Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.[CH2:23]([N:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[C:26](Cl)=[O:27])[CH3:24].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:26](=[O:27])[N:25]([CH2:23][CH3:24])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: CCN(C(=O)Cl)c1ccccc1OC
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C#CC(C)(C)N1CCC(OC(=O)N(CC)c2ccccc2OC)N(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-ethyl-N-(2-methoxyphenyl)carbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-[N-ethyl-N-(2-methoxyphenyl)-carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[N+:19]([O-])=[N:18][C:17]2=[O:28])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.O.[Zn]>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[N:19]=[N:18][C:17]2=[O:28])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)nnc3ccc(Cl)cc32)CC1
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of tert-butyl{1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 206) (0.43 g) in acetic acid (8 mL) and water (2 mL) was added zinc dust (0.50 g). After 30 minutes, the solution was filtered and the filtrate concentrated. The residue was then treated with potassium ferricyanide (1.0 g) in water (20 mL). After 2 hours, the reaction was diluted with ethyl acetate. The aqueous layer was collected, the pH adjusted with solid Na2CO3 and extracted with ethyl acetate. The combined organic washes were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica gel with 0-25% acetone in dichloromethane to yield 66 mg of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:17][OH:18]>C1C=CC=CC=1>[CH3:17][O:18][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][N:14]1[CH2:15][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][C:13]1=[O:16]
Reactant: CO
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(CN2CC(c3ccc(OC)c(OC)c3)CC2=O)cc1OC
Temperature: 60 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
30 g (0.136M) of the pyrrolidone (9) was treated with Triton B (60 ml of a 40% methanol solution in 400 ml of benzene. Benzene was distilled off in vacuo, and 400 ml of benzene was again added to the residue. This procedure was repeated three times, and 25.31 g of 3,4-dimethoxybenzyl chloride was added thereto at room temperature. The mixture was stirred at 60° C. for 6 hr, and water was added to the reaction mixture. The resultant organic phase was separated and washed twice with water and once with a saturated saline solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off in vacuo. The residue was recrystallized from ethanol to prepare 41.54 g (yield: 82%) of the intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH:23]=O)[CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:26]1([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][N:35]2[CH2:36][CH2:37][C:32]([OH:38])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:33][CH2:34]2)[CH2:10][C:11]([N:13]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[CH:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=CCC(CC(=O)n1ccc2ccccc21)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
1-[3-(3,4-dichlorophenyl)-1,5-dioxopentyl]-1H-indole (740 mg), in MeOH/THF (1:1, 30 mL) was treated sequentially with molecular sieves 3A (880 mg), 4-phenyl-4-hydroxypiperidine HCl (880 mg) and NaBH3CN (130 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was with quenched with water (20 mL) and diluted with CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude oil. Silica gel chromatography eluting with 1-2% MeOH/CH2Cl2 gave the title compound (600 mg). Mass spectrum (CI): 521.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[CH:16]([C:19]1[CH:23]=[CH:22][NH:21][N:20]=1)([CH3:18])[CH3:17]>>[OH:12][C:10]1[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([N:21]2[CH:22]=[CH:23][C:19]([CH:16]([CH3:18])[CH3:17])=[N:20]2)[N:11]=1
Reactant: COc1ccc2c(O)nc(Cl)nc2c1C
Reactant: CC(C)c1cc[nH]n1
Product: COc1ccc2c(O)nc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 155 °C
Yield: 63.4 %

Procedure:
A mixture of 2-chloro-4-hydroxy-7-methoxy-8-methylquinazoline (140) (502 mg, 2.23 mmol) and 3-isopropylpyrazole (500 mg, 4.55 mmol) was heated at 155° C. for 10 min. Then, the reaction mixture was successively cooled down to room temperature, partitioned between CH2Cl2 and water, dried (Na2SO4) and evaporated. The residue was triturated in ether and filtered to give the title compound (422 mg, 63%) as white needles: m/z=299 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:20][C:21]([NH:27]C)([CH2:25][CH3:26])[C:22]([NH2:24])=[O:23]>>[C:22]([C:21]([NH:27][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:20])[CH2:25][CH3:26])(=[O:23])[NH2:24]
Reactant: CCC(C)(NC)C(N)=O
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: Cl
Product: CCC(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Methyl-2-methylamino-butyramide hydrochloride (CAN 18305-22-1) as starting materials and isolated (19.6 mg, 16%) as a white solid; MS (ESI, m/z): 360.5 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>C1COCC1>[C:27]([O:26][C:24]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[CH2:17][NH:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ccnc(Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (300 mg, 1.25 mmol) and tert-butyl 2-(aminomethyl)-piperidine-1-carboxylate (540 mg, 2.50 mmol) in THF (10 mL) is added diisopropylethyl-amine (0.43 mL, 2.50 mmol). The reaction is heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 268 mg (51% yield) of the desired compound: MS (ESI, pos. ion) m/z: 418 (M+1).
Reaction SMILES: [C:1]1([CH3:42])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17][N:16]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:43][C:44]1([CH3:52])[O:51][CH2:50][CH:49]2[CH:47]([O:48]2)[CH2:46][O:45]1>CN(C)C=O>[OH:48][CH:49]1[CH2:50][O:51][C:44]([CH3:52])([CH3:43])[O:45][CH2:46][CH:47]1[N:13]1[CH2:14][CH2:15][N:16]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:17][CH2:18][N:19]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH2:20][CH2:21][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:42])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH2:11][CH2:12]1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Reactant: CC1(C)OCC2OC2CO1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN(C3COC(C)(C)OCC3O)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1

Procedure:
50 g (78.76 mmol) of 4,7,10-tris(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane and 13.63 g (94.51 mmol) of 4,4-dimethyl-3,5,8-trioxabicyclo-[5.1.0]-octane are dissolved in 300 ml of dimethylformamide and heated in an autoclave for 24 hours to 170° C. It is evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone: 10/5/1). The main fractions are concentrated by evaporation and recrystallized from methyl tert-butyl ether/methanol. Yield: 52.76 g (86% of theory) of a cream-colored powder.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19].ClCCl.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(Cl)(Cl)Cl>[N:11]1([CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:4][CH:3]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(OCCCN2CCOCC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(OCCCN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
[3-(Morpholin-4-yl) propoxy] benzene-4-sulfonyl chloride was prepared by chlorosulfonylation of 4-(3-phenoxypropyl)morpholine using chlorosulfonic acid in the presence of dichloromethane or chloroform. For example, to a solution of 2.2 g (10 mmole) of N-(3-phenoxypropyl) morpholine in 20 ml of chloroform, 2 ml of chlorosulfonic acid (30 mmole) was slowly added at −10° C. and stirred for 30 min. The reaction mixture was stirred at room temperature for 5 hr. Chloroform was removed from lower layer. Lower layer was treated with chopped-ice to give solids. To a mixture of ice and solid product, 10 g of sodium phosphate (tribasic) was added and stirred with cooling. Chlorosulfonyl compound was extracted with dichloromethane (300 ml). Dichloromethane extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 1.6 g of [3-(morpholin-4-yl) propoxy]benzene-4-sulfonyl chloride was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](OCC)=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(CCCCCO)CC1
Yield: 97.6 %

Procedure:
To a stirred mixture of ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)valerate (26.8 g), tetrahydrofuran (200 ml) and sodium borohydride (13.4 g) is added dropwise methanol (40 ml) for 1.5 hours at 70°-80° C. After the addition is complete, the mixture is refluxed for 2 hours with stirring. After evaporation of solvent, the residue is diluted with water (300 ml) and extracted with ethyl acetate (300 ml). The extract is washed successively with 1N hydrochloric acid and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 5-(1-benzyloxycarbonyl-4-piperidyl)pentanol (23 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH:23]([C:25]3[CH:26]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=[C:29]4[C:33]=3[N:32](C)[CH:31]=[CH:30]4)[CH3:24])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH:23]([C:25]3[CH:26]=[C:27]([C:35]([F:37])([F:36])[F:38])[CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[CH:30]4)[CH3:24])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2ccn(C)c12
Agent: O=C=O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2cc[nH]c12

Procedure:
Enantiomers A and B of tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate. (±)-tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate (derived from tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate by methylation) was subjected to chiral HPLC on a chiralcel OD-H column with a mobile phase of 95% CO2/5% ethanol/0.1% diethylamine. The early-eluting enantiomer is Enantiomer A of tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate and the late-eluting enantiomer is Enantiomer B of tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([N:13]([CH3:37])[C:14]([N:16]([CH3:36])[C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:40].CC(O)C>>[ClH:40].[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([N:13]([CH3:37])[C:14]([N:16]([C@@H:17]2[C@@H:21]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:20][NH:19][CH2:18]2)[CH3:36])=[O:15])[CH:4]=[C:3]([C:2]([F:39])([F:1])[F:38])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C(=O)N(C)[C@H]1CNC[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To the compound (0.30 g) obtained in Example 139 was added 2N hydrogen chloride/2-propanol (5 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (0.23 g, 87%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20]CC)=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(Cl)n3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2cccc(Cl)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(6-chloropyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (6 mL, 1:1) was added aqueous NaOH solution (100 mg in 1.5 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 3 using 1 M HCl. This was then extracted with EtOAc, the organic layers were combined, washed by brine and concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.2 (b, 1H), 7.90 (t, J=7.6 Hz, 1H), 7.24 (m, 2H), 7.09 (s, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.54 (dd, J=9.6, 2 Hz, 1H), 3.10 (dd, J=15.6, 2.4 Hz, 1H), 2.32 (s, 3H), 2.17 (dd, J=15.6, 9.6 Hz, 1H). 1 proton assumed to be exchanged with solvents. MS (ESI) m/z=332 [M−H]+.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:15](=[O:31])[NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][CH2:49][C@@H:50]([C:51]#[N:52])[N:42]2[C:41]1=[O:53]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])=[O:31])[C:9]([NH:39][C@H:40]1[CH2:46][CH2:45][S:44][C@H:43]2[CH2:47][CH2:48][CH2:49][C@@H:50]([C:51]#[N:52])[N:42]2[C:41]1=[O:53])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Product: N#C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N12

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-2-oxo-1-phenylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 24 (10 mg, 0.020 mmol) and Intermediate 36 (6.1 mg, 0.023 mmol) to give a white solid (8.0 mg, 57% yield). Anal. Calcd. for C42H49N5O4S m/z 719.7. found: 720.7 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.32 (2H, m), 7.29-7.05 (13H, m), 7.00-6.91 (2H, m), 5.39-5.34 (1H, m), 5.31-5.25 (1H, m), 5.02-4.93 (1H, m), 4.85-4.76 (1H, m), 3.99-3.89 (1H, m), 3.63-3.54 (1H, m), 3.00-2.90 (1H, m), 2.89-2.68 (4H, m), 2.66-2.57 (1H, m), 2.45-2.31 (2H, m), 2.20-2.08 (2H, m), 2.03-1.62 (11H, m), 1.62-1.47 (3H, m), 1.43-1.26 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH3:22])=[O:21].[C:23](OCC)(=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].[H-].[Na+].Cl>C(O)C>[CH2:27]([O:26][C:24]([C:23]1[O:1][C:2]2[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:3]=2[C:20](=[O:21])[CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2o1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
5.0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone was suspended in 85 ml of ethanol. Thereto was added 4.5 ml of diethyl oxalate. Further, 3.1 g of sodium hydride (purity: 60%) was added thereto in portions in 10 minutes. The mixture was refluxed for 1.5 hours. The reaction mixture was introduced into 300 ml of ice water. The resulting mixture was adjusted to pH 2 with 4N hydrochloric acid. The resulting crystal was collected by filtration and then suspended in 50 ml of acetic acid. 1 ml of concentrated hydrochloric acid was added thereto. The mixture was stirred for 10 minutes at 80° C. After the completion of the reaction, 200 ml of water and 200 ml of ethyl acetate were added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to obtain 3.5 g (yield: 56%) of 2-ethoxycarbonyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[S:27])[N:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1c2ccc(Cl)cc2nc2n1CCCCC2
Solvent: Cc1ccccc1
Product: S=c1c2ccc(Cl)cc2nc2n1CCCCC2

Procedure:
10 g of 3-chloro-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one was treated with 15 g of Lawesson's reagent in toluene at reflux under nitrogen, until the starting material was consumed, as checked by TLC, using chloroform as eluent (24 hours). The mixture was concentrated in vacuo and chromatographed on silica gel, using chloroform as eluent. The bright yellow material was recrystallized from hexane-ethyl acetate, giving lemon-yellow needles, m.p. 99° C.-101° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@@H:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:1]([O:5][C:6](=[O:17])[C@@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@@H:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCC[C@H](O)CC(=O)OC(C)(C)C
Reactant: CCCCCCI
Product: CCCCCCC[C@H](O)[C@H](CCCCCC)C(=O)OC(C)(C)C

Procedure:
The target compound (2.20 g, 41%) was obtained in the same manner as in Production Example C-1, except that the (S)-3-hydroxydecanoic acid t-butyl ester (4.00 g, 16.4 mmol) obtained in Production Example B-6 and 1-iodohexane (5.20 g, 24.5 mmol) were used.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:24][C:20]1([CH3:23])[CH2:21][CH2:22][CH:18]([N:13]2[C:12]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19]1
Reactant: CC1(C)CCC(n2nc3c(c2OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC3)C1
Reactant: OB(O)c1ccc(F)cc1
Product: CC1(C)CCC(n2nc3c(c2-c2ccc(F)cc2)CCNCC3)C1
Yield: 38.4 %

Procedure:
The title compound (52.6 mg) was prepared as in Example 177, Steps C and D, using 201.7 mg of 2-(3,3-dimethyl-cyclopentyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 221, Step A) and 180 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C20H26FN3, 327.44; found, m/z 328.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 2H), 7.33-7.28 (m, 2H), 4.62-4.53 (m, 1H), 3.44-3.39 (m, 2H), 3.31-3.29 (m, 2H), 3.21-3.17 (m, 2H), 2.80-2.75 (m, 2H), 2.20-2.03 (m, 2H), 2.00-1.94 (m, 1H), 1.80-1.73 (m, 2H), 1.49-1.41 (m, 1H), 1.16 (s, 3H), 0.93 (s, 3H).