Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[O:17]C(=O)[N:15]3[CH2:19][CH2:20][CH2:21][C@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[OH-].[K+]>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)([C@H:14]2[CH2:21][CH2:20][CH2:19][NH:15]2)[OH:17])[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:8]=1
Reactant: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN1
Temperature: 65 °C
Reaction time: 22 h
Yield: 79 %

Procedure:
To a stirred solution of crude (7aR)-1,1-bis(3,5-bis(trifluoromethyl)phenyl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one ((R)-32, 11.03 g, 20.0 mmol) in methanol (MeOH, 80 mL, 1975 mmol) was added solid potassium hydroxide (KOH, 3.366 g, 60.0 mmol, 3.0 equiv) at room temperature. The resulting dark reaction mixture was heated to 65° C. and stirred at 65° C. for 22 h. When LCMS showed the reaction was deemed complete, the reaction mixture was cooled to room temperature before the solvent was evaporated under reduced pressure. The residue was then treated with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was then purified by Combiflash (SiO2) with 0-30% EtOAc/hexane gradient elution to afford (2R)-bis(3,5-bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol ((R)-33, 8.30 g, 10.51 g theoretical, 79% yield for 2 steps) as a yellow viscous paste. For (R)-33: 1H NMR (CD3OD, 400 MHz) δ ppm 8.24 (s, 2H), 8.16 (s, 2H), 7.85 (s, 2H), 4.49 (t, 1H, J=7.7 Hz), 2,92 (m, 2H), 1.74 (m, 2H), 1.67 (m, 1H), 1.55 (m, 1H); C21H15F12NO (MW, 525.33) LCMS (EI) m/e 526.0 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:32][CH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:23])[CH2:26]1
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: NCC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl piperidin-3-ylmethylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 2.96 minutes; C22H23Cl2N5O2 (460.36); mass spectrum: (M+H)+=460.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: COc1ccc2c(c1)C(N)CC2
Product: COc1ccc2c(c1)C(NC(=O)CN1CCc3cc(OC)c(OC(C)C)cc3C1Cc1ccc(OC)c(OC)c1)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-6-methoxy-indane
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[H-].[Na+].Br[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[C:12]=2[CH3:21])[CH:5]=1
Reactant: CC(Br)c1ccccc1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2c(C)n(C(C)c3ccccc3)c3cc(Cl)ccc23)c1
Reaction time: 1 h

Procedure:
3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.100 g, 0.30 mmol) was dissolved in DMF (3 mL) then sodium hydride (60% dispersion in mineral oil, 0.015 g, 0.36 mmol) was added followed by (1-bromoethyl)benzene (0.045 mL, 0.33 mmol). After 1 hour, the reaction was quenched with HCl (1N), followed by standard workup. Silica gel chromatography yielded the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl-:22].[NH4+]>CS(C)=O>[Cl:22][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)CC1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Temperature: 160 °C
Yield: 27 %

Procedure:
A mixture of 9-bromo-5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (530 mg, 1.50 mmol) and cuprous chloride (1.0 g, 10.1 mmol) in dimethyl sulfoxide (5 mL) was heated at 160° C. for 4.5 h and poured into 1N aqueous ammonium chloride (200 mL). The mixture was extracted with a mixed solvent of THF and ethyl acetate (600 mL). The extract was washed with 1N aqueous ammonium chloride (200 mL×2) and brine (200 mL), dried over magnesium sulfate, and concentrated. The residue was recrystallized from ethanol to give 125 mg of the title compound (27%): mp 218°~220° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.08 (bs, 1H), 7.08 (d, 1H, J=2 Hz), 7.02 (d, 1H, J=2 Hz), 5.04~5.13 (m, 1H), 3.62 (s, 3H), 2.94 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.78 (dm, 1H, J=17.1 Hz), 2.63 (dd, 1H, J=18, 7.2 Hz), 2.57 (dd, 1H, J=18, 3.6 Hz), 2.09 (dm, 1H, J=13.5 Hz), 1.80~1.95 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[C:9](=[CH:15]OCC)[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([S:20][CH3:21])[C:3]=1[CH2:22][S:23][CH3:24].Cl.[NH2:26]O.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:15]=[N:26][O:11][C:10]=2[CH:12]2[CH2:14][CH2:13]2)=[O:19])=[C:4]([S:20][CH3:21])[C:3]=1[CH2:22][S:23][CH3:24]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(Cl)c(CSC)c1SC)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CSCc1c(Cl)ccc(C(=O)c2cnoc2C2CC2)c1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
A mixture of 1-[4-chloro-3-(methylsulphenylmethyl)-2-(methylsulphenyl)phenyl]-2-ethoxymethylene-3-cyclopropylpropan-1,3-dione (2.3 g), hydroxylamine hydrochloride (0.52 g) and sodium acetate (0.46 g) in ethanol was stirred at room temperature overnight. The resulting mixture was filtered and the solid collected, washed with water and air dried to yield 4-[4-chloro-2-(methylsulphenyl)-3-(methylsulphenylmethyl)benzoyl]-5-cyclopropylisoxazole (Compound 3, 0.46 g) as a yellow solid, m.p. 79.9°-80.5° C.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[C:14]=2[C:13](C(OC)=O)([C:27]([O:29][CH3:30])=[O:28])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].FC(F)(F)C(O)=O>CO.C1COCC1.[Na+].[Cl-]>[C:4]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[C:14]=2[CH:13]([C:27]([O:29][CH3:30])=[O:28])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)C1(C(=O)OC)CN(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])c3ccccc3c21
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])c3ccccc3c21
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
NaOMe (5.61 mL of a 0.62 M solution in MeOH, 3.48 mmol) was added dropwise to a stirred solution of 10 (1.00 g, 2.32 mmol) in THF (20 mL) at 10° C. After 15 min at 20° C., trifluoroacetic acid (0.29 mL, 3.8 mmol) was added in one portion, causing dissipation of the deep purple colour of the solution. The reaction was diluted with saturated NaCl, extracted with CH2Cl2 and the extract was washed twice with water and dried (Na2SO4). The CH2Cl2 solution was filtered through a short column of silica gel, eluting with additional CH2Cl2, and the solvent was evaporated under reduced pressure below 30° C. to give crude 3-(tert-butyloxycarbonyl)-1-methoxycarbonyl-5-nitro-1,2-dihydro-3H-benz[e]indole (11) (0.85 g, 98%), which was used without further purification. 1H NMR (CDCl3) δ8.89 (br s, 1 H, H-9), 8.38 (br s, 1 H, H-7), 7.87 (d, J=8.3 Hz, 1 H, H-4), 7.63-7.51 (m, 2 H, H-5,6), 4.61 (dd, J=10.5, 3.9 Hz, 1 H, NCH2CH), 4.50 (br s, 1 H, NCH2CH), 4.32 (t, J=11.1 Hz, 1 H, HCH2CH), 3.72 (s, 3 H, CO2CH3), 1.61 (s, 9 H, C(CH3)3).
Reaction SMILES: [Ca].[C:2]([O:6][C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.O>[CH3:26][N:25]([CH3:27])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:13][CH2:14][C@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:5])([CH3:3])[CH3:4])[CH2:11]2)=[CH:21][CH:20]=1)(=[O:23])=[O:24]
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [Ca]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 16.9 %

Procedure:
A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0° C., and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and diisopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide. (2) In 600 ml of DMSO were suspended 25 g of (S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassium carbonate, and the mixture was stirred at 130° C. for 1 day. To the reaction mixture were added water and ethyl acetate, the resulting mixture was stirred and the liquids were separated. The organic layer washed with water, and then dried, and the solvent was evaporated. The residue was dissolved in chloroform, NH silica gel was added thereto and the mixture was allowed to stand for a while, and silica gel was filtered off. The silica gel was further washed with ethyl acetate. The filtrate and the washed solution were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.
Reaction SMILES: [NH2:1]N.C[N:4](/[CH:6]=[C:7]1/[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]/1=O)C>C(O)C>[N:1]1[NH:4][CH:6]=[C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]=12
Reactant: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1

Procedure:
A solution of hydrazine (3 mL) and tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (19.22 g) in ethanol (40 mL) was heated at 85° C. in a sealed tube for 4 h. Solvent was removed under reduced pressure, and the residue was triturated with dichloromethane (160 mL) and ethyl acetate (15 mL). The resulting solid was filtered. The filtrate was concentrated and the resulting solid was triturated again and filtered. The combined solids were used without further purification. LC/MS: 210.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([N:17]2[CH2:38][CH2:37][C:20]3([NH:24]/[C:23](=[N:25]/[C:26]([C:28]4[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=4)=[O:27])/[NH:22][CH2:21]3)[CH2:19][CH2:18]2)=[O:16])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].O[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48](F)(F)F)=[O:42].OCCN1CCCCC1=O>>[O:42]=[C:41]1[CH2:40][CH2:45][CH2:46][CH2:47][N:43]1[CH2:44][CH2:48][O:7][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]2[CH2:18][CH2:19][C:20]3([NH:24]/[C:23](=[N:25]/[C:26]([C:28]4[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=4)=[O:27])/[NH:22][CH2:21]3)[CH2:37][CH2:38]2)=[O:16])=[CH:12][C:2]=1[Cl:1]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)O)c(Cl)c4)CC3)N2)nc1Cl
Reactant: O=C(CO)N1CCCC1C(F)(F)F
Agent: O=C1CCCCN1CCO
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)OCCN5CCCCC5=O)c(Cl)c4)CC3)N2)nc1Cl

Procedure:
The title compound was prepared by an analogous method to Example 4.0, replacing 3-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid with [2-Chloro-4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid (Ex. 3, step 2), and 2-hydroxy-1-(2-(trifluoromethyl)pyrrolidin-1-yl)ethanone (Int. D) with 1-(2-hydroxy-ethyl)piperidin-2-one; 1H NMR (400 MHz, DMSO-D6) δ 11.1 (1H, s), 9.34 (1H, s), 9.06 (1H, s), 7.55-6.9 (4H, m), 4.84 (4H, s), 4.22 (2H, m), 3.95-3.41 (10H, m), 3.29 (2H, s), 2.77 (2H, m), 2.64 (2H, m), 2.59 (2H, m), 2.21 (2H, t), 1.88-1.59 (4H, m); LC-MS Rt 0.91 mins; 690.4 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])[CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl>[N+:24]([C:18]1[CH:19]=[C:20]([NH:21][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)[CH:22]=[CH:23][C:17]=1[CH3:16])([O-:26])=[O:25]
Reactant: O=C(Cl)c1cccc(N2CCOCC2)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of 3-morpholinobenzoyl chloride (0.24 g) in methylene chloride (5 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (0.15 g), pyridine (0.24 ml) and methylene chloride (10 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4) and evaporated. The residual solid was triturated under diethyl ether and the resultant solid was isolated and dried to give N-(3-nitro4-methylphenyl)-3-morpholinobenzamide (0.28 g); NMR: (DMSOd6) 3.2 (t, 4H), 3.3 (s, 3H), 3.78 (t, 4H), 7.19 (s, 1H), 7.4 (m, 2H), 7.47 (d, 2H), 8.0 (d, 1H), 8.83 (s, I1H), 10.23 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH:5]([NH:12][C:13]1[C:14]([N+:28]([O-])=O)=[C:15]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.NN.[CH2:35](O)C>[Ni]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH:5]([N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)[C:14]=2[N:28]=[CH:35]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(Nc1cccc(N2CCC(C(=O)O)CC2)c1[N+](=O)[O-])c1ccccc1
Reactant: CCO
Agent: [Ni]
Agent: NN
Solvent: O
Product: COC(=O)CC(c1ccccc1)n1cnc2c(N3CCC(C(=O)O)CC3)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-{3-[(3-methoxy-3-oxo-1-phenylpropyl)amino]-2-nitrophenyl}-4-piperidinecarboxylic acid (696 mg, 1.63 mmol) in ethanol (5 mL) was added Raney-Nickel (catalytic, ca. 5 mg) and hydrazine hydrate (316 μL, 6.52 mmol). The solution was stirred at room temperature for 3 hours, filtered, and evaporated in vacuo. The residue (560 mg) was dissolved in triethylorthoformate (5 mL), and heated at 60° C. for 0.5 hour. The resulting solution was cooled to room temperature, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (92:8) to afford the title compound, 1H NMR: (CD3OD) 8.27 (s, 1H), 7.34-7.28 (m, 5H), 7.10 (t, J=8.06, 1H), 6.99 (br d, J=8.06, 1H), 6.68 (d, J=8.06, 1H), 6.08 (dd, J=9.16, 6.22, 1H), 3.95-3.91 (m, 2H), 3.59 (obs dd, J=16.11, 9.16, 1H), 3.59 (s, 3H), 3.45 (dd, J=16.11, 6.22, 1H), 2.86-2.80 (m, 2H), 2.47-2.43 (m, 1H), 2.06-1.98 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[N:11]2[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=[C:10]2[C:9](=[O:18])[NH:8][CH2:7]1)[CH3:2].[ClH:20]>C(O)C.[Pd]>[ClH:20].[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[N:11]2[CH:12]=[C:13]([NH2:15])[CH:14]=[C:10]2[C:9](=[O:18])[NH:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CNC(=O)c2cc([N+](=O)[O-])cn21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CNC(=O)c2cc(N)cn21
Yield: 97.4 %

Procedure:
To a solution of ethyl(7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (V, where R1=OCH2CH3) (0.55 g, 2.1 mmol) in ethanol 100% (20 mL) was added hydrochloric acid (4 M solution in 1,4-dioxane, 0.52 mL, 2.1 mmol). The reaction mixture was stirred at room temperature in the presence of Pd-C (10%) (0.11 g), under hydrogen atmosphere (50 psi). After 7 h the solid was filtered through celite (washed with ethanol) and the solvent evaporated under vacuum, to obtain compound ethyl(7-amino-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate hydrochloride (I) as a light-brown solid (0.56 g, 98% yield), used without further purification in the next steps. Very hygroscopic product. To be stored for a short time and under inert gas atmosphere.
Reaction SMILES: [CH3:1][P:2](=[O:14])([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:13][P:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10])([CH3:1])=[O:14]
Reactant: CP(C)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CP(C)(=O)Cc1cccc(N)c1
Yield: 97.4 %

Procedure:
The dimethyl(3-nitrobenzyl)phosphane oxide (153 mg) produced as described above was hydrogenated in the presence of 10% Pd/C (100 mg) in MeOH (5 mL) overnight. The mixture was filtered and the filtrate concentrated in vacuo to afford 128 mg of the desired 3-[(dimethylphosphoryl)methyl]aniline (yield: 96%), which was used in further chemistries without purification. 1H-NMR (CDCl3, 400 MHz): δ=1.44 (d, J=12.8 Hz, 6H), 3.06 (d, J=15.6 Hz, 2H), 3.81 (s, br, 2H), 6.55-6.58 (m, 3H), 7.08 (t, J=7.6 Hz, 1H). MS (ES+): m/z 184.02 (MH+). HPLC: tR=0.58 and 0.90 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[S:3][CH2:4][C:5](=[N:7][OH:8])[CH3:6].[CH3:11][N:12]=[C:13]=[O:14]>C(N(CC)CC)C.ClCCl>[CH3:11][NH:12][C:13]([O:8][N:7]=[C:5]([CH3:6])[CH2:4][S:3][C:2]([F:10])([F:9])[F:1])=[O:14]
Reactant: CC(CSC(F)(F)F)=NO
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C)CSC(F)(F)F

Procedure:
A mixture of 1-trifluoromethylthio-2-propanone oxime (0.02 mole) from Step 2, methyl isocyanate (0.22 mole) and 2 drops of triethylamine in 25 ml of dichloromethane was heated at its reflux temperature overnight. The solvent was removed by evaporation under vacuum. The residual oil was recrystallized from a mixture of petroleum ether and diethyl ether to give a pure sample of 1-trifluoromethylthio-2-propanone O-methylcarbamoyl oxime, m.p. 56°-58°C. The structure of the product was confirmed by elemental and spectral analyses.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:5][CH:4]([OH:6])[CH2:3]1.C(N(CC)C(C)C)(C)C.ClC(Cl)(O[C:21](=[O:27])OC(Cl)(Cl)Cl)Cl.[Br:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40](=[O:42])[CH3:41])[C@@H:35]([CH3:43])[CH2:34][NH:33]2>ClCCCl>[C:40]([N:36]1[C:37]2[C:32](=[CH:31][C:30]([Br:29])=[CH:39][CH:38]=2)[N:33]([C:21]([O:6][CH:4]2[CH2:5][C:2]([F:7])([F:1])[CH2:3]2)=[O:27])[CH2:34][C@@H:35]1[CH3:43])(=[O:42])[CH3:41]
Reactant: OC1CC(F)(F)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CC(F)(F)C2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 250-mL round-bottom flask was charged with 3,3-difluorocyclobutan-1-ol (2.41 g, 22.3 mmol), 1,2-dichloroethane (50 mL), N,N-diisopropylethyl amine (3.5 mL, 20 mmol) and triphosgene (1.33 g, 4.48 mmol). The resulting solution stirred 30 minutes at 50° C., and then a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one (600 mg, 2.23 mmol) and N,N-diisopropylethyl amine (3.5 mL, 20 mmol) in 1,2-dichloroethane (30 mL) was added. The resulting solution stirred overnight at 50° C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with saturated sodium carbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 2:3, ethyl acetate/petroleum ether) to afford 3,3-difluorocyclobutyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (800 mg, 89%) as a brown solid. MS (ESI, pos. ion) m/z 404, 405 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[N:18][N:19]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:13]=3[CH:12]=2)C=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)([Cl:29])(=O)=O.[CH2:31]([Cl:33])Cl>>[Cl:29][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:31]([Cl:33])[C:5]=1[C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[N:18][N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[C:13]=2[CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: ClCCl
Reactant: COc1cc(OC)cc(-c2cc3c(cn2)cnn3C2CCCCO2)c1
Product: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)cnn3C2CCCCO2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At r.t. to a solution of 6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.66 g, 1.9 mmol) in methylene chloride (10 mL) with stirring was added drop-wise sulfuryl chloride (300 μL, 3.7 mmol)(Acros Organics, Cat. No. 37815). The mixture was stirred at r.t. for 2 h. LCMS showed 25% product formed, and 75% was mono-chlorinated product. Additional sulfuryl chloride (100 μL) was added to the mixture. It was stirred at r.t. for 5 h, and then concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.78 g). LCMS (M+H)+=408.0.