol (volume ratio; 10:1). The fractions containing the desired compound were collected and the solvent was distilled off from the eluate under reduced pressure to give the purified object compound (3.05 g.).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:10])[S:6][C:7]=1[C:8]#[CH:9])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:10])[S:6][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: C#Cc1sc(N)nc1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1nc(N)sc1CC
Yield: 70.3 %

Procedure:
The above prepared 4-ethyl-5-ethynyl-thiazol-2-ylamine (0.255 g, 1.675 mmol) was dissolved in 8 mL of ethyl acetate and hydrogenated over 0.125 g of Pd on charcoal (10%) at atmospheric pressure and ambient temperature over night. Filtration over a pad of Ceite and evaporation off all solvents, followed by flash chromatography (SiO2, hexane/ethyl acetate=6/4), yielded 0.184 g of the title product as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[CH2:23]([O:30][C@H:31]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]([CH2:43]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:23]([O:30][C@H:31]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]([CH2:43][O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:32]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(CCc2ccccc2OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)c1
Yield: 59.2 %

Procedure:
Following a procedure similar to that described in Example 40(a), 400 mg of 2-[2-(3-methylphenyl)ethyl]phenol (prepared as described in Preparation 25), 232 mg of potassium t-butoxide and 870 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine were reacted in 25 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 560 mg (yield 59%) of the title compound as a colorless oil.