Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[Cl:34])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)C>C1COCC1.Cl.C(OCC)(=O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[Cl:34])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(C(C)(C)C)n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)n1
Reaction time: 3 h
Yield: 8.5 %

Procedure:
Ethyl 7-(4-(6-tert-butylpyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (10 mg, 0.020 mmol) was diluted with THF (200 μL) followed by the addition of NaOH (98 μL, 0.098 mmol) and ethanol (100 μL). After stirring for 3 hours, the reaction was diluted with 0.5N HCl and ethyl acetate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a 0.5 mm preparative TLC plate, eluting with 10% methanol/DCM to yield the desired compound (0.8 mg, 0.0017 mmol, 8.5% yield). MS (ESI)=481.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])=[O:14].C([O-])(=O)C.C([O-])(=O)C.C1([I+2])C=CC=CC=1.FC(S(O)(=O)=O)(F)F>>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:13]1[O:14][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=2)=[N:9][CH:12]=1
Reactant: CC(=O)c1c(Cl)cccc1Cl
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [I+2]c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ncc(-c3c(Cl)cccc3Cl)o2)cc1

Procedure:
4-Nitrobenzonitrile and 2,6-dichlorophenyl methyl ketone can be reacted with phenyliodine (III) diacetate and trifluoromethylsulfonic acid by the method of R. S. Varma, et al, J. Heterocyclic Chem., 1998, 35(6), 1533–1534 to give 5-(2,6-dichlorophenyl)-2-(4-nitrophenyl)-1,3-oxazole. The nitrophenyl group can be reduced to the corresponding aniline with tin (II) dichloride or iron powder and ammonium chloride. Reaction of this aniline with 2,2-dichloroacetyl chloride and triethylamine can then give 2,2-dichloro-N-[4-[5-(2,6-dichlorophenyl)-2-(1,3-oxazolyl)]phenyl]acetamide.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[C:29]#[N:30].C(#N)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Yield: 45 %

Procedure:
A 2 mL microwave vial was charged with N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (50 mg, 0.16 mmol), 5-chloro-2-fluorobenzonitrile (150 mg, 0.97 mmol), acetonitrile (0.4 mL), and N,N-diisopropylethylamine (84 μL, 0.48 mmol). The mixture was subjected to a microwave irradiation at 200° C. for 2 h. The mixture was diluted with chloroform (7 mL), and washed with 0.1 M NaH2PO4 (10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column to yield a light yellow solid (32 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[C:12]([C:13]#N)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[PH2]([O-])=[O:17].[Na+]>[Ni].O.CC(O)=O.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[C:12]([CH:13]=[O:17])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: O=[PH2][O-]
Reactant: CCOC(=O)CNc1ncccc1C#N
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CNc1ncccc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
(3-Cyanopyridin-2-ylamino)acetic acid ethyl ester (2.6 g, 12.6 mmol) was dissolved into a 1:1:2 mixture of H2O/CH3COOH/pyridine (75 mL) under argon. Sodium hypophosphite (5.0 g) and Raney nickel (2.0 g) were added and the mixture was stirred at room temperature for 3 h. The slurry was filtered through a bed of celite and the filter cake was washed with water. Concentrated NH4OH was added to the filtrate until pH 10 was reached. The solution was extracted with ethyl acetate (4×50 mL). The organic phase was washed with brine (50 mL), dried over MgSO4 and concentrated. The product was purified by silica gel chromatography (CH2Cl2/EtOAc 9:1) to give the title compound as a clear yellow oil (2.16 g, 83%). 1H NMR (300 MHz, CDCl3) δ 9.86 (s, 1H), 8.69 (bs, 1H), 8.31 (dd, J=4.8, 1.9 Hz, 1H), 7.79 (dd, J=7.6, 2.0 Hz, 1H), 6.72 (dd, J=7.6, 4.8 Hz, 1H), 4.32 (d, J=5.5 Hz, 2H), 4.24 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH:3]=[O:4].C([OH:46])(C)(C)C.CC(=CC)C.Cl([O-])=O.[Na+]>O>[CH3:5][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)=[CH:32][C:25]=3[S:24]4)=[CH:19][CH:20]=2)=[O:13])[CH:7]=1)([CH3:1])[C:3]([OH:46])=[O:4]
Reactant: CC(C)(C=O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: CC(C)(C(=O)O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C

Procedure:
2-Methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5) is prepared by following a general procedure given in J. Org. Chem. 2002, 67, 411. To a stirred solution of 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a) (1 equivalent) in a 5:1 mixture of tert-butanol and water at rt are added sequentially dihydrogen sodium phosphate (3 equivalents), 2-methyl-2-butene (6 equivalents), and sodium chlorite (1 to 1.5 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The separated aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane. The combined organic layers are washed with water or brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([OH:36])=O)[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[S:50][C:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=2)=[CH:52][CH:53]=1>>[C:60]([C:57]1[CH:56]=[CH:55][C:54]([C:51]2[S:50][C:49]([CH2:48][C@H:47]([NH:62][C:34]([C@@H:20]3[CH2:19][C:18]4[CH:17]=[C:16]5[O:37][CH2:38][C@H:13]([C:10]6[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]7[CH:39]=[CH:40][C:41]([Cl:42])=[C:2]([Cl:1])[CH:3]=7)=[CH:8][CH:9]=6)[O:14][C:15]5=[CH:24][C:23]=4[CH2:22][N:21]3[C@H:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH3:27])=[O:36])[C:46]([OH:63])=[O:45])=[CH:53][CH:52]=2)=[CH:59][CH:58]=1)#[N:61]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)s1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)s1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) was coupled with (S)-2-amino-3-[5-(4-cyano-phenyl)-thiophen-2-yl]-propionic acid methyl ester hydrochloride according to General Procedure L. The resulting ester (25 mg) was hydrolyzed according to General Procedure B to give the title compound (22 mg). LCMS (m/z): 861.
Reaction SMILES: [C:1]([OH:4])(=S)[CH3:2].[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)=[CH2:6]>CN(C=O)C>[CH:10]([C:9]1[CH:8]=[CH:7][CH:5]=[CH:6][C:2]=1[CH:1]=[O:4])=[CH2:11].[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)=[CH2:6]
Reactant: CC(O)=S
Agent: C=Cc1ccc(C=O)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccccc1C=O

Procedure:
Aldehyde 11 was synthesized by radical addition (Lub et al. (1997) Liebigs Ann. Recueil, 2281–2288) of thioacetic acid to 4-vinylbenzaldehyde. Vinyl benzaldehyde was synthesized by the procedure of Ren et al. (1993) Bull. Chem. Soc. Jpn. 66: 1897–1902 with the following changes: The addition of DMF was performed at a 38 mmol scale at 0° C. Purification by column chromatography (silica, Et2O/hexanes, 1:3) afforded 4-vinylbenzaldehyde in 60% yield (FIG. 37).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15])[CH2:8][NH:9][C:10]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]2)=[O:11]
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1cc2c(N)cccc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1
Temperature: 25 °C

Procedure:
The product from Example 192A (4.4 mmol) in toluene (10 mL) was treated with 5-amino-3-methylisoquinoline (460 mg, 2.9 mmol) and DIEA (3 mL). The mixture was heated at 80° for 1.5 hours, cooled to room temperature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.77 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.70-7.81 (m, 3H), 7.38-7.53 (m, 3H), 7.19 (t, 1H, 6.1 Hz), 4.47 (d, 2H, J=5.8 Hz), 2.65 (s, 3H); MS (ESI+) m/z 378 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10]2)=[CH:4][CH:3]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)=[CH:30][CH:29]=2)C=CC=CC=1.Cl.C(OCC)C>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][NH:18][C:26]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[N:38]([CH3:39])[N:37]=[N:36][N:35]=4)=[CH:32][CH:33]=3)=[O:25])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: Cn1nnnc1-c1ccc(NC(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1nnnc1-c1ccc(NC(=O)NCCCN2CCC[C@@H](Cc3ccc(F)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 25 mg 3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]propylamine (0.1 mmol, 1 eq) in 1 ml of dry acetonitrile was added 32.5 mg [4-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (0.1 mmol, 1.1 eq). This mixture was stirred at room temperature for two hours, then concentrated in-vacuo to a pale yellow oil. This oil was purified via radial chromatography, eluting with a 19:1 mixture of methylene chloride and methanol, to yield a white solid. This solid was dissolved in methylene chloride and treated with 1 M hydrochloric acid in diethyl ether (0.1 ml, 1 eq). This mixture was stirred for 30 minutes, then concentrated in-vacuo to a white solid. This solid was dissolved in a 1:1 mixture of acetonitrile and water, and lyophilized to 26 mg of a white solid as product. NMR (300 MHz, CD3OD) δ 7.72 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.21-7.16 (m, 2H), 7.01 (dd, 2 H, J=8, 17 Hz), 4.17 (s, 3H), 3.59-3.54 (m, 1H), 3.40-3.11 (m, 4H), 2.89-2.81 (m, 1H), 2.73-2.59 (m, 3H), 2.10-1.70 (m, 7H), 1.43-1.34 (m, 1H). MS (ESI+) 452 (M−Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[O:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][CH:22]=3)=[CH:26][CH:27]=2)[C:32]1=[O:36])[CH3:12]
Reactant: Cc1nc(-c2ccc(-n3cc[nH]c3=O)cc2)co1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: Cc1nc(-c2ccc(-n3ccn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c3=O)cc2)co1

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(2-methyl-4-oxazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2-methyl-4-oxazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 37).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:34][N:35]1[C:39]([C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[OH:49])=[CH:38][CH:37]=[N:36]1.[N:50]1([CH2:56][CH2:57]O)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C1COCC1>[CH3:34][N:35]1[C:39]([C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[O:49][CH2:57][CH2:56][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=[N:36]1
Reactant: OCCN1CCOCC1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A mixture of triphenylphosphine (7.5 g, 1.8 eq), and diisopropylazodicarboxylate (5.66 mL, 1.8 eq) in 50 mL THF was stirred at 0° C. for 10 minutes, then 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (3.5 g, 15.9 mmole), and 2-morpholinyl-ethanol (3.66 mL, 1.8 eq) was added into the mixture at 0° C. Reaction mixture was stirred at room temp for another 1 hour. The mixture was purified by HPLC to give title compound as a yellow gummy solid (9.436 g, 89%). Exact mass calculated for C16H20N4O5 332.2. found 333.3 (MH+).
Reaction SMILES: O1CCN[C:2]1=O.[C:7]([NH:17][CH2:18][C:19]([OH:21])=[O:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:7]([N:17]([CH2:18][C:19]([OH:21])=[O:20])[CH3:2])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: O=C1NCCO1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
The oxazolidinone from Cbz-glycine (221 mg, 1.0 mmole) was dissolved in 10 ml of CHCl3 and triethylsilane (193 ∥l=174 mg, 1.5 mmoles) and trifluoroacetic acid (770 μl, 10 mmoles) were added. The solution was stirred at room temperature for 2 hrs. and concentrated in vacuo. CHCl3 was added and the solution was reconcentrated to a colorless oil. Silica gel chromatography gave 107 mg (48%) of Cbz-sarcosine, identified by NMR (N-Me, 2.98 ppm) and amino acid analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C[O:13][C:14](=O)[CH2:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18].C(N)CN>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:18][CH:17]([CH3:19])[C:16](=[O:20])[CH2:15][C:14]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1)=[O:13]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)CC(=O)C(C)C
Solvent: CCOC(C)=O
Solvent: NCCN
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)CC(=O)C(C)C)cc1

Procedure:
To a solution of methyl-4-aminobenzoate (250 g, 1.65 moles) in toluene (2.4 L) was added methyl-4-methyl-3-oxopentanoate (237.7 g, 1.648 moles) and ethylene diamine (1.15 ml, 0.016 moles). The reaction mixture was refluxed for about 20-25 hours. The solvent was removed under reduced pressure to obtain a solid residue. The residue was dissolved in ethyl acetate (2.4 L). The organic phase was washed with an acid (e.g., 20% w/w hydrochloric acid 0.5 L) followed by de-ionized water. It was further washed with a 10% sodium bicarbonate solution, followed by de-ionized water and saturated brine. The solvent was removed under reduced pressure. To this was added hexane while stirring and the solid precipitated out completely. The solid was filtered and washed with hexane. The solid was dried to yield the title product in 99.45% purity.
Reaction SMILES: [CH2:1]([C:5]1(O)[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[CH:10][CH:11]=2)[O:6]1)[CH2:2][CH2:3][CH3:4].Br[CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]1.C(=O)([O-])[O-:32].[K+].[K+].Cl>CN(C=O)C>[CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([O:32][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(O)CCc2ccc(F)c(F)c2O1
Reactant: CCCCC[C@H]1CC[C@H](CBr)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](COc2cc3c(c(F)c2F)OC(CCCC)CC3)CC1

Procedure:
To 20.5 g of 2-butyl-7,8-difluorochroman-2-ol which was dissolved in 70 mL of DMF, 25.1 g bromo-trans-4-pentylcyclohexylmethane and 11.7 g of anhydrous potassium carbonate were added, and heated to reflux for 1 hour. After the reaction solution was poured into 10% hydrochloric acid, and stirred for a while, the solution was extracted with toluene. An organic layer was washed using 10% hydrochloric acid twice, water, a 5% sodium hydroxide aqueous solution twice, water, a saturated sodium hydrogen carbonate aqueous solution twive, and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the obtained brown oily material was purified by carrying out column chromatography (silica gel, hexane), recrystallization (acetone/methanol), distillation under a reduced pressure (227° C./0.6 mmHg), column chromatography (silica gel, hexane/toluene), recrystallization (acetone/methanol), and recrystallization (acetone/methanol), to obtain 8.8 g of 2-butyl-7,8-difluoro-6-(trans-4-pentylcyclohexylmethoxy)chroman (Ie) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]([CH3:13])([CH3:12])[CH2:10][C:9]1=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[Li+]>O1CCCC1.CCOCC.O>[C:1]([O:5][C:6]([NH:8][C:11]([CH3:13])([CH3:12])[CH2:10][C:9]([OH:14])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC1(C)C
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
A 3 L, 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, nitrogen bubbler and addition funnel was charged with 180.3 g (0.89 mol) of N-(t-butoxycarbonyl)-4,4-dimethylazetidin-2-one dissolved in 1 L of tetrahydrofuran. The solution was cooled to 0°-5° C. and treated dropwise with 890 mL of 1.0M aqueous lithium hydroxide over 30 minutes. The reaction mixture was stirred at 0°-5° C. for 2 hours then diluted with 1 L of ether and 1 L of water. The layers were allowed to separate and the aqueous layer reextracted with an additional 1 L of ether. The aqueous layer was acidified by the addition of 1 L of saturated aqueous sodium bisulfate, then extracted with 1×1 L and 2×500 mL of ether. The combined organic layer and ether extracts were washed with 500 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum to 173 g of a yellow oil that solidified upon standing. The material was slurried with warm hexane then filtered and dried under high vacuum to afford 168.5 g (0.775 mol, 87%) of product as a white solid. 1H NMR (200 MHz,CDCl3): 1.39 (s,6H), 1.44 (s,9H), 2.72 (s,2H). FAB-MS: calculated for C10H19NO4 217; found 218 (M+H,54%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.[F:39][CH:40]([F:50])[CH2:41]OS(C(F)(F)F)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:41][CH:40]([F:50])[F:39])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[CH2:16][CH2:15]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Cc1cccc(O[C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(O[C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(CC(F)F)C4)CC2)n1
Temperature: 25 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (0.10 g, 0.24 mmol) and N,N-diisopropylethylamine (0.080 ml, 0.49 mmol) in dichloromethan (1 ml) was treated with trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (63 mg, 0.29 mmol) at 0° C. The cooling bath was removed after 30 min. and the reaction mixture was stirred at room temperature over night. The mixture was partitioned between aqueous saturated ammonium chloride solution (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with one 50-ml portion of ethyl acetate. The combined organic layers were washed with two 50-ml portions of a 1 M aqueous solution of sodium carbonate. The aqueous layers were each extracted with one 50-ml portion of ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concenrated in vacuo. Purification by flash column chromatography gave the title compound (98 mg, 85%) as white solid.