Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:26](=[O:27])[CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 15 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-phenylacetyl chloride to afford the title compound (11 mg, 15%). 1H-NMR (δ, ppm, DMSO-d6): 3.62 (s, 2H, CH2), 6.45 (d, 1H, HPy,5, J=6.0 Hz), 6.83 (d, 1H, Harom, J=8.0 Hz), 7.22-7.47 (m, 8H, Harom), 7.78 (d, 1H, HPy,6, J=6.0 Hz), 10.28 (s, 1H, NHamide), 11.15 (s, 1H, NHPy3), 11.37 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C20H17N4O3: 361.1301; found: 361.1299.
Reaction SMILES: Br.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[C:16]([O:28][CH3:29])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(Cl)Cl>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:28][CH3:29])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)c2ccnc3ccccc23)ccc1OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccnc3ccccc23)ccc1O
Reaction time: 4.5 h

Procedure:
15 ml of 33 percent hydrobromic acid in glacial acetic acid are added dropwise within 5 minutes at room temperature to 7.5 g of 4-(benzyloxy)-3-methoxyphenyl 4-quinolyl ketone dissolved in 150 ml of methylene chloride. After stirring at 20° for 4.5 hours, the reaction mixture is poured portionwise into 250 ml of saturated sodium bicarbonate solution. The methylene chloride phase is separated: the aqueous phase is extracted twice with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/hexane. There is obtained 4-hydroxy-3-methoxyphenyl 4-quinolyl ketone of m.p. 190°-192°.
Reaction SMILES: CC1N=C([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)C=CC=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=1.[C@@H]12NC[C@@H]1CCN(C(OC(C)(C)C)=O)C2>>[CH3:25][C:19]1[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=[C:17]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[N:18]=1
Reactant: Cc1nc(Cl)nc(C)c1C
Reactant: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Product: Cc1nc(N2C[C@@H]3CCNC[C@@H]32)nc(C)c1C

Procedure:
(1R,6S)-8-(4,5,6-Trimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane was prepared in a manner analogous to Intermediate 40, using Intermediate 66 and Intermediate 39 as starting materials. MS (ESI) mass calcd. for C13H20N4, 232.17; m/z found, 233.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][Si](C)(C)C)=[CH:9][N:8]([C@@H:17]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[CH2:18]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[CH:12])=[CH:9][N:8]([C@@H:17]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[CH2:18]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c2ncnc(N)c12
Yield: 73 %

Procedure:
200 mg of compound (23) are dissolved in 20 ml of MeOH. Adding 8 mg of K2CO3 results in hydrolysis after 1 h of stirring. After the solution has been subjected to rotary evaporation, the residue is chromatographed on silica gel in the eluent methylene chloride/MeOH (8:1). Recrystallization from MeOH results in colorless crystals (73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][CH3:12].Br[CH:14]=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=2[CH2:19][CH2:18][C:17]2[CH:27]=[CH:28][CH:29]=[CH:30][C:16]1=2>>[Cl:26][C:25]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[C:15](=[CH:14][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:11][CH3:12])[CH:4]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(B(O)O)ccc1Cl
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Product: COc1cc(C=C2c3ccccc3CCc3c(Cl)cccc32)ccc1Cl
Yield: 70.6 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 4-chloro-3-methoxyphenylboronic acid (160 mg,0.85 mmol) with 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (249 mg, 0.78 mmol) to give 440 mg crude product. Purify by chromatography to give 210 mg (71%) colorless oil. HPLC (ISO90-10M) shows 51% at t=7.62 min and 45% at t=9.86 min.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[CH:15]([CH2:25]O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CCN(CC)CC.S([O-])(=O)(=O)C.[Li+].[Cl-:40]>C(Cl)Cl.CN(C=O)C.O>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[CH:15]([CH2:25][Cl:40])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Cl-]
Reactant: CC(C)(C)OC(=O)N1CC(CO)c2ccc([N+](=O)[O-])cc21
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
Methanesulfonyl chloride (0.57 mL, 7.4 mmol) was added dropwise to a solution of 1-(t-butyloxycarbonyl)-3-(hydroxymethyl)-6-nitroindoline (1.21 g, 4.11 mmol) and Et3N (1.15 mL, 8.2 mmol) in CH2Cl2 (70 mL) at 0° C., and the pale yellow solution stirred for 5 min. Water was added, the mixture was extracted with CH2Cl2 (×2), and the extracts dried (Na2SO4) and evaporated. The crude mesylate was dissolved in DMF (10 mL) with LiCl (0.70 g, 16 mmol) and the mixture stirred at 80° C. under nitrogen for 1 h. The DMF was evaporated, the residue dissolved in EtOAc and water, extracted once more with EtOAc, and the organic extracts dried (Na2SO4) and evaporated. Dry column chromatography, eluting with EtOAc/petroleum ether (1:9), gave title compound as pale yellow foam (1.12 g, 87%). A sample was crystallised from benzene-petroleum ether to give a yellow crystalline solid, mp 111-111.5° C. 1H NMR (CDCl3) δ8.67, 8.34 (2 x br s, 1H, H-7), 7.86 (dd, J=8.2, 2.2 Hz, 1H, H-5), 7.35 (d, J=8.2 Hz, 1H, H-4), 4.22 (dd, J=11.6, 9.6 Hz, 1H, H-2), 4.04-3.97 (m, 1H, H-2), 3.82-3.74 (m, 2H, CHHCl, H-3), 3.68-3.62 (m, 1H, CHHCl), 1.60 (s, 9H, t-Bu); 13C NMR δ151.8, 149.0, 144 (br), 138 (br) (C-6,8,9, NCO2), 124.6, 117.8, 110.0 (C-4,5,7), 82.0 (OCMe3), 52.4 (C-2), 46.3 (CH2Cl), 41.7 (C-3), 28.4 (C(CH3)3). Anal. Calculated for C14H18ClN2O4 : C, 53.8; H, 5.5; N, 11.3; Cl, 11.3. Found: C, 54.0; H, 5.5; N, 9.1; Cl, 11.5%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([F:9])[C:5]([CH3:8])([OH:7])[CH3:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.O>CN(C)C=O>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:7][C:5]([CH3:8])([CH3:6])[C:4]([F:10])([F:9])[F:3])[CH:14]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(OCc1cccc(Cl)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a suspension cooled to 0° C. of sodium hydride (126 mg, 60 wt. % oil dispersion) in N,N-dimethylformamide (5 ml) was added dropwise, 1,1,1-trifluoro-2-methylpropan-2-ol (320 μL) under argon atmosphere, and the mixture was stirred for 15 minutes. To this reaction mixture was added dropwise 1-bromomethyl-3-chlorobenzene (320 μL), and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 40/1) to give the titled compound (389 mg).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[N:13]=[C:12]2[CH3:29])[CH:5]=1.[OH-].[Na+]>O1CCCC1>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([OH:30])=[O:2])[C:12]([CH3:29])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.1 %

Procedure:
To a solution of 3-[5-chloro-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step A (230 mg, 0.53 mmol) in tetrahydrofuran (3 mL) was added 1N sodium hydroxide (1 mL) and the solution was stirred at ambient temperature for four hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to give a light orange semi-solid (230 mg, quantitative yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:40](OC(=O)C)(=[O:42])[CH3:41]>O1CCCC1.ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:40](=[O:42])[CH3:41])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(Cl)c2)CO1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(Cl)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
Add triethylamine (138 μL, 0.99 mmol) to a solution of (2R,5R)-5-[(1S,2S)-2-amino-3-(3-chloro-5-fluorophenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.428 g, 0.901 mmol) in tetrahydrofuran (5 mL) followed by acetic anhydride (91 μL, 0.991 mmol). Stir at room temperature for 30 minutes, dilute with dichloromethane, wash with 0.1 N hydrochloric acid (30 mL), saturated aqueous sodium chloride (30 mL), dry (sodium sulfate), filter and purify (silica gel chromatography, eluting with 2:98 to 10:90 methanol:dichloromethane) to give the title compound as a white foam (0.212 g, 45%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.CN1CCCC1=O.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:19]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(I)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NNC(=O)c1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
Into a 300 mL three-neck flask was put 15 g (57 mmol) of 4-iodobenzoylhydrazine, 15 mL of N-methyl-2-pyrrolidone (NMP) was added thereto, and the mixture was stirred for 10 minutes at a room temperature. After the stirring, 50 mL of a mixed solution of 5 mL of N-methyl-2-pyrrolidone and 7.9 mL (69 mmol) of benzoyl chloride was dripped into the solution through a dropping funnel, and the solution was stirred at a room temperature for 18 hours. After the stirring, water was added into the solution, and a solid was precipitated. The precipitated solid was collected by suction filtration. The collected solid was added into about 500 mL of a saturated aqueous solution of sodium hydrogen carbonate, stirred, and washed. After the washing, the mixture was subjected to suction filtration to obtain a solid. The obtained solid was added into about 500 mL of water, stirred, and washed. After the washing, the mixture was subjected to suction filtration to obtain a solid. The obtained solid was washed with methanol to give 20 g of a powdery white solid in a yield of 97%.
Reaction SMILES: [CH:1]1([CH:6](Cl)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(C(C)=O)C(C)C>[CH:1]1([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:19][CH2:20]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC(c1ccccc1)C1CCCC1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)C2CCCC2)CC1
Reaction time: 72 h
Yield: 20.1 %

Procedure:
Into 35 ml of methyl isobutyl ketone were dissolved 2.92 g of cyclopentyl-phenylmethyl chloride, 2.80 g of 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 1.94 g of N,N-diisopropylethylamine, and the resultant solution was heated under reflux with stirring for 72 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with ethyl acetate-ethanol-dichloromethane (1:1:1) by silica gel column chromatography to give 0.88 g of oily 4-(cyclopentyl-phenylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)[CH2:2][CH3:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:16][CH2:15][C:11]2[CH:10]=[CH:9][C:8]3[CH2:7][CH2:6][C@@H:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])[CH2:14][C:13]=3[CH:12]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCCN(CCC)[C@@H]1CCc2ccc(CN)cc2C1
Product: CCCN(CCC)[C@@H]1CCc2ccc(CNS(=O)(=O)c3ccc(Cl)cc3)cc2C1

Procedure:
Using procedure 9, (R)-7-(dipropylamino)-5,6,7,8-tetrahydro-2-naphthalenemethanamine (9) was treated with 4-chlorobenzenesulfonyl chloride. Purification by chromatography gave a solid which was crystallized from hexane to give the title compound colorless crystals (m.p. 72° C.). [α]D =+47° (25° C., CH3OH, c=0.6095).
Reaction SMILES: B([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)(O)O.Br[C:17]1[C:18](=[O:26])[N:19]([CH3:25])[N:20]=[CH:21][C:22]=1[O:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+].Cl>CC#N.CO>[NH2:10][C@@H:9]([CH2:8][C:7]1[CH:14]=[CH:15][C:4]([C:17]2[C:18](=[O:26])[N:19]([CH3:25])[N:20]=[CH:21][C:22]=2[O:23][CH3:24])=[CH:5][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1cnn(C)c(=O)c1Br
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1cnn(C)c(=O)c1-c1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
4-Borono-L-phenylalanine (0.30 g, 1.0 mmol), 4-Bromo-5-methoxy-2-methyl-2H-pyridazin-3-one (0.35 g, 1.0 mmol), tetrakistriphenylphosphine palladium(0) (0.09 g), and 2.0 M aqueous sodium carbonate (3.0 mL) were refluxed in MeCN (900 mL) for 4 d. The mixture was acidified with 2.0 N HCl and treated with MeOH. The solid was filtered off and the mixture was concentrated in vacuo. The crude solid was purified using a Gilson HPLC containing a Kromasil column (10 u, 100 Å C18, column length 250×50 mm, gradient 100:0 to 10:90 H2O:MeCN) to give 2-(S)-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid. MS (ES+) 304.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH3:6][O:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].C(N(CC)CC)C>ClCCl.C(OCC)C>[CH3:6][O:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][O:11][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)C(C)(C)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(C)CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
TMSCl (2.30 mL, 0.018 mol) was added dropwise to a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (2.0 g, 0.015 mot) and triethylamine (3.16 mL, 0.023 mol) in dichloromethane at 0° C. After stirring for 1 h, the reaction was warmed to room temperature and stirred for an additional 1.5 h. Volatiles were removed under reduced pressure to provide a solid that was slurried in a mixture of ethyl ether and hexanes. The solid was removed by filtration and the filtrate was concentrated to provide a yellow liquid that was purified by bulb to bulb distillation under reduced pressure to provide 2,2-dimethyl-3-trimethylsilanyloxy-propionic acid methyl ester (2.8 g, 91%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[C:26]3[O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH:18]=[C:17]([Cl:34])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7].CO.[OH-].[Na+].Cl>C1COCC1.O>[Cl:34][C:17]1[CH:18]=[C:19]([C:21]2[C:26]3[O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH:20]=[C:2]([Cl:1])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(-c2cccc3c2oc2ccccc23)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(-c2cccc3c2oc2ccccc23)cc1Cl
Reaction time: 3 h

Procedure:
A solution of Example 1B (1.03 g, 2.10 mmol) in a mixture of THF (4 mL), methanol (6 mL), and water (3 mL) at room temperature was treated with NaOH (0.42 g, 10.5 mmol), stirred for 3 hours, adjusted to pH <7 with 1N HCl, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide a quantitative yield of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]([CH3:22])[CH:20]=O>>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][CH2:18][CH:19]([CH3:22])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1
Reactant: CC(C)C=O
Product: CC(C)CNC[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Yield: 91.1 %

Procedure:
Using general procedure A, ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (472 mg, 2.00 mmol) and 2-methylpropionaldehyde (181 μL, 2.00 mmol) afforded ((R)-2-(2-methylpropyl)amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (533 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.O[CH2:26][CH:27]1[CH2:31][CH2:30][O:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:26][CH:27]3[CH2:31][CH2:30][O:29][CH2:28]3)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: OCC1CCOC1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OCC3CCOC3)c2)sc2ccc(Cl)cc12
Yield: 64 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 3-hydroxymethyltetrahydrofuran (10.2 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 64% yield (16.5 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.67 (dddd, J=12.56, 7.90, 7.00, 5.96 Hz, 1 H) 2.06 (dddd, J=12.56, 8.61, 7.70, 5.54 Hz, 1 H) 2.45 (s, 3 H) 2.61-2.70 (m, 1 H) 3.62 (dd, J=8.86, 5.45 Hz, 1 H) 3.77 (ddd, J=8.61, 7.70, 7.00 Hz, 1 H) 3.86 (dd, J=8.86, 7.06 Hz, 1 H) 3.88 (ddd, J=8.61, 7.90, 5.54 Hz, 1 H) 4.19 (dd, J=10.89, 7.81 Hz, 1 H) 4.28 (dd, J=10.89, 6.49 Hz, 1 H) 7.02 (s, 1 H) 7.37 (dd, J=8.00, 7.66 Hz, 1 H) 7.43 (ddd, J=8.06, 2.32, 1.22 Hz, 1 H) 7.44 (dd, J=8.67, 1.95 Hz, 1 H) 7.72 (dd, J=8.67, 0.53 Hz, 1 H) 7.71 (dd, J=1.95, 0.53 Hz, 1 H) 7.71-7.72 (m, 1 H) 7.82 (ddd, J=7.66, 1.55, 1.22 Hz, 1 H). MS (ESI+) m/z 466 [M+H]+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](SC2C=CC=CC=2)=[CH:9][CH:8]=1)C>C1C=CC=CC=1>[O:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:4]=[CH:5]1
Reactant: CCOC(COc1ccc(Sc2ccccc2)cc1)OCC
Solvent: c1ccccc1
Product: c1ccc2occc2c1
Temperature: 25 °C
Yield: 169.3 %

Procedure:
A mixture of (4-(2,2-Diethoxyethoxy)phenyl)(phenyl)sulfane (2.7 g, 8.5 mmol) and polyphosphoric acid (2.7 g, 27 mmol) in benzene (70 mL) was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature, decanted from the PPA and filtered through a plug of silica gel, which was washed with hexanes. The filtrate and the wash were combined and concentrated under reduced pressure to yield 1.7 g (89%) of benzofuran: 1H NMR (400 MHz, CDCl3) δ 7.74 (d, 1H), 7.64 (dd, 1H), 7.49-7.39 (m, 2H), 7.29-7.16 (m, 5H), 6.74 (dd, 1H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[C:17]([O:20][C:21](=[O:23])[CH3:22])(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([OH:20])(=[O:19])[CH3:18].[C:17]([OH:20])(=[O:19])[CH3:18].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:21](=[O:23])[CH3:22])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2csc(NC(=N)N)n2)c1
Reaction time: 18 h

Procedure:
To a solution of 2-guanidino-4-(3-aminophenyl)thiazole (0.24 g.) in acetic acid (5 ml.) was added acetic anhydride (0.25 g.). The mixture was allowed to stand for 18 hours and the white solid precipitate (0.25 g.) was filtered off to give 2-guanidino-4-(3-acetylaminophenyl)thiazole diacetate, m.p. 171°-173° C., solidifies and remelts at 258°-261° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cccc(C)c3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cccc(C)c3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 77.7 %

Procedure:
A mixture of 2.81 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-6-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.35 g of 2-(dimethylamino)ethyl chloride hydrochloride, 2.7 g of potassium carbonate and 40 ml of acetone is refluxed for 16 hours. After the reaction is completed, the inorganic materials are removed by filtration and then washed with chloroform. The filtrate and the washing are combined and then evaporated to remove solvent. The residue is converted into its hydrochloride and then recrystallized from a mixture of ethanol and ether. 2.93 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-6-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 3/4 hydrate are obtained. Yield: 77%