Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]([O:52][CH3:53])=[O:51])[C:43]1=[O:54]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]([O:52][CH3:53])=[O:51])[C:43]1=[O:54])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)CN1CCCC[C@H](N)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)CN1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C(=O)OC)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(2-methoxy-2-oxoethyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 28 (5.0 mg, 0.025 mmol) to give a white solid (2.8 mg, 29% yield). Anal. Calcd. for C40H52N4O8S m/z 748.5. found: 749.5 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.28-7.08 (m, 10H), 5.53 (dd, J=6.3, 3.0 Hz, 1H), 5.03-4.95 (m, 2H), 4.65-4.55 (m, 1H), 4.25-4.15 (m, 1H), 4.08-4.01 (m, 1H), 3.72 (dd, J=15.4, 10.4 Hz, 1H), 3.67 (s, 3H), 3.64 (s, 3H), 3.35 (d, J=2.7 Hz, 1H), 3.11-3.01 (m, 1H), 2.83 (ddd, J=14.3, 6.9, 3.0 Hz, 1H), 2.80-2.62 (m, 6H), 2.34 (d, J=13.7 Hz, 1H), 2.15-2.04 (m, 1H), 2.03-1.94 (m, 1H), 1.90-1.82 (m, 1H), 1.79-1.51 (m, 13H), 1.35-1.25 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:30]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added MeI (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 62 mg (59%) of the title compound as an off white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[C:13](OC)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[O:20]=[C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COC(=O)c1cccnc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1cccnc1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of n-butyl lithium in hexanes (9.0 mL, 1.6 M, 14 mmol) was added over 10 min. to a solution of dimethyl methylphosphonate (1.50 mL, 1.72 g, 13.8 mmol) in THF (60 mL) cooled in a dry ice/isopropanol bath. After 30 min., a solution of methyl nicotinate (757 mg, 5.52 mmol) in THF (6 mL) was added over 2 min. The solution was stirred in the cooling bath for 45 min. before being allowed to warm to 0° C. over 1 h. The reaction was quenched with saturated aq. NHCl (50 mL) and then partitioned between saturated aq. brine (50 mL) and methylene chloride (200 mL). The aq. layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried (sodium sulfate) decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with ethyl acetate followed by 97:3 v/v methylene chloride/CH3OH, gave material containing some residual impurity. Further purification by flash column chromatography on silica gel, eluting with 50:50:5 v/v/v to 50:50:10 v/v/v toluene/ethyl acetate/CH3OH gave 1.15 g of the title compound. For the title compound: 1H NMR (500 MHz, CDCl3) δ 9.26-9.20 (bs, 1H), 8.83 (d, J=4, 1H), 8.34 (dt, J=8, 2, 1H), 7.70 (dd, J=8, 4, 1H), 3.82 (d, J=11, 6H), 3.67 (d, J=24, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[CH:13]([O:16][C:17]([N:19]1[C:28]2[C:23](=[N:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C@H:22]([NH:31][CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[CH2:21][C@@H:20]1[CH3:47])=[O:18])([CH3:15])[CH3:14]>ClCCl>[CH:13]([O:16][C:17]([N:19]1[C:28]2[C:23](=[N:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C@H:22]([N:31]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:21][C@@H:20]1[CH3:47])=[O:18])([CH3:15])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(OC)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
Add ethyl chloroformate (0.118 mL, 1.240 mmol), followed by pyridine (0.205 mL, 2.52 mmol), to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.210 g, 0.415 mmol) in dichloromeihane (3 mL). After stirring at room temperature for 12 h remove the solvent in vacuo. Purify using silica gel chromatography, eluting with ethyl acetate/hexane (gradient eluent, 0-30% ethyl acetate in hexane) to afford the title compound (0.218 g, 92%): MS (ES+): 578 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[F:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CC(C)C(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(F)c1
Product: CC(C)C(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(F)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.06 mmol, Step-1, single enantiomer) and isobutyryl chloride (120 mg, 1.1 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([S:14](F)(=[O:16])=[O:15])[S:12][CH:13]=2)=[N:6][CH:7]=1.[NH2:23][CH2:24][CH:25]1[CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CC(O)CC>[CH:25]1([CH2:24][NH:23][S:14]([C:11]2[S:12][CH:13]=[C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:18][CH:19]([CH3:22])[CH2:20][OH:21])[C:2]([Br:1])=[CH:7][N:6]=3)[CH:10]=2)(=[O:16])=[O:15])[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: C[C@H](CO)Nc1nc(Nc2csc(S(=O)(=O)F)c2)ncc1Br
Agent: CN(C)c1ccncc1
Solvent: CCC(C)O
Solvent: CCN(CC)CC
Product: CC(CO)Nc1nc(Nc2csc(S(=O)(=O)NCC3CC3)c2)ncc1Br

Procedure:
A reaction mixture of 130 mg (0.31 mmol) of (R)-4-[5-bromo-4-(2-hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonyl fluoride, 22 mg (0.31 mg) of aminomethylcyclopropane, 43 μl (0.31 mmol) of triethylamine as well as 38 mg (0.31 mmol) of DMAP in 2-butanol is stirred under reflux for 43 hours. It is mixed again with 22 mg (0.31 mg) of aminomethylcyclopropane, 43 μl (0.31 mmol) of triethylamine as well as 38 mg (0.31 mmol) of DMAP and stirred for another 24 hours under reflux. After cooling, the batch is purified by chromatography (Flashmaster II, DCM/ethanol 95:5), and the crude product that is obtained is recrystallized (ethanol/diisopropyl ether). 35 mg (0.08 mmol, 26% of theory) of the product 4-[5-bromo-4-(2-hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonic acid cyclopropylmethyl-amide is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[N:17]=[CH:18][S:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:33]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[N:17]=[CH:18][S:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nccc3c2)cc1
Temperature: 125 °C

Procedure:
To a solution of 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)isoquinoline-6-sulfonamide (0.10 g, 0.224 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.064 g, 0.292 mmol) and cesium carbonate (0.292 g, 0.897 mmol) in DME (2.437 ml) and Water (0.366 ml) was added Pd(PPh3)4 (0.026 g, 0.022 mmol) in one portion. The resulting mixture was heated to 125° C. in the microwave for 2 hours. The resulting mixture was transferred to a seperatory funnel and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude mixture was purified by the silica gel chromatography (100% hexanes to 25% EtOAc in hexanes to 90% EtOAc in heptanes). m/z (ESI) 586.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O)(=O)C>ClCCCl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccn1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(CNc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a solution of 4-nitrobenzaldehyde (3.02 g) and 2-aminopyridine (1.88 g) in 1,2-dichloroethane (70 ml) were added triacetoxy sodium boro hydride (5.93 g) and acetic acid (1.14 ml), and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours and concentrated. To the residue was added sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, washed with brine, dried (anhydrous magnesium sulfate) and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1/1), and to the purified materials were added ethyl acetate/diethylether and 1N hydrochloric acid. The aqueous layer was extracted and washed with diethylether, and to the mixture was added sodium carbonate. The mixture was extracted with ethyl acetate, and the extract was dried (anhydrous magnesium sulfate), concentrated and recrystallized from ethyl acetate/hexane to give 2-[(4-nitrophenyl)methylamino]pyridine (1.63 g) as pale yellow crystals.
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(CCNc1ccc(C#N)cn1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl) [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-cyanopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl{2-[(5-cyano(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]OS(C)(=O)=O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][S:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ccc(S)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cccc(COS(C)(=O)=O)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-thiol (161 mg) in DMF (2.6 mL) were added ethyl 3-cyclopropyl-3-(3-(((methylsulfonyl)oxy)methyl)phenyl)propanoate (207 mg) and potassium carbonate (146 mg) at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (267 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1-c1ccc(F)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: Fc1ccc(-c2ccccc2CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4′-Fluoro[1,1′-biphenyl]-2-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.Cl.[CH2:15]([O:18][NH2:19])[CH:16]=[CH2:17]>CN(C=O)C.CCOC(C)=O>[CH2:15]([O:18][N:19]=[CH:1][C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[C:16]1[CH:5]=[CH:4][CH:3]=[CH:1][CH:17]=1
Reactant: C=CCON
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)/C=C/c1ccc(C=NOCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
a solution of trans 4-formyl-cinnamic acid A (Y═CH═CH, R1, ═H, R3═H, 0.346 g, 1.96 mmol.) and B O-Allylhydroxylamine hydrochloride (0.258 g, 2.37 mmol.) dissolved in 2 mL of DMF was warmed at 50° C. and stirred for 5 h. Then the solution was diluted with AcOEt and washed with water. Organic layer was dried on Na2SO4 and then concentrated under reduced pressure to give 0.421 g of the intermediate C (2E)-3-(4-{[(benzyloxy)imino]methyl}phenyl)acrylic acid (93% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C=O)C>[Cl:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCCC1
Yield: 82 %

Procedure:
A solution of 6methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (228 mg, 7.9 mmol) in thionyl chloride (5 ml) and DMF (0.2 ml) was heated at reflux for 1 hour. Toluene was added and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and cooled aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (200 mg, 82%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]#[N:7])=[O:4].FC(F)(F)C1C(C2C=CC=CC=2)=C(N)O[N:19]=1>>[F:1][C:2]([F:14])([F:15])[C:3]1[O:4][N:7]=[C:6]([NH2:19])[C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1onc(C(F)(F)F)c1-c1ccccc1
Reactant: N#CC(C(=O)C(F)(F)F)c1ccccc1
Product: Nc1noc(C(F)(F)F)c1-c1ccccc1
Yield: 83.2 %

Procedure:
A crude product was obtained according to the same procedure as described in Example 1 except that α-(trifluoroacetyl)phenylacetonitrile (23.12 g, 0.10 mole) was used. Crude yield: 3.69 g (16.2%). According to the measurement of NMR, it was found that this compound contained 83.2% of the title compound and 11.8% of 3-trifluoromethyl-4-phenyl-5-aminoisoxazole. The crude product was purified by column chromatography on silica gel as described in Example 1 to give the title compound (3.06 g, 13.4%) as colorless crystals, m.p. 91.5°-92.0° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH3:21])[N:16]([CH:18]([F:20])[F:19])[CH:17]=2)=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>ClC(Cl)(Cl)Cl>[Cl:4][C:17]1[N:16]([CH:18]([F:20])[F:19])[C:15]([CH3:21])=[N:14][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nc(-c2ccc(Cl)cc2)cn1C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(-c2ccc(Cl)cc2)c(Cl)n1C(F)F
Reaction time: 2 h

Procedure:
26.7 g (0.19 mol) of sulfuryl chloride were added dropwise with ice-cooling to a suspension of 24 g (98 mmol) of 4-(4-chlorophenyl)-1-difluoromethyl-2-methyl-1H-imidazole in 200 ml of tetrachloromethane. After the reaction mixture had been stirred for 2 hours, an excess of saturated aqueous sodium hydrogen carbonate solution was added dropwise (still with ice-cooling). The solids were subsequently filtered off. The organic phase was washed with water until neutral, dried over magnesium sulfate and concentrated. The crude product was purified by means of silica gel column chromatography (eluent: hexane/ethyl acetate=8:1). Yield: 7.4 g.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH3:19]I>C1COCC1.CCOC(C)=O>[CH3:19][N:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cccc(Nc2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cccnc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
NaH (61 mg, 2.5 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (6 mL) was added. The slurry was cooled to 0° C. and compound 15 (500 mg, 2.33 mmol, 1.00 eq) was added as a solution in THF (6 mL). After stirring at 0° C. for 30 minutes methyl iodide (159 μL, 2.54 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 340 mg (64%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J=2.7 Hz, 1H), 8.35 (dd, J=4.7, 1.4 Hz, 1H), 7.70-7.66 (m, 1H), 7.66-7.64 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.60 (t, J=2.3 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.42 (dd, J=8.3, 4.7 Hz, 1H), 7.32 (dd, J=8.3, 2.5 Hz, 1H), 3.37 (s, 3H); ES-MS [M+1]+: 230.2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:15]C(=O)[NH:13][CH:12]2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].O>C(O)C>[NH2:13][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=1)[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[OH:15]
Reactant: CS(=O)(=O)c1ccc(C2OC(=O)NC2Cc2cccc(OC(F)(F)C(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(O)C(N)Cc2cccc(OC(F)(F)C(F)F)c2)cc1

Procedure:
To a solution of (4RS,5SR)-5-[4-(methylsulfonyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (1.80 g, 4.02 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (1.51 ml, 12.07 mmol) and the mixture was heated under reflux for 3 hrs. To the reaction solution was added water (100 ml) and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from hexane-diethyl ether to give the objective substance (1.49 g, 86%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20]1)=[O:19])([CH3:1])([CH3:3])[CH3:4]
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1Cc2ccccc2C1

Procedure:
N-t-Boc-L-phenylalanine (1 mmol) and isoindoline (J. Org. Chem. 1988, 53, p5382, 70-80% purity, 1 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 20% and 50% ethyl acetate-hexanes giving an amber oil (88 mg, 23%): TSPMS 367 (MH+, 100%).