Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([Cl:26])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccccc1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC1C=CC(S(O[C@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)(=O)=O)=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@:24]2([O:33][C@H:32]([CH2:34][OH:35])[C@@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[OH:25])=[CH:20][C:19]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@:24]2([O:33][C@H:32]([CH2:34][OH:35])[C@@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[OH:25])=[CH:20][C:19]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][C@@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O[C@@H]4CCOC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 75 °C
Reaction time: 14 h

Procedure:
0.19 g (S)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75° C. for 4 h, before another 0.29 g caesium carbonate and 0.19 g (S)-3-(4-methylphenyl-sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75° C. the mixture is cooled to ambient temperature, and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu](C#N)[C:25]#[N:26]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:23])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([C:25]#[N:26])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 170 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (Compound A4, 10.45 g, 28.2 mmol) and copper cyanide (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml) and stirred at 170° C. for 17 hours. The reaction mixture was suspended in ethyl acetate (500 ml) and distilled water (200 ml). The insoluble matters were filtered off using Celite, and washed with ethyl acetate (300 ml×2). The organic layer was washed once with aqueous solution of disodium EDTA (200 ml) and twice with saturated brine (200 ml) in order, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resultant was suspended and washed with a small amount of CPME to give the title compound as a colorless crystal (6.58 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:27]2[CH:28]=[CH:23][N:24]=[C:25]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:26]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: C[Si](C)(C)CCOc1nccc(Cl)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(OCC[Si](C)(C)C)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (1 g, 3.20 mmol) and 4-chloro-2-[2-(trimethylsilyl)ethoxy]pyrimidine (0.739 g, 3.20 mmol) (see J. Het. Chem., 1994, 989-995) as the starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH2:22][O:21][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: COC[C@@H]1CCCN1C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (2S)-2-methoxymethyl-pyrrolidine (0.087 g, 0.76 mmol) gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22](C)[CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:28][CH:30]3[O:32][CH2:31]3)=[CH:24][CH:25]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3c2CCCC3)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(C(c2ccc(OCC3CO3)cc2)c2cccc3c2CCCC3)cc1
Temperature: 120 °C

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane (410 mg, 0.001 mol), epichlorohydrin (25 ml) and anhydrous K2CO3 (2.0 gm, 0.014 mol) was refluxed at 120° C. for 6 hrs, K2CO3 was filtered off and the filtrate was concentrated. The residue obtained was dissolved in ethyl acetate and washed with water, dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel using hexane:chloroform as the eluent to give the title compound. Yield 388 mg (82.37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[C:11]([F:32])=[CH:12][C:13]([O:20][C@H:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:14]([CH:19]=1)[C:15]([O:17]C)=O)(=[O:9])=[O:8].[OH-].[Na+].Cl.C[N:49]1CCOCC1.ClC(OCC(C)C)=O.O.N>C1COCC1>[CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[C:11]([F:32])=[CH:12][C:13]([O:20][C@H:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:14]([CH:19]=1)[C:15]([NH2:49])=[O:17])(=[O:8])=[O:9]
Reactant: CN1CCOCC1
Reactant: COC(=O)c1cc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccnn1C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C(N)=O)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
To a solution of the methyl 5-{[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-4-fluoro-2-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzoate (83.3 mg, 0.133 mmol) prepared in Example 62b in THF (2.0 mL), a 5 M aqueous sodium hydroxide solution (2.0 mL) was added, and the reaction solution was stirred at room temperature for 15 hours. To the reaction solution, 1 M hydrochloric acid (10 mL) was added with cooling on ice, followed by extraction with ethyl acetate. The thus obtained organic layer was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and vacuum concentrated, and THF (2.0 mL) was added to the obtained residue. To the reaction solution, 4-methylmorpholine (20.0 μL, 0.183 mmol) and isobutyl chloroformate (23.0 μL, 0.183 mmol) were added in that order with cooling on ice, and the mixture was stirred for 1 hour with cooling on ice. Then, 28% ammonia water (2.0 mL) was added thereto, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, saturated saline was added, followed by extraction with ethyl acetate. The thus obtained organic layer was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and vacuum concentrated, and the obtained residue was purified with silica gel chromatography (dichloromethane/methanol=85:15) to yield the title compound (64.2 mg, 86%) as a colorless amorphous solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][N:20]=3)[C:15](=[O:30])[N:14]([CH3:31])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:32]1[N:41]=[CH:40][C:39]2[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=2)[C:33]1=[O:47])(=O)C.[Li+].[OH-]>O1CCOCC1>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])=[CH:21][N:20]=4)[C:15](=[O:30])[N:14]([CH3:31])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:41]=[CH:40]2)([CH3:43])([CH3:44])[CH3:45]
Reactant: CCS(=O)(=O)c1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)nn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
In a 250 mL round-bottomed flask, 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(ethylsulfonyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (159 mg, 241 μmol) was combined with dioxane (5 ml) and 1M LiOH (1 ml) to give a brown solution. The reaction mixture was stirred at 25° C. for 18 h. The crude reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 4% MeOH in DCM) to afford 0.039 g (54%) of the title compound as a tan solid. (M−H)+=617 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.85 (d, J=2.3 Hz, 1H), 8.79 (s, 1H), 8.63 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.06 (dd, J=8.7, 2.3 Hz, 1H), 7.43-7.73 (m, 5H), 7.07 (d, J=8.7 Hz, 1H), 4.45 (s, 2H), 3.94 (s, 3H), 3.15 (d, J=7.2 Hz, 2H), 1.44 (s, 9H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][CH2:23]CO2)=[C:16](COCOC)[CH:15]=1.Cl>C1COCC1.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[B:20]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[O:24][CH2:23][C:18]=2[CH:19]=1
Reactant: Brc1cccnc1
Reactant: COCOCc1cc(F)ccc1B1OCCO1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)COB2c1cccnc1
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a solution of 3-bromopyridine (731 mg, 4.63 mmol) in THF (5 mL) was added isopropylmagnesium chloride (1 M in THF; 2.3 mL) at room temperature under nitrogen atmosphere, and the mixture was stirred for 1 h. To the mixture was added compound 6 (1.11 g, 4.63 mmol) in THF (4 mL), and the mixture was stirred at room temperature overnight. Water was added and the pH was adjusted to 7 with 1 N HCl. Then the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was dissolved in THF (30 mL). To the mixture was added 1 N HCl (10 mL), and the mixture was refluxed overnight. The pH was adjusted to 7 with aqueous NaHCO3 and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was recrystallized from i-Pr2O to afford compound 15 (76 mg, 7.7%): mp 210-212° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.94 (s, 2H), 6.9-7.1 (m, 2H), 7.36 (br s, 1H), 7.66 (dd, J=6.7, 5.3 Hz, 1H), 8.19 (d, J=6.7 Hz, 1H), 8.24 (br s, 1H), 8.64 (d, J=5.3 Hz, 1H): ESI-MS m/z 214 (M+H)+; Anal (C12H9BFNO.0.6H2O)C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:8][S:7][C:6]=2[CH:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:18]1([CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:8][S:7][C:6]=3[CH:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)Nc1csc2cc(O)ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Nc1csc2cc(OCc3ccccc3)ccc12
Yield: 83.6 %

Procedure:
A mixture comprising 2 g (8.4 mmol) of ethyl (6-hydroxybenzo[b]thien-3-yl)carbamate, 2.16 g (12.6 mmol) of benzyl bromide and 2.3 g (16.8 mmol) of potassium carbonate in 30 ml of acetonitrile is heated at reflux for 11 hours. The mixture is filtered, the solvent is evaporated under reduced pressure and the residue is triturated in petroleum ether. 2.3 g of product are obtained.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1>C1COCC1>[CH3:1][S:2][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Sodium thiomethoxide (805 mg, 11.5 mmol) was added to a solution of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (Intermediate 182, 3.20 g, 11.5 mmol) and THF (15 ml) at 0° C. The resultant mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was quenched with water (15 ml) and diluted with ethyl acetate (150 ml). The organic phase was separated and washed with brine. The combined aqueous phase was back extracted with ethyl acetate (50 ml). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (hexanes/ethyl acetate, 7:1) to provide the title compound (2.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1.[C:21](OC(=O)CC)(=O)[CH2:22][CH3:23]>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[C:2]([NH:1][CH2:21][CH2:22][CH3:23])[CH:7]=1
Reactant: COc1ccc(C2CCc3cc(O)ccc3C2)c(N)c1
Reactant: CCC(=O)OC(=O)CC
Product: CCCNc1cc(OC)ccc1C1CCc2cc(O)ccc2C1

Procedure:
Synthesized from 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (500 mg) and propionic anhydride (1 ml) according to an analogous synthetic method to Example 36, the title compound (270 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:15]C(OC(C)(C)C)=O)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23].CCOCC>>[ClH:23].[NH2:15][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NC(CCOCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CCOCC
Product: NC(CCOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a round bottom flask containing 4-benzyloxy-2-tert-butoxycarbonylamino-butyric acid (1.0 mmol), add 1M hydrochloric acid in ether (1.7 mmol) and stir at room temperature for two days. The product precipitates out as the hydrochloride salt. Collect by centrifugation in which the mother liquor is decanted off of the product. Rinse two times with ether, transfer solid to a flask and concentrate in vacuo.
Reaction SMILES: S(=O)(=O)(O)N.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15])[CH:10]=[O:11].Cl([O-])=[O:18].[Na+]>O.C(O)(C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15])[C:10]([OH:18])=[O:11]
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(C=O)cc(Cl)c1O
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(C(=O)O)cc(Cl)c1O
Temperature: 12 °C
Yield: 52 %

Procedure:
A solution of sulfamic acid (11.8 g, 121.5 mmol) in water (25 mL) was added with vigorous stirring to 3-chloro-4-hydroxy-5-methylbenzaldehyde (16.00 g, 93.8 mmol) in tert-butanol (100 mL). The mixture was cooled (˜12° C.) and a solution of sodium chlorite (12.00 g, 106.1 mmol) in water (25 mL) was added in 5 mL portions with vigorous stirring. The reaction was exothermic and the temperature at the end of the addition was approximately 50° C. The two layers were separated and the aqueous layer was extracted with ether (2×50 mL). The organic layers were washed with brine and evaporated to dryness. Water was added, and the mixture was stirred and filtered. The solid was dissolved in warm ether (250 mL), and the solution was dried, filtered, concentrated to 100 mL, and cooled in the freezer (approx. −20° C.). Filtration and washing with cold ether gave 3-chloro-4-hydroxy-5-methylbenzoic acid (9.10 g, 52%), as a yellow solid, mp 242–244° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:14])=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1.CC(O)=O.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH2:20]>CO>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:19][CH2:20][NH:1][C:2]1[C:3]([F:14])=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1c(F)ccc(N)c1F
Reactant: C=Cc1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1c(F)ccc(NCCc2ccccn2)c1F

Procedure:
A solution of 402 mg (2.0 mmol) of methyl 3-amino-2,6-difluorophenylacetate (prepared in step 3 of example 24) in 15 mL of MeOH was treated with 1.1 mL (20.0 mmol) of HOAc and 0.28 mL (2.6 mmol) of 2-vinylpyridine. The reaction mixture was stirred at reflux for 16 h. The mixture was cooled and the acetic acid was removed in vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO3 (4×5 mL), water (1×10 mL) and brine. Column chromatography (1:4 EtOAc/Hex) afforded methyl 3-(2-pyridylethyl)amino-2,6-difluorophenylacetate.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[S:46][C:47]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:48]([CH3:50])[N:49]=2)=[CH:41][C:40]=1[N:56]1[CH:60]=[N:59][N:58]=[N:57]1>O1CCCC1.O.C1(C)C=CC=CC=1>[OH:4][CH2:3][CH:2]([CH3:1])[CH2:5][O:6][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[S:46][C:47]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:48]([CH3:50])[N:49]=2)=[CH:41][C:40]=1[N:56]1[CH:60]=[N:59][N:58]=[N:57]1
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(-n3cnnn3)c2)nc1C
Reactant: CC(CO)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)CO)c(-n3cnnn3)c2)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 168 %

Procedure:
A solution was prepared by dissolving 13.5 mg of 2-methypropan-1,3-diol in 1 mL of tetrahydrofuran and adding 39.3 mg of triphenylphosphine and 65 μL of a 40% toluene solution of diethyl azodicarboxylate to the mixture. After stirring the resultant solution at room temperature for 30 minutes, a reaction mixture solution prepared by adding 33.1 mg of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate to the solution was stirred at room temperature for 3 hours. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure, followed by purifying by a conventional method to obtain 67.7 mg of ethyl 2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [N:1]([CH:4]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][N:15]3[CH2:19][CH2:20][CH2:21][CH:14]3[C:13]=2[C:12]2[CH:11]=[C:10]([CH3:22])[CH:9]=[CH:8][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+].N>C(O)C.O.[Zn]>[CH3:22][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:5][CH:4]([NH2:1])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:18]3[CH2:17][CH2:16][N:15]4[CH2:19][CH2:20][CH2:21][CH:14]4[C:13]=3[C:12]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN2CCCC12
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN2CCCC12
Temperature: 80 °C
Yield: 10.8 %

Procedure:
6-(2-Azido-2-pyridin-4-yl-ethyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (400 mg, 1.07 mmol) was dissolved in ethanol-water (10 mL:1 mL). Zinc dust (280 mg, 4.3 mmol) and ammonium chloride (228 mg, 4.3 mmol) were added and the reaction mixture was heated at 80° C. for 1 h. After consumption of starting material, the reaction mixture was filtered through Celite and filtrate was concentrated to obtain the residue. The residue was basified with aq ammonia and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 40 mg of 2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyridin-4-yl-ethylamine as the TFA salt. 1H NMR (CDCl3, freebase): δ (ppm): 8.58 (d, 2H), 7.28 (d, 1H), 7.25 (s, 1H), 7.23 (d, 2H), 7.1 (d, 1H), 4.9 (m, 1H), 4.42 (t, 1H), 4.13 (dd, 1H), 3.63 (m, 1H), 3.4 (m, 2H), 3.01 (m, 2H), 2.71 (m, 2H), 2.45 (s, 3H), 2.23 (m, 2H), 2.01 (m, 1H). Chiral HPLC separated the racemate into diastereomers II-4-a-d.