Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][CH:9]=2)[O:6][C:5](=[O:19])[NH:4]1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[Si:24]([O:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)[O:6][C:5](=[O:19])[NH:4]1)([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO)cc1
Product: COCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for intermediate 10 [(4S,5S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(4-methoxyphenyl)oxazolidin-2-one] from (4S,5S)-4-(hydroxymethyl)-5-(4-(2-methoxyethoxy)phenyl)oxazolidin-2-one and TBDMS-Cl to afford after purification by column chromatography (using EtOAc in heptane from 5% to 50%) intermediate 11 as a light yellow oil. TLC (heptane/EtOAc 1:1) Rf=0.26; tR=1.28 min (UPLC 1); LC-MS: [M+H] 382.2; Rt 1.17 min; (LCMS method 2); 1H NMR (400 MHz, CDCl3): 7.30 (d, 2H), 6.97 (d, 2H), 5.44 (br s, 1H), 5.23 (d, 1H), 4.18 (dd, 2H), 3.70-3.85 (m, 5H), 3.48 (s, 3H), 0.91 (s, 9H), 0.11 (s,
Reaction SMILES: COCCOC[O:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:28])/[CH2:20][CH:21]([NH2:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([O:29][CH3:30])[C:14]([CH3:31])=[C:13]2[C:9]=1[C:10](=[O:32])[O:11][CH2:12]2.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[OH:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:28])/[CH2:20][CH:21]([NH:27][S:41]([CH3:40])(=[O:43])=[O:42])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([O:29][CH3:30])[C:14]([CH3:31])=[C:13]2[C:9]=1[C:10](=[O:32])[O:11][CH2:12]2
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(N)C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Ethyl (E)-6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2-amino-4-methyl-4-hexenoate (373 mg) was dissolved in CH2Cl2 (10 ml), cooled to 0° C., and triethylamine (0.17 ml) and methylsulfonyl chloride (0.09 ml) were added. The mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 (10 ml), washed with water (10 ml), dried over Na2SO4, and evaporated to dryness to give a residue which was passed through a column (silica gel, hexanes-EtOAc 1:1) giving 368 mg (82%) of ethyl (E)-6-(4-hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5yl) -2-methylsulfonylamino-4-methyl-4-hexenoate as a colorless oil.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[C:14]([O:13][C:11](=[O:12])[NH:10][CH2:9][CH2:8][C@H:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][N:26]=[N+:27]=[N-:28])([CH3:17])([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 85A from 200 mg (0.52 mmol) of (2S)-2,4-bis[(tert-butoxycarbonyl)amino]butyl methanesulfonate (Example 90A) in 15 ml of dimethylformamide with 34 mg (0.52 mmol) of sodium azide. The product is reacted without further purification.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16](=O)[CH:17](OC)[O:18]C.CC(=O)C.Cl>C(O)C>[CH:17]([C:16]1[N:2]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[N:3]=[CH:14][CH:15]=1)=[O:18]
Reactant: N#Cc1ccc(NN)cc1
Reactant: COC(OC)C(=O)/C=C/N(C)C
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: N#Cc1ccc(-n2nccc2C=O)cc1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of 4-hydrazinylbenzonitrile hydrochloride (10.14 g, 59.78 mmol, 1.00 equiv), (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (17.6 g, 101.61 mmol, 1.70 equiv), propan-2-one (30 mL) and 6N hydrochloric acid (30 mL) in ethanol (300 mL) was stirred at 78° C. for 3.5 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. Water (300 mL) and ethyl acetate (200 mL) were added to dissolve the residue. The resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers was washed with water (1×100 mL) and brine (1×100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 4 g (34%) of 4-(5-formyl-1H-pyrazol-1-yl)benzonitrile as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.87 (s, 1H), 8.09-7.98 (m, 3H), 7.85-7.83 (m, 2H), 7.36 (d, J=1.5 Hz, 1H) ppm. LCMS (method A, ESI): RT=1.28 min, m/z=198.0 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([O:13][C:14]1[CH:15]=C(C=[CH:20][CH:21]=1)C=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:3]([C:2]1[CH:1]=[CH:20][CH:21]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:15]=1)=[CH2:4]
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(OCc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (51 g, 143 mmol) in tetrahydrofuran (500 mL) under argon at -20° C. was added butyllithium (56 mL, 140 mmol) over 20 minutes. The reaction was stirred for 10 minutes, then 3-benzyloxybenzaldehyde (29 g, 137 mmol) in tetrahydrofuran (60 mL) was added over 15 minutes. The reaction was stirred for 6.5 hours and left to stand overnight. The solvent was decanted off and the residue dissolved in dichloromethane (100 mL) and extracted with a heptane/diethyl ether mixture (9:1) until all the product was removed. The combined organics were filtered through silica and the solvent removed in vacuo to give the product as a clear oil, 122 mmol, 89%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([NH:13][CH:14]([B:27]3[O:35][CH:34]4[C:29]([CH3:39])([CH:30]5[CH2:36][CH:32]([CH2:33]4)[C:31]5([CH3:38])[CH3:37])[O:28]3)[CH2:15][C:16]3[C:17]([O:25][CH3:26])=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])=[O:12])=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[C:40]([NH:47][CH2:48][CH:49]=O)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CO>[C:43]([O:42][C:40]([NH:47][CH2:48][CH2:49][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:13][CH:14]([B:27]3[O:35][CH:34]4[C:29]([CH3:39])([CH:30]5[CH2:36][CH:32]([CH2:33]4)[C:31]5([CH3:38])[CH3:37])[O:28]3)[CH2:15][C:16]3[C:17]([O:25][CH3:26])=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])=[O:12])[CH:5]=2)[CH2:1]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: COc1c(CC(NC(=O)Cc2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC=O
Solvent: CO
Product: COc1c(CC(NC(=O)Cc2ccc3c(c2)CN(CCNC(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Reaction time: 91 h

Procedure:
A solution of 3-[2-(2-2,3-Dihydro-1H-isoindol-5-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid (0.110 g, 0.207 mmol) (prepared following the procedures in Steps 1-4 in Example 48), N-Boc-2-aminoacetaldehyde (0.06 g, 0.427 mmol), and methanol (2.5 mL) was purged with argon. Palladium on carbon (10%, 0.051 g) was added, the flask evacuated, and the reaction placed under hydrogen for 91 hr. The reaction mixture was filtered through a Celite-plugged filter frit, washed with CH3OH and CH2Cl2, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 676 (MH)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:8]=1.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](Cl)=[O:34].CC(O)C>CCOCC>[Br:27][C:28]1[CH:36]=[C:32]([C:33]([C:7]2[C:15]3[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=3[NH:9][CH:8]=2)=[O:34])[CH:31]=[N:30][CH:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2c(Cl)ncnc21
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C(c1cncc(Br)c1)c1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
n-BuLi (11.3 mL, 2.5 M in Hexane, 28.3 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 25.7 mmol) in Et2O (250 mL) at −78° C. and stirred for 0.5 h. 5-Bromo-nicotinoyl chloride (6.8 g, 30.8 mmol) was added to the reaction mixture slowly and stirred for 3 h, warmed to room temperature, and stirred for an additional 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl (150 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with brine (300 mL), dried (Na2SO4), filtered, and concentrated in vacuo to provide a crude solid. Trituration with 2-propanol provided the title compound as a pure white solid (7.5 g, 86%). MS: 337.5/339.5 (MH+); HPLC Rf: 4.02 min. (HPLC method 4).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([NH:17][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
4-Nitrobenzoyl chloride (18.9 g, 0.1 mol) dissolved in 60 ml of methylene chloride is added, over 30 minutes at a temperature of 0-5° C., to a solution of tert-butylamine (8.3 g, 0.112 mol) and of triethylamine (15.6 ml, 0.112 mol) dissolved in 170 ml of dichloromethane in a reactor. The reaction mixture is brought back to laboratory temperature and left stirring for 2 hours. The organic phase is washed twice with water and dried. After removing the solvent under reduced pressure, the solid obtained is recrystallized from isopropanol. 17.1 g (Yield: 77%) of N-(tert-butyl)-4-nitrobenzamide are obtained in the form of a pale yellow powder (m.p. 161-2° C.) which is used as is in the following stage.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>CO.CS(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:22][C@H:21]([OH:20])[CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(C(F)(F)F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.50 g, 1.9 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.35 g, 1.9 mmol). The product was isolated as a white foam. Yield 250 mg (29%). mp 100°-105° C. FDMS m/e=457 (M+ of free base). α[D]589 =+8.13 (c=1.01, methanol/dimethylsulfoxide).
Reaction SMILES: [Br-:1].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[CH:17][O:16][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1.[C:20]1(C2C(N)=NOC=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>NC1C=CON=1>[Br-:1].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][O:16][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Reactant: Nc1nocc1-c1ccccc1
Agent: Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1nocc1-c1ccccc1

Procedure:
This compound is prepared by an analogous method to (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) by replacing in 3-aminoisoxazol in step (Ai) with 4-phenylisoxazol-3-ylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=2)=[O:22])[O:28][N:27]=1)([CH3:25])[CH3:23]
Reactant: CC(C)c1cc(CN)on1
Reactant: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Product: CC(C)c1cc(CNC(=O)c2ncc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 41, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid (example W) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN 543713-30-0) as starting materials; LC-MS (UV peak area/ESI) 98.43%, 455.0 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:56]([C:57](O)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[C:56]([C:57]([N:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:3]3)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:50][CH:51]=1
Reactant: CCC(O)(CC)C1CCCNC1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(CC)C1CCCN(C(=O)c2conc2-c2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A solution of 3-piperidin-3-ylpentan-3-ol hydrochloride (8 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C21H28N2O3: 356.2100, found 356.2098.
Reaction SMILES: C(O)(C(F)(F)F)=O.C[O:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:28]3[CH2:34][CH:33]4[N:35]([CH3:36])[CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[C:17]3[C:22]([O:23][C:24]=2[CH:25]=1)=[C:21]([O:26][CH3:27])[CH:20]=[CH:19][CH:18]=3)=[O:11].[OH-].[Na+].COC(C1C=CC2N(C3CC4N(C)C(CC4)C3)C3C(OC=2C=1)=CC=CC=3)=O>O1CCOCC1>[CH3:27][O:26][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[O:23][C:24]1[CH:25]=[C:12]([C:10]([OH:11])=[O:9])[CH:13]=[CH:14][C:15]=1[N:16]2[CH:28]1[CH2:34][CH:33]2[N:35]([CH3:36])[CH:30]([CH2:31][CH2:32]2)[CH2:29]1
Reactant: COC(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2C
Agent: COC(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1Oc1cc(C(=O)O)ccc1N2C1CC2CCC(C1)N2C

Procedure:
To a solution of the TFA salt of 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2e (270 mg, 0.7 mmol) in dioxane (15 mL) was added sodium hydroxide (31 mg, 0.77 mmol) for 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2a, the title compound 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid, 3e was obtained as a mixture of endo and exo isomers. MS m/z (MH+) 381.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)OCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 538.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].N1CCCCC1.C([O-])(=O)C=C>C(Cl)(Cl)Cl>[CH3:12][O:11][C:7]([CH2:8][S:9][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CS
Agent: C=CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: COC(=O)CCSCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Methyl acrylate (4.25 g, 49.5 mmol) was added dropwise over 20 min to a stirred solution of methyl thioglycolate (5 g, 47.16 mmol) and piperidine (0.10 mL) at rt. When about half of the acrylate had been introduced, more piperidine (0.10 mL) was added. After completion of the addition of the acrylate, the reaction mixture was stirred for 1 h at rt. The mixture was diluted with 100 mL of chloroform. The chloroform layer was washed with water, brine and dried over Na2SO4. The solution was filtered and evaporated the solvent to give the product as an oil (9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]([C:30]([F:33])([F:32])[F:31])=[N:20]2)[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]([C:30]([F:33])([F:32])[F:31])=[N:20]2)[CH:14]=1)=[O:9]
Reactant: Nc1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1)c1cc(Cl)ccc1O
Yield: 74.4 %

Procedure:
Using 5-chlorosalicylic acid and 1-(3-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:18]([NH:20][C:21]([C:24]([O:26]C)=[O:25])([CH3:23])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>C1COCC1.O>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:18]([NH:20][C:21]([C:24]([OH:26])=[O:25])([CH3:23])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C(=O)O
Temperature: 22 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A solution containing about 260 mg of compound 7 and 91.5 mg of LiOH monohydrate in 7.5 ml of THF/H2O (2:1) was stirred at 22° C. for about 3 hours. The organic solvent was evaporated and the aqueous solution was extracted with Et2O (2×10 ml) and then acidified to a pH of less than 1 with 1 N HCl. The mixture was extracted again with Et2O (3×10 ml) and the combined organic extracts were dried over Na2SO4 and evaporated to yield about 240 mg of Boc-Tyr(OBn)-Aib-OH. A solution containing about 200 mg of Boc-Tyr(OBn)-Aib-OH in 10 ml of dry CH3CN was treated at 0° C. with 95 mg of DCC and stirred for about 2 hours. After filtration through florosil, the solution was evaporated to dryness. The resulting crude product (8) was dissolved in 2 ml of dry THF and added at -78° C. to a mixture of 130 mg of compound 4 and 165 μM of a 1.5 M solution of N-BuLi in hexanes in 4 ml of dry THF. After addition of about 13 mg of DMAP, the cold bath was removed and the reaction mixture stirred at 22° C. for about 2 hours. The solvent was evaporated and 4 ml of water added. After extraction with CH2Cl2 (3×10 ml), the combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on SiO2 (EtOAc/hexanes, 1:1) to yield about 285 mg of compound 9.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:17])[CH:15]=[CH2:16]>CO>[N+:11]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[CH:6]=[N:7][C:2]=1[NH:17][CH2:14][CH:15]=[CH2:16])([O-:13])=[O:12]
Reactant: C=CCN
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Product: C=CCNc1ncc(C(=O)O)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-5-nitro-3-pyridinecarboxylic acid (4.72 g, 23.30 mmol) in methanol (70 mL) at room temperature was added allyl amine (5.25 mL, 70.0 mmol) and the mixture was stirred overnight. The reaction was then concentrated in vacuo and the residue taken up into water (100 mL). The solution was brought to pH 3 by addition of 1 M HCl aqueous solution. The resulting suspension was extracted with EtOAc (50 mL). The aqueous phase was back-extracted with additional EtOAc (2×50 mL). The organic phases were combined, dried with MgSO4, and filtered. The solution was concentrated in vacuo providing 5-nitro-6-(2-propenylamino)-3-pyridinecarboxylic acid which was used without further purification.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].CCO[C:14]([S-:16])=[S:15].[K+].Cl>CN(C)C=O.O>[F:10][C:6]1[C:7]([F:9])=[CH:8][C:2]2[S:15][C:14]([SH:16])=[N:4][C:3]=2[CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(F)c(F)cc1F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc2nc(S)sc2cc1F
Temperature: 95 °C
Yield: 39.8 %

Procedure:
A mixture of 1 g (6.80 mmol) 2,4,5-trifluoroaniline and 1.33 g (8.16 mmol) potassium ethylxanthogenate in 5 mL dry N,N-dimethylformamide was heated in a 95° C. oil bath for 7 h. The reaction mixture was cooled to room temperature and diluted with water (15 mL). The mixture was acidified with aqueous HCl 2N. The precipitate was collected by filtration, washed with water and dried to provide 0.55 g (40%) of the titled compound as a light yellow solid. MS(m/e): 201.9 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:9]2)[CH:7]=1.C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32]>CN(C=O)C>[NH2:32][C:31]1[N:33]=[C:18]([C:10]2[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[N:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH3:25])[N:9]=2)[CH:19]=[CH:20][N:30]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc(C(=O)/C=C/N(C)C)nn1-c1cc(Cl)ccc1C
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-n1nc(-c2ccnc(N)n2)cc1C(=O)O
Temperature: 110 °C
Yield: 65.7 %

Procedure:
To a mixture of ethyl 1-(5-chloro-2-methylphenyl)-3-[(2E)-3-(dimethylamino)prop-2-enoyl]-1H-pyrazole-5-carboxylate (260 mg, 0.72 mmol) in DMF (4 mL), guanidine carbonate (130 mg, 0.72 mmol) was added. The mixture was heated at 110° C. overnight under efficient stirring. The resulting mixture was concentrated, dissolved in MeOH (0.5 mL) and THF (0.5 mL) and treated with NaOH 1N (0.5 mL). After 1 h the mixture was concentrated, dissolved in water and washed with AcOEt. To the aqueous phase cooled to 5° C., a saturated solution of citric acid was added under stirring. The resulting precipitate was collected by filtration to give the title compound (156 mg, 65%).