Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH3:11])(=O)OCC)C.[CH2:18]([O:20][C:21]([C@H:23]1[C@H:25]([CH:26]=O)[C:24]1([CH3:29])[CH3:28])=[O:22])[CH3:19].O>O1CCCC1>[CH2:18]([O:20][C:21]([CH:23]1[CH:25]([CH:26]=[C:9]([CH2:10][CH3:11])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]1([CH3:28])[CH3:29])=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@H]1[C@H](C=O)C1(C)C
Reactant: CCOP(=O)(OCC)C(CC)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1C(C=C(CC)c2ccccc2)C1(C)C
Reaction time: 6 h
Yield: 52 %

Procedure:
51.2 g (0.2 mol) of 1-phenylpropyl-phosphonic acid diethyl ester, dissolved in 30 ml of anhydrous tetrahydrofuran, were added dropwise to a mixture of 24 g (0.214 mol) of potassium tert.-butylate and 300 ml of anhydrous tetrahydrofuran at 20°-25° C., while stirring. After the mixture had been subsequently stirred at 20°-25° C. for a further 2 hours, 34 g (0.2 mol) of cis/trans-2,2-dimethyl-3-formyl-cyclopropanecarboxylic acid ethyl ester, dissolved in 50 ml of anhydrous tetrahydrofuran, were added dropwise at 25° C., while stirring. Stirring was then continued at 60° C. for a further 6 hours. 500 ml of water were then added and the reaction mixture was extracted twice with 300 ml of methylene chloride each time. The organic phases were separated off and dried over magnesium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was distilled in vacuo. 28.3 g (52% of theory) of 2,2-dimethyl-3-(2-ethyl-2-phenyl-vinyl)cyclopropanecarboxylic acid ethyl ester (isomer mixture) were obtained as a yellow oil with a boiling point of 142°-150° C./2 mbar.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].N([O-])=[O:17].[Na+]>S(=O)(=O)(O)O>[F:15][C:14]1[CH:13]=[CH:12][C:4]([C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[OH:17]
Reactant: Nc1cc(C(=O)CCC(=O)O)ccc1F
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)CCC(=O)c1ccc(F)c(O)c1

Procedure:
3-(3-amino-4-fluorobenzoyl)propionic acid was diazotised in sulphuric acid solution with sodium nitrite and the diazonium salt solution was added dropwise to boiling aqueous sulphuric acid to give 3-(4-fluoro-3-hydroxybenzoyl)propionic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[S:5][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[CH2:37]([NH:44][C:7]([C:6]1[S:5][C:4]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])=[N:3][C:2]=1[CH3:1])=[O:9])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylic acid (0.30 g, 1.00 mmol) and 4-methylmorpholine (0.15 mL, 1.10 mmol) in tetrahydrofuran (50 mL) was added isobutyl chloroformate (0.15 mL, 1.3 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours and benzylamine (0.20 mL, 1.80 mmol) was added. The reaction mixture was kept stirring for 17 hours at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 7% yield (0.030 g): mp 234-236° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=5.7 Hz, 1H), 7.60 (d, =7.8 Hz, 2H), 7.39-7.12 (m, 8H), 4.35 (d, J=5.7 Hz, 2H), 4.14-3.92 (m, 4H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.6, 156.7, 152.7, 150.7, 139.5, 138.9, 128.8, 128.1, 127.1, 126.6, 123.3, 118.3, 117.8, 42.4, 42.3, 41.2, 17.0; MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].C(Cl)CCl.[CH:11]1[CH:12]=[CH:13][C:14]2[N:19](O)N=[N:17][C:15]=2[CH:16]=1.NCC1C=CC=CN=1>C1COCC1>[N:17]1[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=1[CH2:14][NH:19][C:1](=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CCCC(=O)O
Agent: NCc1ccccn1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCCC(=O)NCc1ccccn1
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of butyric acid (4.5 mL, 48.7 mmol) in THF (50 mL) was added EDC (11.2 g, 58.4 mmol) and HOBt (7.88 g, 58.4 mmol). The mixture was stirred for 10 min. then 2-(aminomethyl)pyridine (4.7 mL, 46.3 mmol) was added. The solution was allowed to stir for 3 h then quenched with water (100 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield N-pyridin-2-ylmethyl-butyramide (5.82 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH3:39])[CH2:37][OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH:36]([CH3:39])[CH2:37][OH:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-2-amino-1-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.1 (1H, br), 10.16 (1H, d, J=7 Hz), 8.56 (1H, s), 7.16 (2H, dd, J=8.5, 6 Hz), 7.03 (2H, t, J=8.5 Hz), 6.93 (1H, s), 4.96 (1H, d, J=7 Hz), 4.89 (1H, d, J=7 Hz), 4.27 (1H, m), 4.11 (2H, s), 3.74 (1H, m), 3.66 (1H, m), 3.50 (2H, t, J=5.5 Hz), 3.43 (2H, t, J=5.5 Hz), 2.23 (1H, m), 1.69 (2H, m), 1.52 (4H, m), 1.29 (3H, d, J=7 Hz); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2186.
Reaction SMILES: [Li].Br[C:3]1(Br)[CH2:8][CH:7]=[CH:6][CH:5]=[C:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:16](Cl)(Cl)([Cl:18])[Cl:17]>CCCCC.CCOCC>[Cl:17][Si:16]1([Cl:18])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[C:3]1=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: BrC1(Br)CC=CC=C1c1ccccc1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Li]
Solvent: CCCCC
Solvent: CCOCC
Product: Cl[Si]1(Cl)c2ccccc2-c2ccccc21

Procedure:
Lithium wire (3.33 g, 0.08 mol) was washed with pentane, carefully cut into small pieces, and suspended in 150 mL of Et2O. While stirring, 2,2-dibromobiphenyl (25 g, 0.08 mol) 100 mL of diethyl ether was added dropwise over 1 hour and the contents were allowed to stir for 10 hours. The mixture was filtered through a frit to remove any unreacted Li and LiBr. The filtrated was loaded into an addition funnel and slowly dropped into a solution containing SiCl4 (50 g, 0.08 mol) in 200 nL of Et2O. After addition, the contents were stirred at room temperature for 5 hours. The solvent was removed in vacuo and 300 mL of pentane was added. The solution was filtered to remove LiCl and the solvents were again removed in vacuo. The solids were then loaded into a sublimator and allowed to sublime at 150° C. under full vacuum. Yield was 10.0 g (51%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)([O:13][CH2:14][CH3:15])=[O:12].CN1C[CH2:32][CH2:31]N(C)C1=O.BrCCCl>O1CCCC1>[C:11]([C:16]1([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:32][CH2:31]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CN1CCCN(C)C1=O
Reactant: CCOC(=O)CSCc1ccc(OC)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClCCBr
Product: CCOC(=O)C1(SCc2ccc(OC)cc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
Cool lithium hexamethyldisilazane (6 mL of a 1.0M solution tetrahydrofuran, 6.0 mmol) to -78° C. Add, by cannula transfer, a solution of 1-(carboethoxy)-1-(4-methoxybenzylthio)methane (1.36 g, 5.66 mmol) in tetrahydrofuran (10 mL). Stir for 45 minutes, add 1,3-dimethyl -3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (0.73 mL, 6.0 mmol) followed by 1-bromo-2-chloroethane (050 mL, 6.0 mmol) and stir to room temperature overnight. Cool to -78° C., add lithium hexamethyldisilazane (6.0 mL, 6.0 mmol) and stir at room temperature for 24 hours. Quench with saturated ammonium chloride (5 mL) and partition between ethyl acetate (30 mL) and water (30 mL). Separate the organic phase, dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (5:1 hexane/ethyl acetate to 2.5:1 hexane/ethyl acetate) to give 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclopropane (317 mg, 21%).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:1]1([CH2:7][NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NCC1CCCCC1)c1ccccc1
Reaction time: 16 h

Procedure:
Cyclohexylmethylamine (4.37 mL, 33.6 mmol) was added to a solution of benzoyl chloride (2.47 mL, 21 mmol) in THF (20 mL) at 0° C., and stirring continued 16 h. The mixture was filtered, diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The product crystallised (2.1 g, 45%) 1H-NMR (300 MHz, CDCl3) δH 7.76 (1H, m, Ar); 7.29 (8H, m, Ar); 1.04 (2H, m, CH2); 1.14 (2H, m, CH2); 1.61 (7H, m, 3×CH2); 3.23 (2H, t, J=6.78 Hz, N—CH2); 6.15 (1H, s, NH); 7.37 (3H, m, ArH), 7.70 (2H, m, ArH); LCMS (ESI+) 218 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:17])[C:9]1=[O:18])[C:5]([OH:7])=O)[CH3:2].C([O-])(=O)C.[NH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([CH2:24][NH:23][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:17])[C:9]2=[O:18])=[C:26]([N+:33]([O-:35])=[O:34])[CH:27]=1)#[N:30]
Reactant: CCOC(C(=O)O)N1Cc2c(C)cccc2C1=O
Reactant: N#Cc1ccc(CN)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Product: CCOC(C(=O)NCc1ccc(C#N)cc1[N+](=O)[O-])N1Cc2c(C)cccc2C1=O

Procedure:
According to general procedure C, (RS)-ethoxy-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetic acid (intermediate of example 44) was coupled with 4-aminomethyl-3-nitrobenzonitrile (CAS 701269-65-0) to give (RS)-N-(4-cyano-2-nitro-benzyl)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide as off-white crystals, MS 409.4 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C1C(=O)N(Cc2ccccc2)c2ccc(O)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of N-benzyl-5-methoxyisatin (3.0 g, 11.2 mmol) in dichloromethane (60 mL), aluminum chloride (3.7 g, 28.1 mmol) was added, and the resulting mixture was stirred at 100° C. for 1 hour. Water was added thereto, and the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated sodium hydrogencarbonate aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the aimed product (yield: 78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[S:16][C:15]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[N:14][C:13]=3[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=2)=[N:7][CH:8]=1)#[N:2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[S:16][C:15]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[N:14][C:13]=3[CH:12]=[C:11]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)[CH:10]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccc(C#N)cn3)c2s1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccc(C#N)cn3)c2s1
Temperature: 80 °C

Procedure:
A stirred mixture of the crude trifluoro-methanesulfonic acid 7-(5-cyano-pyridin-2-yl)-2-(3-ethyl-ureido)-benzothiazol-5-yl ester (108 mg, 0.23 mmol), 3-pyridineboronic acid (56 mg, 0.46 mmol), aqueous caesium carbonate (0.155 ml, 0.57 mmol, 3.7M), dimethylformamide (2.4 ml) and water (0.4 ml) was purged with nitrogen for 15 min. treated with tetrakistriphenylphosphine palladium (0) (27 mg, 0.023 mmol), sealed and heated at 80° C. for 8 h. After cooling to ambient temperature, the mixture was filtered through celite and washed through with methanol. The filtrate was evaporated in vacuo to give the crude 1-[7-(5-Cyano-pyridin-2-yl)-5-pyridin-3-yl-benzothiazol-2-yl]-3-ethyl-urea as a brown solid.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([O:5]C1C=CC([N+]([O-])=O)=CC=1)=O.[NH:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25].O>CN(C=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:2][C:3]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Boc-Gly-ONp (50 g, 0.17 mol.) and proline (20.7 g, 0.175 mol.) were dissolved in 300 ml DMF. 20 ml TEA and 30 ml water were added while stirring the solution. The stirring was continued overnight and TLC analysis showed no more starting materials. The solvents were removed under reduced pressure and the resulting mixture was dissolved in 250 ml saturated Na2CO3. The aqueous solution was extracted by 3×100 ml ethyl acetate to remove p-nitrophenol. Then, after chilling to 0° C., the aqueous solution was acidified to about pH=3 by addition of concentrated HCl slowly (vigorously swirling the solution at the same time). The product was extracted from the aqueous phase by 3×150 ml ethyl acetate. The organic phase was combined and washed by saturated NaCl (brine) 3×20 ml, and dried using Na2SO4. TLC analysis showed there was still p-nitrophenol in the solution. The ethyl acetate was removed under reduced pressure and column chromatography (elution solvents: E/H, 2:1) was carried out to obtain the pure product Boc-Gly-Pro-OH (white solid, 41.2 g, 88%). TLC Rf=0.25 (CMA, 85:15:3). FAB-MS, observed (M+H)+ =273. 1H-NMR (360 MHz, DMSO-d6, 20° C.) δ 12.55 (s, 1H, carboxyl), 6.79 (s, NH-major), 6.44 (s, NH-minor), 4.50 (dd, 0.25H, Pro-α-minor), 4.20 (dd, 0.71H, Pro-α-major), 3.81-3.62 (m, 1.7H, Gly-α-major), 3.47-3.33 (m, 2.5H, Pro-δ and Gly-α-minor), 2.25-2.00 (m, 1.2H, Pro-β), 1.96-1.60 (m, 2.7H, Pro-β and Pro-γ), 1.36 (s, 9H, Boc-CH3)b.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@@:13]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C@H:17](OS(C)(=O)=O)[C@@H:16]2[C@H:14]1[C@H:15]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1OCCOCCOCCOCCOC1.CN(C)C=O>O>[N:1]([C@H:17]1[C@@H:16]2[C@@H:14]([C@H:15]2[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C@:13]([NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:11])([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@@H:18]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](OS(C)(=O)=O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](N=[N+]=[N-])[C@H]1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 71.8 %

Procedure:
Sodium azide (8.29 g, 127.45 mmol) is added to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-[(methylsulfonyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (16.99 g, 25.49 mmol) and 15-crown-5 (508.57 μL, 561.46 mg, 2.55 mmol) in dimethylformamide (254.90 mL, 240.96 g, 3.30 moles) at 85° C. and stirred. After 7 days, the reaction is cooled to room temperature then diluted with water and extracted with ethyl acetate (3×). The combined organics are washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving a residue. The residue is purified by flash chromatography eluting 2-60% ethyl acetate in hexanes to yield the title compound (11.2 g, 18.3 mmol, 72%). MS (m/z): 635/637 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]2[C@@H:5]([C@H:6]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:3]1[CH2:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1.C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48]>ClCCl>[C:47]([NH:1][C@H:2]1[C@@H:7]2[C@@H:5]([C@H:6]2[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[C@:4]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[C@@H:3]1[CH2:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1)(=[O:49])[CH3:48]
Reactant: Cc1cc(SC[C@@H]2[C@@H](N)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1CSc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
Di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-amino-2-(tert-butoxycarbonylamino)-3-[(4-fluoro-3-methyl-phenyl)sulfanylmethyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.15 g, 264.67 μmol) is dissolved in dichloromethane (10 mL). To this mixture is added triethylamine (55.34 μL, 397.01 μmol) and acetyl chloride (28.25 μL, 397.01 μmol). The mixture is stirred at ambient temperature for 10 minutes. The solvent is removed under reduced pressure to give a residue. The residue is purified by flash chromatography (10% to 100% ethyl acetate/hexanes) to give the title compound (100 mg, 164.27 μmol, 62.06% yield); 1H NMR (CD3Cl) δ 1.44 (t, 27H), 1.95 (s, 3H), 2.16 (m, 1H), 2.22 (s, 3H), 2.60 (dd, 1H), 2.78 (bs, 1H), 3.10 (dd, 1H), 4.59 (m, 1H), 5.50 (d, 1H), 6.92 (t, 1H), 7.06 (m, 1H), 7.11 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][Cl:35])=[O:32]>ClCCl>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]([C:31]([O:33][CH2:34][Cl:35])=[O:32])[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[C:4]2[CH:3]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(s1)=Nc1ccccc1N(C(=O)OCCl)C=2N1CCN(C)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of olanzapine (18.0 g, 57.7 mmol) and triethylamine (16 mL, 0.12 mol) in dichloromethane (250 mL) was warmed to 35° C. and once a clear solution formed, the reaction was cooled to 5° C. To this was added chloromethyl chloroformate (7.6 mL, 86.5 mmol) over 20 minutes. The reaction was stirred at room temperature for 30 min and allowed to warm to room temperature. After 15 min at room temperature the reaction mixture was diluted with dichloromethane (100 mL), then washed with aq satd NaHCO3 (75 mL) and water (350 mL). The organic phase was dried over MgSO4 and filtered. The organic phase was then concentrated under vacuum at 45° C. to a volume of −150 mL. The mixture was diluted with ethyl acetate (30 mL) and ˜20-30 mL further was evaporated under vacuum. The mixture was cooled to room temperature and the resulting solid precipitate filtered and washed with ethyl acetate. After drying under vacuum at 35° C. for 90 min chloromethyl 2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate [A] (17.1 g, 73%) was obtained as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ 7.62-7.14 (4H, m), 6.27-6.22 (1H, m), 5.84-5.69 (1H, m), 5.47-5.23 (1H, m), 3.89-3.63 (4H, m), 2.66-2.22 (10H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]2[CH2:4][CH:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1cccc2c1cc1n2CCNC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Brc1cccc2c1CC1CNCCN21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.2 %

Procedure:
9-Bromo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (3.5 g, 13.9 mmol) was dissolved in THF (15 mL) and trifluoroacetic acid (30 mL) and cooled to 0° C. Sodium borohydride (1 g, 27.9 mmol) was added in portions, the mixture was stirred for 90 min at room temperature and added to an ice/water mixture (150 mL). After addition of sodium hydroxide solution (28%, 35 mL) to render the mixture basic it was extracted with dichloromethane. Organic phases were pooled, washed with brine, dried with MgSO4 and the solvent was evaporated. Chromatography on silica gel (dichloromethane/methanol/ammonia 180:10:1) yielded 9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (2.4 g, 68%) as a yellowish solid, MS: m/e=252.0 (M+).