Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Br-].[Br-].B.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:11][CH2:10]2.C(OC(=O)C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCC.CO>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCN(c1cnccc1C)C2=O
Agent: B
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccncc1N1CCc2cc(O)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.7 %

Procedure:
Boran tri-bromide (0.68 mL, 0.6715 mmol) was added dropwise to a solution of 6-methoxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (11A: 0.120 g, 0.4477 mmol) in DCM (2 mL) at −78° C. over a period of 5 minutes under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (80% ethylacetate in hexane). Since unreacted starting material was observed, a further 1.5 equivalents of boran tri-bromide (0.68 mL, 0.6715 mmol) was added and stirring was continued for a further 3 hours at room temperature. Methanol and saturated NaHCO3 were added to the reaction mixture and diluted with DCM. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (80% ethylacetate in hexane), followed by preparative TLC afforded 0.011 g of the product (9.7% yield).
Reaction SMILES: COC[O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH2:15][CH3:16])=[CH:7][C:6]=1[C:17]1[CH:31]=[CH:30][C:20]2[O:21][C:22]([C:24]([CH3:29])=[CH:25][C:26]([OH:28])=[O:27])=[CH:23][C:19]=2[CH:18]=1>C1COCC1.CO>[OH:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([CH2:15][CH3:16])=[CH:7][C:6]=1[C:17]1[CH:31]=[CH:30][C:20]2[O:21][C:22]([C:24]([CH3:29])=[CH:25][C:26]([OH:28])=[O:27])=[CH:23][C:19]=2[CH:18]=1
Reactant: CCc1cc(-c2ccc3oc(C(C)=CC(=O)O)cc3c2)c(OCOC)c(C(C)(C)C)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(-c2ccc3oc(C(C)=CC(=O)O)cc3c2)c(O)c(C(C)(C)C)c1
Temperature: 40 °C
Yield: 61.9 %

Procedure:
A mixture of 9 mg (0.021 mmol) of 3-[5-(2-methoxymethoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid in 0.5 mL of THF, 0.5 mL of methanol and 2 mL of 6 N aqueous HCL was heated to 40° C. overnight. The solvents were evaporated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude acid is directly recrystallized from acetonitrile to afford 5 mg (0.013 mmol, yield: 62%) of 3-[5-(2-hydroxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid as a white solid. 1H NMR (CDCl3), δ: 7.67 (s, 1H), 7.59 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 6.73 (s, 1H), 3.80 (broad s, 1H), 2.64 (dd, J=15.2, 7.4 Hz, 2H), 2.59 (s, 3H), 1.45 (s, 9H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][CH:39]=[C:40]([C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])[N:41]=1>>[CH:45]1([NH:44][C:42]([C:40]2[N:41]=[C:37]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)[S:38][CH:39]=2)=[O:43])[CH2:46][CH2:47]1
Reactant: O=C(NC1CC1)c1csc(Br)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2nc(C(=O)NC3CC3)cs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-N-cyclopropylthiazole-4-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.252 min, m/z=542.1; 1H NMR (CDCl3) 0.61 (m, 2H), 0.81 (m, 2H), 1.04 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.06-2.24 (m, 5H), 2.29-2.40 (m, 1H), 2.71-2.89 (m, 2H), 5.62 (m, 1H), 6.94-7.01 (m, 2H), 7.19-7.31 (m, 5H), 7.35 (s, 1H), 7.61 (m, 2H), 8.01 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@H:10]([CH2:19][CH2:20]O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[C@H](CCO)NC(OC(C)(C)C)=O)C=C.[CH2:41]([O:48][CH2:49][N:50]1[CH:55]=[C:54]([F:56])[C:53](=[O:57])[NH:52][C:51]1=[O:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:1]([O:8][C:9](=[O:22])[CH:10]([CH2:19][CH2:20][N:52]1[C:53](=[O:57])[C:54]([F:56])=[CH:55][N:50]([CH2:49][O:48][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:51]1=[O:58])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Reactant: O=c1[nH]c(=O)n(COCc2ccccc2)cc1F
Agent: C=CCOC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NC(CCn1c(=O)c(F)cn(COCc2ccccc2)c1=O)C(=O)OCc1ccccc1
Yield: 54 %

Procedure:
In a similar manner to that described in Example 1(1), a reaction was carried out using (±)-N-(tert-butoxycarbonyl)homoserine benzyl ester, instead of (±)-N-(tert-butoxycarbonyl)homoserine allyl ester, and using 1-benzyloxymethyl-5-fluoro-pyrimidin-2,4-dione instead of phthalimide, to afford the desired compound (yield 54%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:37][CH2:36][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH:33]([CH3:35])[CH3:34])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9](O)=[O:10].[CH3:38][O:39][CH:40]([O:49][CH3:50])[CH2:41][NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:18][CH2:19][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH:33]([CH3:34])[CH3:35])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:36][CH2:37]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([N:42]([CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH2:41][CH:40]([O:49][CH3:50])[O:39][CH3:38])=[O:10]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
Reactant: COC(CNC1CCCCC1)OC
Product: COC(CN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1Cl)C1CCCCC1)OC

Procedure:
Prepared by the method of Example 7, step e using 3-(2-chloro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 27, step d] (0.28 g) in place of 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid, and N-(2,2-dimethoxyethyl)cyclohexanamine [WO 2008075025] (0.10 g) in place of N-(2,2-dimethoxyethyl)cycloheptanamine. Yield 0.11 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].[O:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:15]2[CH:16]=[CH:17][O:13][CH:14]=2)[N:6]=1)=[O:4]
Reactant: OB(O)c1ccoc1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccoc2)cnc1N
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of palladium (II) acetate (145 mg, 0.65 mmol) and 1,1′-bis(diphenylphosphino)-ferrocene (493 mg, 0.86 mmol) in DMF (70 ml) was stirred at 50° C. for 15 minutes and cooled to r.t. The mixture was evacuated and vented with argon. 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (5.0 g, 21.5 mmol), furan-3-yl-boronic acid (2.79 g, 23.7 mmol) and triethylamine (4.51 ml, 32.3 mmol) were added and the reaction mixture was stirred at 90° C. for 16 h. The solvent was evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (2.92 g, 61.8%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C@H:11]([CH2:16][C:17]#[CH:18])[C:12](OC)=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].CCN(CC)CC.CCOC(C)=O>CO.O.[Fe]>[CH2:16]([C@@H:11]1[C:12](=[O:13])[NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[NH:10]1)[C:17]#[CH:18]
Reactant: C#CC[C@@H](Nc1ncccc1[N+](=O)[O-])C(=O)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C#CC[C@H]1Nc2ncccc2NC1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To (R)-methyl 2-(3-nitropyridin-2-ylamino)pent-4-ynoate (2.6 g, 10 mmol) in MeOH (60 mL) was added ammonium chloride (2.8 g, 52 mmol) in water (50 mL) and iron (2.7 g, 48 mmol) and the reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to room temperature and Et3N (1.3 mL) was added. After 10 h, EtOAc (100 mL) was added and the mixture was stirred for 2 h. The solution was decanted and evaporated. Water (15 mL) was added and the reaction mixture was filtered and washed with water to give colored solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:22]([O-])=O)[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])c1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
rac-(5-Fluoro-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine (1.1 g, 3.4 mmol) were dissolved in ethyl acetate (60 ml). Upon addition of Pd/C (10%) the reaction mixture was stirred for 2 h at ambient temperature under an atmosphere of hydrogen. Then the catalyst was filtered off, the filter washed with ethyl acetate and the filtrate evaporated. rac-N2-(5-Fluoro-indan-1-yl)-quinoline-2,6-diamine was obtained as a yellow foam (1.0 g, 99%); MS: m/e=294.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].N1C=CC=CC=1.[Cl:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44].O>ClCCl>[Cl:39][CH2:40][CH2:41][CH2:42][C:43]([O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2)=[O:44]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCCCl)c3cc(Cl)ccc32)c(C)c1

Procedure:
Tolvaptan (10.0 g, 22.3 mmol) was dispersed in dichloromethane (100 ml). Pyridine (2.7 ml) was added thereto, and the mixture was stirred. 4-Chlorobutyric acid chloride (3.74 ml) was gradually added to the obtained mixture, and the mixture was stirred at room temperature over night. The reactant was then poured into water, and the mixture was extracted with dichloromethane, washed with a sodium hydrogen sulfate aqueous solution, dried over magnesium sulfate. After filtration and concentration under reduced pressure, the resulted residue was crystallized with diethyl ether. The resulted crystals were collected by filtration, and dried to obtain 10.7 g of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-chlorobutyrate as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[CH:23]=[C:24]([Br:26])[S:25][C:8]=2[C:7]1=[O:27])=[O:5])[CH3:2].S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:23]=[C:24]([Br:26])[S:25][C:8]=2[C:7]=1[OH:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2sc(Br)cc2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2cc(Br)sc2c1O
Reaction time: 5 h

Procedure:
2-Bromo-5-(2,4-dimethoxy-benzyl)-7-oxo-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 21.c, 5.66 g, 12.5 mmol) was dissolved in 85 mL of anhydrous dichloromethane. To the solution was added 1.37 mL of thionyl chloride, and the reaction mixture was stirred for 5 hours. The solution was filtered on a fine glass frit filter to collect a white solid precipitate. The solid was washed twice with cold dichloromethane and then partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to 3.1 g of off-white solid: MS: (+) m/z 300.0, 301.9 (M+1, 79Br/81Br)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:24]([CH2:31][CH2:32][CH2:33]Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[O:24]([CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCCOc1ccccc1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OCCCOc3ccccc3)cc2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A solution of methyl 4-(4′-hydroxyphenyl)benzoate (2 g) in N,N-dimethylformamide (20 ml) was treated with potassium carbonate (1.21 g) and 3-phenoxypropylbromide (2.07 g) was stirred for 15 hours at room temperature and 4 hours at 85° C. After cooling, the reaction was quenched with water and the precipitate was collected, washed thoroughly with water and dried to give methyl 4-[4′-(3-phenoxypropyloxy)phenyl]-benzoate (2.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1NC1CCCC1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Commercially available 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (6) (25 g, 107 mmol) was dissolved in THF. Subsequently, triethylamine (32.6 g, 322 mmol) and cyclopentylamine (10 g, 117 mmol) were added to the reaction mixture. The combination was stirred over night at room temperature. Precipitated salts were filtered away from solvent and discarded. The collected solvent was then evaporated in vacuo to give an oil. The resultant oil was dissolved in ethyl acetate, washed with sodium bicarbonate, and then dried over Na2SO4. The drying aid was filtered away and the resultant solvent was evaporated under vacuum to give 23.3 g of product (7). 1H NMR (300 MHz, CDCl3), δ 8.60 (s, 1H), 8.25 (br s, 1H), 4.49-4.54 (m, 1H), 4.30 (q, 2H), 2.52 (s, 3H), 2.00-2.10 (m, 2H), 1.50-1.79 (m, 6H), 1.35 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 mL round bottom flask, the stirred solution of 2-amino-4-chlorobenzoic acid (42.8 g, 250.29 mmol, Aldrich) was dissolved anhydrous THF (200 mL) and the solution was cooled in an ice-bath. Lithium aluminum hydride (11.76 g, 312.86 mmol) was added portionwise to the above solution at the ice-bath temperature under nitrogen atmosphere. The resulting mixture was stirred at rt for 8 h. On completion of reaction the reaction mixture was cooled to ice-bath temperature and quenched by sequential addition of cold water (12 mL), 15% NaOH (12 mL) and water (36 mL). The resulting slurry was stirred at rt for 30 min and filtered through a CELITE™ pad. The solid residue was washed with ethyl acetate (1000 mL) and combined filtrate was concentrated under reduced pressure to give (2-amino 4-chlorophenyl)methanol as an off white solid. Yield: 32 g (81.6%). LCMS (ESI, m/z): 181 (M+23)+
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([NH2:30])[CH:17]=1)=[O:15]>N1C=CC=CC=1.O>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:18]([NH:30][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])[CH:17]=1)=[O:15]
Reactant: Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 4.7 g (32.8 mmol) of dimethylsulfamyl chloride in 5 ml of dry pyridine is added to 5.0 g (16.4 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone in 100 ml of dry pyridine at 0°-10° C. The reaction mixture is stirred in the cold overnight and then poured in water and extracted with ether. The ether extract is washed with water and extracted with dilute aqueous KOH. This basic extract is washed with ether, acidified with hydrochloric acid and extracted with methylene chloride. The dried organic extract is evaporated in vacuo to give 4-benzyloxy-3-dimethylsulfamoylaminophenyl 2-pyridyl ketone. Hydrogenation over PcO2 according to the procedure of Example 3 gives α-(4-hydroxy-3-dimethylsulfamoylaminophenyl)-2-piperidylcarbinol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>C(OCC)(=O)C>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13]
Reactant: Clc1ccnc2c(Cl)cccc12
Reactant: Oc1ccccc1Cl
Solvent: CCOC(C)=O
Product: Clc1ccccc1Oc1ccnc2c(Cl)cccc12
Temperature: 160 °C

Procedure:
A mixture of 2.0 g of 4,8-dichloroquinoline and 2.6 g of 2-chlorophenol was heated to 160° C. and stirred. Progress of the reaction was monitored by TLC. When no 4,8-dichloroquinoline remained, the reaction mixture was diluted with ethyl acetate, and washed with base to remove most of the excess phenol. To remove phenol remaining after washing, the product was purified using HPLC. Fractions containing product were combined, and solvent was removed using reduced pressure. The oily product crystallized. Yield: 1.36 g (46%). M.P. 56°-58° C.
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:55]=[CH:54][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH:29]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:30]([O:32]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:31])[C:25](=[O:52])[C:24]2=[O:53])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.Cl>[C].[Pd].CN(C)C=O>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH:29]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:30]([OH:32])=[O:31])[C:25](=[O:52])[C:24]2=[O:53])=[CH:54][CH:55]=1)(=[NH:11])[NH2:13]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCCN2CCN(C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)C2=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)c1ccc(OCCCCN2CCN(C(C(=O)O)c3ccccc3)C(=O)C2=O)cc1
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A mixture of 0.25 g of diphenylmethyl α-[4-[4-(4-benzyloxycarbonylamidinophenoxy)butyl]-2,3-dioxopiperazin-1-yl]-α-phenylacetate, 0.13 g of 5% palladium-carbon, 0.34 ml of 1N hydrochloric acid and 5 ml of N,N-dimethylformamide was subjected to hydrogenation at ordinary temperature and atmospheric pressure for 3 hours. Then, the pallasium-carbon was filtered off and the filtrate was concentrated under reduced pressure. To the resulting residue were added 2 ml of ethyl acetate, 5 ml of water and 30 mg of sodium hydrogencarbonate to dissolve the residue. The aqueous layer was separated and then purified by a reversed phase column chromatography (eluent: a 50% aqueous acetonitrile solution) to obtain 0.10 g of α-[4-[4-(4-amidinophenoxy)butyl]-2,3-dioxopiperazin-1-yl]-α-phenylacetic acid as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)=[CH:4][CH:3]=1.[N+]([C:20]1[NH:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1)([O-])=O.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]2([CH3:15])[O:13][C:20]3=[N:24][C:23]([N+:25]([O-:27])=[O:26])=[CH:22][N:21]3[CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: CC1(COC(=O)Nc2ccc(Cl)cc2)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(COC(=O)Nc2ccc(Cl)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.9 %

Procedure:
2-Methyloxiran-2-ylmethyl 4-chlorophenylcarbamate (1.1 g, 4.4 mmol) and 2,4-dinitro-1H-imidazole (0.35 g, 2.2 mmol) were suspended in ethanol (1 ml), and the resulting mixture was stirred at room temperature for 24 hours. Then, sodium acetate (0.36 g, 4.4 mmol) and ethanol (2 ml) were added to the mixture followed by stirring under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was added water, and the resulting mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was crystallized from methylene chloride-diethyl ether to afford 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-chlorophenylcarbamate (0.17 g, yield 22%) as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([CH3:28])[C:25](O)=[O:26])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([CH3:28])[C:25]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=2)=[O:26])=[CH:22][CH:23]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: C[C@@H](C(=O)O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C(=O)Nc1ccc(B(O)O)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.4 %

Procedure:
To a stirred solution of (4-aminophenyl)boronic acid hydrochloride (2.00 g) in DMF (42 mL) was added sodium bicarbonate (2.9 g), (2R)-2-(4-fluorophenyl)propanoic acid (2.04 g) and HATU (6.58 g). The mixture was stirred at room temperature for 72 h. Water (140 mL) was added, and the mixture was stirred for 2 h. The white precipitate was collected by filtration and was washed with water and was dried in vacuum to give 2.86 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH2:16][F:17])[C@@H:14]3[C@@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.BrC1C=CC(F)=C([C@]2(C(F)[F:35])[C@@H]3[C@@H](C3)OC(N)=N2)C=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH:16]([F:35])[F:17])[C@H:14]3[C@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)[C@H]2C[C@H]2O1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Product: NC1=N[C@](c2cc(N)ccc2F)(C(F)F)[C@@H]2C[C@@H]2O1

Procedure:
The title compound was prepared following a procedure similar to that described in step 8 for the synthesis of 6h-B, but using (1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16f-B) MS m/z=272.0 [M+H]+.