Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([C:39]([F:50])([F:49])[CH2:40]OS(C(F)(F)F)(=O)=O)[CH:36]=[CH:37][CH:38]=1>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:40][C:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=3)([F:49])[F:50])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Reactant: O=S(=O)(OCC(F)(F)c1cccc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCC(F)(F)c3cccc(Cl)c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 5.8 %

Procedure:
To a mixture of 230 mg (0.67 mmol) of 2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl ester and 227 mg (1.62 mmol) of potassium carbonate in 6 ml of acetone and 1.7 ml of DMF was added slowly a solution of 437 mg (1.65 mmol) of the compound of step 2. The reaction mixture was stirred for 3 d at room temperature and then evaporated. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 20 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>C(#N)C>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Cc1ccc(C(=O)O)s1
Solvent: CC#N
Product: Cc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)s1
Temperature: 4 °C
Yield: 37.8 %

Procedure:
The procedure is identical to that described in Example 1, but starting with 5-methylthiophene-2-carboxylic acid (4.1 g), N,N'-carbonyldiimidazole (5.6 g) and 2-amino-7-chloro-1,8-naphthyridine (4.85 g). The product produced (3.8 g; m.p. 220° C.) is dissolved in boiling acetonitrile (150 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.066 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-methylthiophene-2-carboxamide (3.1 g) is produced, m.p. 222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][O:12][CH2:13]4.[CH2:20](Br)[CH:21]=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[CH2:10][CH2:11][O:12][CH2:13]3)[CH:21]=[CH2:20]
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCOC3
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(OC)cc13

Procedure:
A mixture of 3-methoxy-6-oxamorphinan (VIII) (0.005 m), allyl bromide (0.006 m) and potassium carbonate (2 g) in 20 ml acetonitrile is heated at reflux for 18 hours. The mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[N:6][CH:7]=[C:8]([CH3:10])[CH:9]=1.[K].[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:17]=1[CH2:18]Cl>C(O)C>[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:17]=1[CH2:18][O:3][C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[N:6][CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1cnc([N+](=O)[O-])c(O)c1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc([N+](=O)[O-])c(OCc2c(C)cccc2C)c1
Yield: 81.1 %

Procedure:
To 0.52 g (8.02 mmol) of 87% KOH and 0.15 g q-iodide in 6 ml 95% ethanol was added a solution of 3-hydroxy-5-methyl-2-nitropyridine (1.2 g, 7.79 mmol) in 25 ml of ethanol. To the resulting suspension of the potassium salt was added dropwise a solution of 2,6-dimethyl benzylchloride (1.24 g, 8.02 mmol) in 13 ml of ethanol. The reaction mixture was refluxed for 1 h. More 87% KOH (0.16 g) and 2,6-dimethylbenzylchloride (0.38 g) were added. The reaction mixture was refluxed for additional 70 min. The mixture was filtered and the inorganic salts were washed with ethanol and methylene chloride. The organic layer was evaporated in vacuo. The residue was dissolved in methylene chloride, washed with aqueous NaHCO3, dried and evaporated in vacuo. The residue was suspended in ether/isopropanol and filtered to give 1.72 g (81%) of the title compound.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[C:5]([C:7]1[C:8]([F:27])=[C:9]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[C:10]([C:12](=[CH:18][N:19]([CH3:21])C)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])#[N:6].C1(N)CC1.O>C1(C)C=CC=CC=1>[C:5]([C:7]1[C:8]([F:27])=[C:9]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[C:10]([C:12](=[CH:18][NH:19][CH:21]1[CH2:2][CH2:1]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])#[N:6]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(C#N)c1F
Reactant: CC(=O)O
Agent: NC1CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C#N)c1F
Temperature: 30 °C
Reaction time: 1 h

Procedure:
30 g of glacial acetic acid are added dropwise to the crude product from step e at 20° C. Then a solution of 15.75 g of cyclopropylamine in 30 ml of toluene is added dropwise. The reaction mixture is stirred at 30° C. for 1 hour. After the addition of 200 ml of water the mixture is stirred for 15 minutes. The organic phase is separated, extracted with 100 ml of water, dried with Na2CO3 and concentrated in vacuo. The crude product is used for the next step without further purification.
Reaction SMILES: [OH-].[K+].C(N(CC)CC)C.[CH3:10][O:11][C:12]1[C:13]([O:29]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:14][C:15]2[CH2:24][CH2:23][C:22](=[O:25])[C:21]3[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[C:26]=1[O:27][CH3:28].CO>O.C(O)(=O)C>[CH3:10][O:11][C:12]1[C:13]([OH:29])=[CH:14][C:15]2[CH2:24][CH2:23][C:22](=[O:25])[C:21]3[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[C:26]=1[O:27][CH3:28]
Reactant: COc1c(OS(=O)(=O)c2ccc(C)cc2)cc2c(c1OC)C1=C(CCC1)C(=O)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: COc1c(O)cc2c(c1OC)C1=C(CCC1)C(=O)CC2
Yield: 89 %

Procedure:
4.5 g of potassium hydroxide, then 10 ml of triethylamine were added to a suspension of 10 g of 9,10-dimethoxy 8-(((4-methylphenyl)sulfonyl)oxy) 2,3,5,6-tetrahydro-benz[e]-azulen-4(1H)-one of Stage B of Example 3 and 100 ml of methanol. The reaction medium was heated for one hour at reflux, acidified by the addition of 20 ml of acetic acid and then 20 ml of water were added. Extraction was carried out with dichloromethane and the extracts were washed with water. The solvent was evaporated at 40° C. under reduced pressure to obtain 5.7 g of the expected product which was used as is for the following stage.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]([CH3:35])[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:32]3[CH2:33][CH2:34][CH:29]([N:28]([CH3:35])[CH3:27])[CH2:30][CH2:31]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.8 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added N,N-dimethylpiperidin-4-amine (40 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 59 as a solid (10 mg).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:28](Br)[CH:29]=[CH2:30]>>[CH2:30]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: C=CCOc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 367 and allyl bromide, white powdery N-[2-(4-allyloxy-3-difluoromethoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 98.
Reaction SMILES: [C:1]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(N(C2CCCCC2)[C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[C:28](C)[CH:27]=2)CCCC1>C1COCC1>[C:1]([N:5]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC1CCCCC1
Reactant: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C. to 5° C.) stirred solution of N-tertbutyl-N-cyclohexyl amine (3.73 g, 24 mmol) and triethylamine (2.5 g, 24 mmol) in dry THF (50 mL) is added dropwise a solution of acid chloride (5.0 g, 23 mmol) in THF (20 mL). The reaction is stirred at room temperature overnight and worked up in the same manner as for 4-bromo-3-methylbenzoic acid N-cyclopentyl-N-cyclohexyl amide. The crude product is purified by either recrystallization or by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:41]=[C:42]([CH3:45])[S:43][CH:44]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[N:41]=[C:42]([CH3:45])[S:43][CH:44]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: Cc1nc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cs1
Yield: 76.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 4-(chloromethyl)-2-methylthiazole (0.55 g) as starting materials, 5-benzyloxy-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.62 g) was obtained.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.C(=O)=O.[CH3:23][C:24]([CH3:26])=[O:25].[Cl-].[NH4+]>C1COCC1>[Br:19][C:15]1[N:14]=[C:13]([C:24]([OH:25])([CH3:26])[CH3:23])[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)c1cccc(Br)n1
Temperature: -76 °C
Yield: 98.1 %

Procedure:
Place a 1.6 M solution of n-butyl lithium in hexane (31.2 mL, 50 mmol) in a dry 250 mL round bottomed flask fitted with a stir bar, septum and temperature probe. Cool in a dry-ice acetone bath to −76° C. Add THF (30 mL) to the solution, then add a solution of 2,6-dibromopyridine (11.5 g, 50 mmol) in THF (60 mL) slowly via syringe maintaining the temperature under −60° C. Stir the dark yellow-brown solution for 30 minutes in the dry-ice bath, then add acetone (6 mL, 80 mmol). Stir the deep green solution in the dry-ice bath for 15 minutes then allow the reaction to warm to room temperature. After an hour add a 5% aqueous solution of ammonium chloride (50 mL) carefully. Extract with dichloromethane, evaporate to give 2-(6-bromo-pyridin-2-yl)-propan-2-ol (10.6 g, 98%) as an orange oil. MS (m/z): 216 and 218 (M+H)+.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([O:10][C:11](=[O:27])[NH:12][CH2:13][CH2:14][C@@H:15]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH2:16][OH:17])([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:15]([CH2:14][CH2:13][NH:12][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:27])[CH2:16][O:17][S:1]([CH3:4])(=[O:3])=[O:2])=[C:19]([O:25][CH3:26])[CH:20]=1
Reactant: COc1cc(Br)ccc1[C@@H](CO)CCNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)ccc1[C@H](CCNC(=O)OC(C)(C)C)COS(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
Mesyl chloride (93.7 μL, 1.21 mmol) was added to a solution of [(S)-3-(4-bromo-2-methoxy-phenyl)-4-hydroxy-butyl]-carbamic acid tert-butyl ester (394 mg, 1.0527 mmol) in DCM (7.5 mL) under argon atmosphere at −78° C., followed by addition of TEA (0.336 mL, 2.42 mmol). The mixture was stirred at −78° C. for 1 hour and then at room temperature for an additional hour. A solution of aqueous NaHCO3 (10%) was added, and the organic layer was separated and dried over Na2SO4. Solvent was evaporated under reduced pressure and to afford 480 mg of crude methanesulfonic acid (S)-2-(4-bromo-2-methoxy-phenyl)-4-tert-butoxycarbonylamino-butyl ester. This material was dissolved in THF (4 mL) under Ar atmosphere and cooled to 0° C. KHMDS (0.5 M in toluene, 2.32 mL, 1.158 mmol) was added, and the reaction mixture was stirred for 1 hour at room temperature. A saturated solution of NH4Cl was added, followed by brine, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 98/2) to give 315 mg (84% yield) of (S)-3-(4-bromo-2-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 99% ee determined by chiralcel HPLC column and hexane/i-PrOH (9/1) as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[CH:14][N:15]([CH3:17])[CH3:16])=[O:5]
Reactant: NC(=O)c1cccc(Cl)c1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
2,3-Dichlorobenzamide (4.96 g, 26.1 mmol) and dimethylformamide dimethylacetal (10 mL) were heated at reflux for 1.5 hours, allowed to cool to room temperature, concentrated under reduced pressure, and the residue was partitioned between diethyl ether and water. The organic phase was washed with water (2×), saturated sodium chloride, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate to provide the title compound. MS (DCI/NH3) m/z 245 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:26])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2Br)[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:26])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:29]#[N:30])[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Br)c2c(=O)n1-c1ccccc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(C#N)c2c(=O)n1-c1ccccc1
Temperature: 90 °C

Procedure:
(S)-tert-butyl(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (500 mg, 1.13 mmol), zinc cyanide (166 mg, 1.41 mmol), and tetrakis(triphenylphosphine)Pd(0) (124 mg, 0.11 mmol) were combined in NMP (5 mL). The mixture was degassed under Ar and heated to 90° C. overnight. The reaction was poured into EtOAc, washed with water (3×), and purified by flash chromatography (40 g silica, 0-50% EtOAc/hexanes) to give (S)-tert-butyl(1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate as a white solid. ES/MS 391.2 (M+H+).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH2:9]([C@@:12]1([CH3:37])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N+:14]2[C@@H:32]([CH2:35][CH3:36])[CH2:33][O:34][C:13]1=2)[CH:10]=[CH2:11].[Na+].[CH:39]1([S:42]([O-:44])=[O:43])[CH2:41][CH2:40]1>C(#N)C>[CH2:9]([C@@:12]1([CH3:37])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[N:14]([C@@H:32]([CH2:35][CH3:36])[CH2:33][S:42]([CH:39]2[CH2:41][CH2:40]2)(=[O:44])=[O:43])[C:13]1=[O:34])[CH:10]=[CH2:11]
Reactant: O=S([O-])C1CC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2CC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CS(=O)(=O)C2CC2)C1=O
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium trifluoromethanesulfonate (75 mg, 0.130 mmol; Example 339, Step A) in acetonitrile (1.3 mL) was added cyclopropanesulfinic acid sodium salt (50 mg, 0.39 mmol) at 25° C. After being stirred at 90° C. for 1 day, the reaction was quenched with sat. aq. NH4Cl solution, extracted (2×EtOAc) and the combined organic layers wer washed with brine (2×), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 35% and 45% EtOAc/hex) provided the title compound as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:7]=3[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1>O1CCOCC1.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:6]2[C:5]3[C:10](=[C:11]([F:12])[C:2]([F:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:13])[C:7]=2[CH:14]=1
Reactant: O=c1oc2c(F)c(F)ccc2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)c(=O)oc1c(F)c(F)ccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.1 %

Procedure:
3,4-Difluoro-8-nitrobenzo[c]chromen-6-one (Reference Compound No. 1-2-(3), 3.75 g, 13.5 mmol) was dissolved in 1,4-dioxane (300 mL), then 5% palladium on charcoal (375 mg) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature for 4 days. After the mixture was filtered, the filtrate was removed under reduced pressure. 1,4-Dioxane was added to the obtained residue, and then filtered to give the titled reference compound (2.44 g) as an orange solid. (Yield 73%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:10]([NH:11][C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH3:13])[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1C(N[C@@H](C)c1cccc(F)c1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1C(N[C@@H](C)c1cccc(F)c1)c1cccc(N)c1
Yield: 29.3 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(2-methoxyphenyl)methyl]-N-[(S)-1-(3-fluorophenyl)ethyl]amine (2.96 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.70 g) and sodium borohydride (1.24 g) were reacted, and the crude product was purified by reverse phase HPLC using a 40:60 by volume mixture of acetonitrile and an acetic acid buffer solution (water/acetic acid/triethylamine=1000:2:2) as the eluant, to afford isomer A of the title compound (540 mg) as a yellow oil and isomer B of the title compound (800 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.CO[C:24](OC)([N:26]([CH3:28])[CH3:27])[CH3:25]>C1(C)C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([N:1]=[C:24]([N:26]([CH3:28])[CH3:27])[CH3:25])[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2N)CC1
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=Nc1nc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1)N(C)C

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(3-amino-5-bromopyrazin-2-yl)piperazine-1-carboxylate (1.0 g, 2.8 mmol), N,N-dimethylacetamide dimethyl acetal (0.44 g, 3.3 mmol) and toluene (20 mL). The mixture was heated at reflux for 11 h. Work-up: the solvent was evaporated to dryness. The product was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[O-:10][C:11]#[N:12].[K+].Cl>O>[C:7]([OH:9])(=[O:8])[CH2:2][NH:1][C:11]([NH2:12])=[O:10].[NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: N#C[O-]
Agent: CSCCC(N)C(=O)O
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCC(=O)O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
150 Grams (1 mole) of DL-methionine and 100 g (1 mole) of potassium cyanate having 80% purity were mixed with 700 ml of water and stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction solution was adjusted to pH 2~3 with 12% hydrochloric acid to obtain 154 g of DL-methionine hydantoic acid having a melting point of 95°~98° C.
Reaction SMILES: [Br:1][CH2:2][Si:3](Cl)([CH3:5])[CH3:4].[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[Br:1][CH2:2][Si:3]([CH3:5])([CH3:4])[NH:11][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)CBr
Solvent: CCOCC
Product: CC(C)(C)N[Si](C)(C)CBr
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a stirred solution of 10.00 g (53.32 mmol) of (bromomethyl)chlorodimethylsilane in 200 ml, of diethylether a solution of 7.80 g (106.64 mmol) of t-butyl amine in 10 mL of ether was added. A white solid deposited instantaneously. The reaction mixture was stirred overnight, filtered through a medium frit and the solvent was removed under reduced pressure to give 11.06 g of colorless liquid. Yield 93 percent.