Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@@H:24]([CH2:26][N:27]=[N+]=[N-])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:1]([N:11]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH2:27])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 3 h

Procedure:
To a stirred solution of (S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-azidomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 7, 1.63 g, 3.84 mmol) in dry THF (20 mL) was added triphenylphosphine (1.11 g, 4.23 mmol). After 3 hr, water (0.69 mL, 38.4 mmol) was added and the reaction stirred for 2 days at which time the solvents were evaporated. The residue was chromatographed over silica gel (150 g, 40-60 μm) eluting with 5-10% methanol-chloroform. The title compound was isolated as a viscous colorless oil. FAB-HRMS: theory 400.1672 (M+1); meas. 400.1676.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[I:16][CH2:17][CH2:18][CH2:19][CH2:20]I.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[I:16][CH2:17][CH2:18][CH2:19][CH2:20][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:15])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1
Reactant: ICCCCI
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=S1(=O)CCN(c2ccc(OCCCCI)cc2)CC1
Reaction time: 4 h

Procedure:
A mixture of 4-(1',1'-dioxothiomorpholino)phenol (10 g, 44 mmol), 1,4-diiodobutane (40.9 g, 132 mmol) and cesium carbonate (42.9 g, 132 mmol) was heated at 50° C. in acetonitrile (400 ml). After 4 hours, the reaction mixture was cooled, filtered and the solid salts washed with acetonitrile. The filtrate was poured into dilute HCl/ice water (1.2 l) and the resultant cream colored solid was isolated by filtration and washed with water. Chromatography on silica gel, with 97:3; dichloromethane:ether, afforded 1-iodo-4-[4'-(1,1-dioxothiomorpholino)phenoxy] butane, II (13.4 g, 74%). Mp. 119-121° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=5)[NH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: COC(=O)c1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.8 g, 8.09 mmol), methyl 3-(piperidin-4-yl)-1H-indole-5-carboxylate (2.09 g, 8.09 mmol) and DIPEA (1.55 mL, 8.90 mmol) in DMF (25 mL) were stirred and heated at 80° C. for 1 hour. The resulting mixture was then cooled to ambient temperature and quenched in water (60 mL) to give a precipitate which was collected by filtration, washed sequentially with water, acetonitrile and ether and dried under vacuum to give methyl 3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carboxylate (3.29 g, 92%) as a cream solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:31]([C:33]2[O:34][C:35]3[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][C:36]=3[N:37]=2)[OH:32])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[C:15]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:53]([NH2:55])[CH3:54].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.CCN=C=NCCCN(C)C.Cl.Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:31]([C:33]2[O:34][C:35]3[CH:41]=[CH:40][C:39]([C:42]([NH:55][CH2:53][CH3:54])=[O:43])=[CH:38][C:36]=3[N:37]=2)[OH:32])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[C:15]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)c1nc2cc(C(=O)O)ccc2o1
Reactant: CCN
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2oc(C(O)C(Cc3ccccc3)NC(=O)Cn3c(-c4ccc(F)cc4)ncc(NC(=O)OCc4ccccc4)c3=O)nc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84848.5 %

Procedure:
To a solution of the objective compound (450 mg, 0.651 mmol) of Step (1), ethylamine hydrochloride (67 mg, 0.82 mmol) and HOBT (176 mg, 1.30 mmol) in DMF (10 mL) were added N-ethylmorpholine (0.10 mL, 0.79 mmol) and WSCI hydrochloride (148 mg, 0.772 mmol) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was added to 1N hydrochloric acid (80 mL) and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained solid was washed with ether and dried in vacuo to give 2-[5-benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-[1-[[5-(ethylaminocarbonyl)benzoxazol-2-yl]hydroxymethyl]-2-phenylethyl]acetamide as a white solid (397 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:11][CH2:10]1.[C:28](=S)=[S:29]>C(O)C>[S:29]=[C:28]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:13][CH2:14]2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: Nc1ccccc1NC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Reactant: S=C=S
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=S)[nH]c3ccccc32)CC1
Yield: 19.7 %

Procedure:
A mixture of 18.3 parts of 1-[3-{4-[(2-aminophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one, 65 parts of carbon disulfide and 60 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated. The residue is crystallized from ethanol. The product is filtered off and dried, yielding 4.5 parts (19.7%) of 1-{3-[4-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 248.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:10]=2[CH3:17])[C:4](=[O:18])[CH:3]=1.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O.C(#N)C.O>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:10]=2[CH3:17])[C:4](=[O:18])[CH:3]=1
Reactant: Cc1ccc(CO)cc1-n1c(C)cc(O)cc1=O
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Reaction time: 8 h

Procedure:
4-hydroxy-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl pyridin-2(1H)-one (from Step 1) (8.0 g, 32.6 mmol) was stirred briskly at room temperature with 2,4-difluorobenzyl bromide (4.2 ml, 32.6 mmol) and K2CO3 (4.5 g, 32.6 mmol) in 50 ml of dimethylformamide. After stirring for 8 hours, H2O (100 ml) was added to reaction mixture. The product was extracted with ethyl acetate. Ethyl acetate layer was separated and dried over Na2SO4. Ethyl acetate was removed in vacuo. A yellow oil was obtained. The oil was passed through a plug of silica gel first eluting with 500 ml of ethyl acetate/hexane (1:1) This eluent was set aside. Next, ethyl acetate (100%) was passed through the plug until desired product was completely flushed from silica (3 liters). Solvent was removed in vacuo. Light yellow oil obtained (7.5 g, 62%). 1H NMR (300 MHz, CD3OD) δ 7.60 (app q, J=6.44 Hz, 1H), 7.42 (d, J=0.81 Hz, 2H), 7.15 (s, 1H) 7.06 (m, 2H), 6.21 (dd, J=1.61, 1.00 Hz, 1H), 6.12 (d, J=2.62 Hz, 1H), 5.16 (s, 2H), 4.65 (s, 2H), 2.07 (s, 3H), 1.93 (s, 3H); LC/MS, tr=2.38 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 372 (M+H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH:16]([O:29][Si](C(C)(C)C)(C)C)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccc(O)cc2)o1
Reaction time: 5 h
Yield: 11.6 %

Procedure:
The title compound was prepared from 4-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenyl acetate (30 mg, 0.059 mmol) following General Procedure D except the reaction with Bu4NF stirred for 5 h. Preparative thin layer chromatography (40% EtOAc) yielded the title compound as a white solid (2.4 mg, 10%): 1H NMR (CDCl3, 600 MHz) δ 7.66 (d, 2H, J=8.4 Hz), 7.37 (s, 1H), 7.27-7.25 (m, 2H), 7.17-7.16 (m, 3H), 6.91 (d, 2H, J=8.4 Hz), 3.06 (t, 2H, J=7.5 Hz), 2.60 (t, 2H, J=7.5 Hz), 1.79-1.75 (m, 2H), 1.65-1.61 (m, 2H), 1.43-1.38 (m, 4H); 13C NMR (CD3OD, 125 MHz) δ 188.7, 161.1, 159.2, 157.7, 143.1, 128.8, 128.7, 127.6, 126.0, 122.7, 120.0, 116.6, 39.3, 36.3, 31.7, 29.5, 29.4, 24.5; MALDI-FTMS m/z 350.1748 (M+H+, C22H24NO3, requires 350.1751).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].CC(C)([O-])C.[K+].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23]>CS(C)=O>[Cl:16][C:17]1[C:18]([O:8][CH2:7][CH:3]2[C:4]([CH3:6])([CH3:5])[C:2]2([CH3:9])[CH3:1])=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[O:23]
Reactant: CC1(C)C(CO)C1(C)C
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)C(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (48 mg, 0.37 mmol) in dry DMSO (5 mL) was added potassium t-butoxide (124 mg, 1.11 mmol) at room temperature. After stirring for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (50 mg, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The mixture was cooled to 0° C., quenched by hydrochloride acid (1N, 30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by prep HPLC (20%-50% MeCN in 0.1% formic acid) to afford the title compound as a white solid (7 mg, 10%). LCMS (ESI) Method A: RT=5.28 min, m/z: 268.1 [M-109]+; 1H-NMR (500 MHz, DMSO-d6): δ 8.13 (br s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.21-7.10 (m, 1H), 4.18 (d, J=7.0 Hz, 2H), 3.02 (s, 3H), 1.10 (s, 6H), 1.03 (s, 6H), 0.74 (t, J=7.5 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16]([CH3:21])[CH2:17][C:18](O)=[O:19])=[C:11]([NH2:23])[C:10]=1[C:24]([NH2:26])=[O:25].O.[NH2:28][NH2:29].CN(C)C=O>C(O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:21])[CH2:17][C:18](=[O:19])[NH:28][N:29]=2)=[C:11]([NH2:23])[C:10]=1[C:24]([NH2:26])=[O:25]
Reactant: CC(CC(=O)O)C(=O)c1ccc(CCN2CCCC2=O)c(C(N)=O)c1N
Reactant: NN
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(CCN2CCCC2=O)c(C(N)=O)c1N

Procedure:
7.2 g (0.02 mole) of 4-(4-(2-(2-oxo-pyrrolidin-1-yl)ethyl)-amino-carbonyl-amino-phenyl)-4-oxo-3-methyl-butyric acid and 1 ml (0.02 mole) of hydrazine hydrate are heated under reflux in 80 ml of ethanol and 10 ml of dimethylformamide for 2 hours. The crude product (6.3 g) which precipitates out on cooling is filtered off with suction and recrystallised from 90% strength ethanol.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:18][C@H:19]1[CH:24]2[CH:22]([C@@H:23]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[O:18]=[C:19]1[CH:24]2[CH:22]([C@@H:23]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:21][CH2:20]1
Reactant: CCOC(=O)[C@H]1C2SC[C@@H](O)C21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)[C@H]1C2SCC(=O)C21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of dimethylsulfoxide (33.4 mL, 471 mmol) in 194 mL of methylene chloride at −70° C. is slowly added a solution of trifluoracetic anhydride (33.2 mL, 235 mmol) in 73 mL of methylene chloride over 30 minutes (temperature maintained below −66° C.). After stirring for 20 min, a solution of ethyl (4S,6S)-4-hydroxy-2-thiabicyclo[3.1.0]hexane-6-carboxylate (34.1 g, 181 mmol) in 194 mL of methylene chloride is added over 60 minutes such that the temperature is maintained below 60° C. After stirring for 1 hour, the reaction is treated with triethylamine (75.7 mL, 543 mmol) over 35 minutes such that the temperature remains below −50° C. The reaction is allowed to stir an additional 1 hour, at which time the cooling bath is removed and 400 mL of 2 N hydrochloric acid is added. Upon warming to 0° C., the layers are separated and the organic layer is washed with 2N hydrochloric acid (1×300 mL), 1N aqueous sodium bicarbonate (1×670 mL), and water (1×300 mL) followed by drying over sodium sulfate, filtering, and concentrating in vacuo to a red oil which solidifies upon standing. The crude product is applied to a pad of silica gel (2 g per 1 g of starting alcohol packed with methylene chloride) and eluted with methylene chloride (200-300 mL). All fractions containing product are collected and concentrated to provide the title compound as an orange/brown solid. Typical corrected yields are in the 85-90% range.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[O:21][C:22]=2[CH3:23])=[CH:9][CH:8]=1)C.[OH-].[Na+].CCOC(C)=O>C1COCC1.CCO>[C:24]([C:20]1[O:21][C:22]([CH3:23])=[C:18]([CH2:17][O:16][C:10]2[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:7]([CH2:6][CH:5]([O:28][CH2:29][CH3:30])[C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)[N:19]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)c2ccsc12)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)c2ccsc12)C(=O)O
Reaction time: 1 h
Yield: 94.6 %

Procedure:
0.125 g of the above prepared 3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-benzo[b]thiophen-7-yl]-2-ethoxy-propionic acid ethyl ester (0.281 mmol) was dissolved in 1.7 ml of THF/EtOH=1/1, treated with 0.840 ml of 1N NaOH (3 eq.), and kept at ambient temperature for 1.0 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase reextracted once more with AcOEt, the combined organic layers washed with water, dried over magnesium sulfate, and evaporated to dryness. Crystallization from hexane/AcOEt yielded finally 0.111 g of the title compound as white crystals of mp. 179–80°.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:39])[CH2:16][NH:17][C:18](=[O:38])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C@H:10]([CH2:40][CH2:41][CH3:42])[CH2:9]1)(C)(C)C.ClCCl>C(O)(C(F)(F)F)=O>[NH2:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([CH2:16][NH:17][C:18]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[NH:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])=[O:38])=[O:39])[C@H:10]([CH2:40][CH2:41][CH3:42])[CH2:9]1
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H]1C[C@H](N)CC[C@@H]1NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Examples 2o and 2p, Step 4: A sample of (1R,3R,4S)-[4-(2-{2-[(morpholine-4-carbonyl)-amino]-5-trifluoromethyl-benzoylamino}-acetylamino)-3-propyl-cyclohexyl]-carbamic acid tert-butyl ester (200 mg) was dissolved in 1:2 TFA:dichloromethane and stirred for 30 min at RT before being concentrated in vacuo. The residue was redissolved in 1:2 TFA:dichloromethane and stirred for 30 min at RT before being concentrated in vacuo. The residue was dissolved in 1 N HCl and washed with Et2O; the aqueous phase was then basified (sat. NaHCO3 & a small amount of 1 N NaOH) and extracted (EtOAc, 2×). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford morpholine-4-carboxylic acid (2-{[(1S,2R,4R)-(4-amino-2-propyl-cyclohexylcarbamoyl)-methyl]-carbamoyl}-4-trifluoromethyl-phenyl)-amide as the free base (90 mg). MS found: (M+H)+=514.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[NH2:17][NH2:18]>C1COCC1>[NH:17]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)[NH2:18]
Reactant: NN
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1NN
Yield: 96 %

Procedure:
A solution of ethyl 4-chloro-2-trifluoromethylpyrimidine-5-carboxylate (0.20 g, 0.79 mmol), hydrazine (0.18 g, 6.0 mmol) and THF was stirred for 1 h at room temperature. The solution was filtered and dried to give the title compound in a 96% yield; 1HNMR (CDCl3) δ 9.26 (s, 1H), 8.90 (s, 1H), 4.40 (q, 2H), 4.24 (bs, 2H), 1.41 (t, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([CH:20]3[CH2:23][N:22]([C:24](=O)[CH2:25][CH3:26])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([CH:20]3[CH2:23][N:22]([CH2:24][CH2:25][CH3:26])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)C1
Agent: B
Solvent: C1CCOC1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.9 %

Procedure:
To a solution of 4-isopropyl-N-[6-(1-propionyl-azetidin-3-yl)-pyridin-3-yl]-benzenesulfonamide (150 mg, 0.38 mmol) in THF (15 ml) was added dropwise 1M BH3.THF (3.8 ml) and the mixture was stirred at room temperature for 12 h. It was then quenched by careful addition of 1N aqueous HCl (10 ml) and the resulting solution was heated at reflux for 4 h. The solution was next cooled to room temperature, adjusted to pH˜8 with 2 N NaOH solution and diluted with CH2Cl2. Separation of the layers, drying (Na2SO4) of the organic phase, filtration and evaporation in vacuo provided the crude material, which was purified by flash column chromatography (CH2Cl2:methanol, 95:5) to give the title compound (95 mg, 66%) as a light yellow oil.
Reaction SMILES: C(OC(=O)[N:7]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][CH:29]=1)[CH2:8][C:9]1[N:10]=[C:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=3)[O:12][CH:13]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:38]1([CH2:37][CH2:36][CH2:35][CH2:34][C:31]2[CH:32]=[CH:33][C:28]([NH:7][CH2:8][C:9]3[N:10]=[C:11]([C:14]4[NH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][C:19]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=5)[O:12][CH:13]=3)=[CH:29][CH:30]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1coc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)n1)c1ccc(CCCCn2ccnn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CNc4ccc(CCCCn5ccnn5)cc4)co3)cc2c1

Procedure:
[4-(4-[1,2,3]Triazol-1-yl-butyl)-phenyl]-[2-(5-trifluoromethoxy-1H-indol-2-yl)-oxazol-4-ylmethyl]-carbamic acid tert-butyl ester (0.31 g, 0.52 mmol) was stirred in a mixture of dichloro methane and trifluoro acetic acid (1:1, 10 ml) for 3 h. After concentration the crude product was purified on silica gel (ethyl acetate) yielding [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-[2-(5-trifluoromethoxy-1H-indol-2-yl)-oxazol-4-ylmethyl]-amine as light yellow solid.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[C:21]1([CH:27]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:28]([NH2:51])[CH:29]=[CH:30][S:31]([CH:34]=[CH:35][C@@H:36]([NH2:50])[CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:33])=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:52]1([CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:28]([NH:51][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH:1][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:29]=[CH:30][S:31]([CH:34]=[CH:35][C@@H:36]([NH:50][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:5])[CH3:6])[NH:1][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)(=[O:33])=[O:32])[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: N[C@H](C=CS(=O)(=O)C=C[C@@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 82 %

Procedure:
Cbz-Leu-Phe-VS-Ph was prepared from Cbz-Leu-OH and Phe-VS-Ph.HCl using standard mixed anhydride coupling method, yield 82%. 1H-NMR (CDCl3) δ 0.8-0.9 (2d, 6H, 2×Leu-CH3), 1.4-1.6 (m, 2H, Leu-CH2), 2.06 (m, 1H, Leu-CH), 2.9-3.0 (m, 2H, CH2-Phe), 3.9-4.0 (m, 1H, α-H), 4.8-4.9 (b, 1H, NH), 4.9-5.0 (m, 1H, α-H), 5.1 (m, 2H, Cbz) 6.3-6.4 (d & b, 2H, NH and CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.4 (m, 10H, 2×Ph), 7.5-7.7 (m, 5H, SO2-Ph). MS (ESI) m/z 535.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCOS(C)(=O)=O)cc1
Temperature: -15 °C
Reaction time: 4 h

Procedure:
4-(3-Hydroxy-propyl)-benzoic acid methyl ester (1.27 g, 6.5 mmol) and triethylamine (1 ml, 7.1 mmol) are dissolved in dichloromethane (30 ml), cooled to −15° C., methanesulfonylchloride (510 μl, 6.5 mmol) is added and stirred at room temperature for 4 h. The reaction mixture is diluted with dichloromethane, washed with potassiumhydrogensulfoate solution and potassiumcarbonate solution, the organic phase is dried over Na2SO4 and concentrated in vacuo. LC (method F): tR=1.88 min; Mass spectrum (ESP): m/z=295 [M+Na]+.