Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].C(N(C(C)C)CC)(C)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.C(Cl)Cl.CCOC(C)=O>[O:26]=[C:24]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:4]([C:3]([O:2][CH3:1])=[O:13])[NH:5]1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1Cc2ccccc2C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
D-Phenylalanine methyl ester (1.56 g of HCl salt, Aldrich in CH2Cl2 washed with saturated NaHCO3 and dried, 7.3 mmol) and diisopropylethylamine (2.1 ml, 8.9 mmol) in 1,2-dichloroethane (13 ml) was added dropwise over 30 min to a stirring solution of triphosgene (1.1 g, 5.2 mmol) in 1,2-dichloroethane (13 ml). After stirring at ambient temperature for 1.5 h, the reaction was cooled to 0° C. and aluminum chloride (2.2 g) was added. After refluxing for 2.5 h, the reaction was once again cooled to 0° C. and quenched by slowly adding water (13 ml). After stirring for 1 h, the reaction mixture was transferred to a separatory funnel with CH2Cl2. Extraction with CH2Cl2 (2×) and drying over MgSO4 afforded 1.8 g of crude product. Flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) afforded pure product (0.65 g, 43% yield). MS (ESI) 206 (M+H).
Reaction SMILES: [C:1]1([N:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[OH-].[Na+]>O.C(O)(=O)C.[Zn]>[C:1]1([N:7]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)N(N=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)N(N)c1ccccc1

Procedure:
To a stirred suspension of zinc dust (5.14 g, 0.079 mol) in water (15 ml) was added dropwise a solution of the compound of Example 560B (3.5 g, 0.02 mol) in acetic acid (9 ml) and the resultant mixture was stirred for 1 hr at r.t. Dichloromethane (20 ml) was added, the mixture was adjusted to pH 8–9 with 15% NaOH, The zinc dust was removed by filtration, and the crude reaction mixture was extracted with dichloromethane. The combined organic layers were dried (MgSO4). Yield 1.97 g (60%).
Reaction SMILES: C([Li])CCC.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH2:15]([Sn:17](Br)([CH2:20][CH3:21])[CH2:18][CH3:19])[CH3:16]>CCOCC>[CH2:15]([Sn:17]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:7]1[O:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)[CH3:16]
Reactant: c1ccc2ocnc2c1
Reactant: CC[Sn](Br)(CC)CC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC[Sn](CC)(CC)c1nc2ccccc2o1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.6M, 6.0 mL, 9.57 mmol) was added to a solution of benzoxazole (950 mg, 7.98 mmol) in anhydrous ether (20 mL) stirred at −78° C. under nitrogen. After 10 min, triethylstannyl bromide (2.28 g, 7.98 mmol) was added, then the reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound as a brown oily residue which was used directly without further purification for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:22]([C:29]1([OH:35])[CH2:34][CH2:33][N:32]([CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:20]=[CH:21][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(NCCCCl)c1ccc(OCc2ccccc2)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C(NCCCN1CCC(O)(Cc2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Yield: 24.6 %

Procedure:
A mixture of 4-benzyloxy-N-(3-chloro-propyl)-benzamide (0.5 g, 1.64 mmol), ), 4-benzyl-4-hydroxy-piperidine (0.315 g, 1.65 mmol), potassium carbonate (0.45 g, 3.29 mmol) and 2-butanone (10 ml) was stirred at 60° C. for 48 h. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride-methanol from 95:5 to 9:1) to give N-[3-(4-benzyl-4-hydroxy-piperidin-1-yl)-propyl]-4-benzyloxy-benzamide (185 mg, 25%) as a light yellow solid. MS: me/e=459 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C.O>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: OCCCc1ccccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCCc1ccccc1Br
Yield: 97 %

Procedure:
Methanesulfonyl chloride (7.7 mL, 97 mmol) in 100 mL dry THF is added to a solution of 3-(2-bromo-phenyl)-propan-1-ol (17.4 g, 80.9 mmol) and triethyl amine (14.7 g, 146 mmol) in 200 mL dry THF at 0° C. under an argon atmosphere. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give 23 g (97%) methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester as an oil. Methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester (23 g, 78 mmol) in 300 mL dry DMF is added to a suspension of potassium cyanide (15.3 g, 235 mmol) in dry DMF. The reaction mixture is stirred at 60° C. for 16 hours. Water is added and the mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo. The residue is placed on a plug of silica gel and eluted with ethyl acetate/heptane (1:4) and concentrated in vacuo to give 16.0 g 4-(2-bromo-phenyl)-butyronitrile (91%) as an oil. 300 mL concentrated HCl is added to 4-(2-bromo-phenyl)-butyronitrile (16.0 g, 71 mmol) in 150 mL acetic acid. The reaction mixture is stirred at 60° C. for 16 hours. The reaction mixture concentrated in vacuo partly and is poured into water. The mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo to give the title compound as a crystalline material.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([N:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([C:40]2[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=2[C:47]#[N:48])=[CH:34][C:33]1=[O:49])[C:22]([O:24]CC1C=CC=CC=1)=[O:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([N:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([C:40]2[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=2[C:47]#[N:48])=[CH:34][C:33]1=[O:49])[C:22]([OH:24])=[O:23])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cn(C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)OCc2ccccc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cn(C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
605 mg (875 μmol) of benzyl 4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate (racemate) were dissolved in 6 ml of tetrahydrofuran, and 2.2 ml (2.2 mmol, 2.5 eq.) of aqueous sodium hydroxide solution (1.0M) were added. The mixture was stirred at RT for another 1 h and then neutralized with aqueous hydrochloric acid (1N). The phases were separated and the aqueous phase was extracted twice with 25 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was used for the next step without further purification. Yield: 568 mg (93% of theory)
Reaction SMILES: [C:1]([NH:4][C:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])(=[O:3])[CH3:2].[BH4-].[Li+].O>O1CCCC1>[OH:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:5]([NH:4][C:1](=[O:3])[CH3:2])([CH3:7])[CH3:6])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(C)(C)NC(C)=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC(C)(C)c1ccc(CO)cc1

Procedure:
To a solution of methyl 4-(1-acetamido-1-methylethyl)benzoate (37.14g) in tetrahydrofuran (370 ml) was added lithium borohydride (6.88 g) and the mixture was refluxed for 19 hr. The reaction mixture was poured into water (1000 ml) and extracted with ethyl acetate (1000 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from ethyl acetate to give the title compound (18.24 m.p.=126-129° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([Cl:19])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:12]([O:11][C:7]1[C:6]([Cl:19])=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][C:8]=1[Cl:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-benzyloxy-3,5-dichloro-benzoic acid methyl ester (CAB02115, 7.20 g, 23.14 mmol) in THF (20 mL) was added slowly with a syringe to a suspension of lithium aluminium hydride (1.50 g, 39.5 mmol) in THF (40 mL). The reaction mixture was stirred for 30 minutes at room temperature and then carefully quenched by addition of 2N sodium hydroxide solution in water. After 20 minutes stirring the colour of the mixture turned from grey to white. The white precipitate was filtered off, the filtrate was dried over sodium sulphate and concentrated under reduced pressure. The residue was recrystallised from dichloromethane/hexane. Yield: 5.83 g (89%) white powder. 1H-NMR (400 MHz, CDCl3) δ 1.85 (t, J=5.9 Hz, 1H, —OH), 4.63 (d, J=5.9 Hz, 2H), 5.04 (s; 2H), 7.33 (s, 2H), 7.35-7.44 (m, 3H), 7.55-7.59 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=64.05, 75.03, 127.36, 128.70, 128.75, 129.91, 136.39, 138.64, 150.32.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)N1CCN(C)CC1
Yield: 69 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (50a) (65 mg, 0.13 mmol), 4-methyl-piperazine (35 μL, 0.27 mmol), WSC hydrochloride (80 mg, 0.42 mmol) and HOBT (18 mg, 0.13 mmol), to obtain 52.1 mg of the title compound as a white solid (69%).
Reaction SMILES: Cl[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:12]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11]1=[O:46])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:47]1([P:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C=CC=CC=1>C1COCC1.O1CCOCC1>[C:6]([O:5][C:3]([C:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:12]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:11]1=[O:46])=[P:53]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:4])([CH3:9])([CH3:7])[CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCOC1CCCCO1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 53.9 %

Procedure:
1-(1-chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(4-tetrahydropyranyloxybut-2-ynylthio) azetidin-2-one (650mg) was dissolved in 1:1 THF/dioxan (12ml) under nitrogen. Triphenylphosphine (525mg) and pyridine (158mg) were added and the mixture heated at 55° for 15.5 hours. The reaction mixture was filtered and the filtrate evaporated. Dry toluene was added to the residue and the solution decanted from any solid and evaporated. Chromatography on silica afforded 1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4(4-tetrahydropyranyloxybut-2-ynylthio)azetidin-2-one as an amorphous solid (470mg).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([C:18](=O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1ccc(C(=O)c2ccccc2)[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(Cc2ccccc2)[nH]1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Triethylsilane (0.323 mL, 2.03 mmol) was added to a stirring, room temperature solution of 5-benzoyl-1H-pyrrole-2-carboxylic acid ethyl ester (29) (0.4180 g, 1.72 mmol) in trifluoroacetic acid (TFA) (4.1 mL, 0.42 M) under N2. After stirring overnight, the reaction did not appear to be complete by HPLC. Addition of addition quantities of triethylsilane did not result in any further changes by HPLC, so the reaction was worked up. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 98:2 to 95:5 Hexanes:EtOAc) to obtain pure 31 (0.2190 g, 55.6%). 1H (CDCl3, 400 MHz): δ 9.05 (1H, broad s), 7.35-7.28 (2H, m), 7.28-7.23 (1H, m), 7.23-7.18 (2H, m), 6.85 (1H, t, J=3.2 Hz), 6.0 (1H, t, J=3.2 Hz), 4.27 (2H, q, J=7.1 Hz), 4.00 (2H, s), 1.32 (3H, t, J=7.3 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 138.51, 136.86, 128.99, 128.88, 126.98, 122.26, 116.08, 109.41, 60.39, 34.37, 14.70 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.70; CH2 carbons: 60.39, 34.37; CH carbons: 128.99, 128.88, 126.98, 116.08, 109.41 ppm. HPLC: 10.014 min.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1>CN1C(=O)CCC1>[CH3:1][NH:2][C:3]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:24][C@H:25]4[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1)=[O:23]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)sc3c2)ccn1
Temperature: 105 °C
Reaction time: 120 h
Yield: 40 %

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (104 mg, 0.3 mmol) in 2 ml of NMP was added (S)-tert-butyl 3-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol). The reaction solution was stirred at 105° C. for 5 days. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)-tert-butyl 3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (56 mg, 0.12 mmol) as white powder. ES/MS m/z 484.2 (MH+).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[I-].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>CO.C1C=CC=CC=1>[C:1]1([O:11][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1cccc2c1CCCC2
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1cccc2c1CCCC2)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 3.70 g of 5,6,7,8-tetrahydro-1-naphthol, 1.188 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed overnight. After cooling to room temperature, the mixture is extracted with 2 × 75 ml of ether. The combined extracts are washed with 50 ml of 5% NaOH, 50 ml of water, 50 ml of saturated brine and dried (MgSO4). Evaporation of the solvent yields a yellow oil. Chromatography on 100 g of silica gel (benzene, 400 ml) yields the product as a yellow oil.
Reaction SMILES: [C:1]12([C:14](=S)[NH:13][C:12](=O)[NH:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2.[Na].Cl.[OH-:19].[K+]>O.C(OCC)C.C(O)CC(C)C>[C:1]12([C:14](=[O:19])[NH:13][CH2:12][NH:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2
Reactant: [OH-]
Reactant: O=C1NC(=S)C2(CCCc3ccccc32)N1
Agent: Cl
Agent: [K+]
Agent: [Na]
Solvent: CC(C)CCO
Solvent: O
Solvent: CCOCC
Product: O=C1NCNC12CCCc1ccccc12
Temperature: 25 °C

Procedure:
In a flame-dried reaction flask containing 10 ml. of freshly distilled isoamyl alcohol, there were placed 300 mg. (0.00129 mole) of 3',4'-dihydro-spiro-[imidazolidine-4,1'(2'H)naphthalene]-2-one-5-thione (prepared as described above) while the entire system was under a dry nitrogen atmosphere. The resulting solution was then treated with 0.5 g. of sodium, which was added in small portions, and the mixture so obtained was heated at 90°-100° C. for a period of 30 minutes. After cooling to room temperature (~25° C.), the excess sodium was destroyed with 10 ml. of methanol and the spent reaction mixture was diluted with water and subsequently extracted with three separate fresh portions of benzene. The combined benzene layers were then washed with water, dried over anhydrous magnesium sulfate and filtered. The resulting filtrate was thereafter evaporated to near dryness while under reduced pressure and the residue so obtained was slurried with diethyl ether and 1 N hydrochloric acid, followed by basification of the aqueous layer with 4 N aqueous potassium hydroxide. Extraction of the latter basified solution with methylene chloride then gave a clear organic extract, which was subsequently washed with water and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was finally obtained 78 mg. (30%) of crude 3',4'-dihydro-spiro-[imidazolidine-4,1'(2'H)naphthalene]-5-one as the desired final product. Recrystallization of the latter material from ethanol then gave analytically pure 3',4'-dihydro-spiro-[imidazolidine-4,1'(2'H)naphthalene]-5-one, m.p. 181°-183° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([C@@H]([NH3+])C)C=CC=CC=1.S(=O)(=O)(O)O>C(O)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(=O)[O-]
Agent: C[C@H]([NH3+])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A suspension of (S)-1-phenylethyl-ammonium (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoate (37.2 g, 77.5 mmol, 99.5% de) in aqueous isopropanol (50% strength, 90 ml) is admixed with 1N sulfuric acid (97 ml, 48.5 mmol) and stirred for 1 h at RT. The solid is filtered off with suction and dried to give (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid (26.5 g, 95%, >99.9% ee) as a colorless solid.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[N:8]([CH2:12][CH2:13][NH:14][C:15](=O)[CH3:16])[CH:9]=[CH:10][CH:11]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>O.C(O)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH3:16][C:15]1[C:9]2[N:8]([C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=3)=[CH:11][CH:10]=2)[CH2:12][CH2:13][N:14]=1
Reactant: CC(=O)NCCn1cccc1-c1ccc(C)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2c1ccc2-c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
N-[2-(2-p-Tolylpyrrol-1-yl)ethyl]acetamide (3.9 g) was treated with 20 ml of phosphorus oxychloride under argon and boiled for 1/2 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 100 ml of 2N sodium hydroxide solution and 100 ml of 28% sodium hydroxide solution, diluted with 1000 ml of water and extracted with methylene chloride (1×200 ml, 2×100 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 1.7 g of a total of 3.5 g of crude product were dissolved in a 25-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 1.8 g (68%) of 3,4-dihydro-1-methyl-6-p-tolylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 186°-189° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][C:19]([CH2:28][C:29]([O:31]CC)=[O:30])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][C:19]([CH2:28][C:29]([OH:31])=[O:30])=[CH:18][CH:17]=3)=[CH:34][CH:35]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccccc2)c1
Reaction time: 2 h
Yield: 16.9 %

Procedure:
Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetate (10 mg, 0.0195 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.0389 ml, 0.195 mmol) and 200 μL of water. After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetic acid (1.6 mg, 16.9% yield) as a white solid. MS ESI negative M−H=485.