Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:51][CH2:52][CH2:53][CH3:54])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH2:14][CH2:15][OH:16])[N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:38])[NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)(=[O:27])=[O:26])=[CH:19][C:18]=2[C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].ClC(Cl)(Cl)[C:57]([N:59]=C=O)=[O:58].C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl.CO>[C:57](=[O:58])([O:16][CH2:15][CH2:14][C:11]1[N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:38])[NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)(=[O:27])=[O:26])=[CH:19][C:18]=2[C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[N:9]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:51][CH2:52][CH2:53][CH3:54])[C:12]=1[Cl:13])[NH2:59]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CCO)c1Cl
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CCOC(N)=O)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a 0° C. solution of N,N-dibutyl-4-chloro-5-(2-hydroxyethyl)-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamide (Example 170, 20 mg, 0.026 mmol) in CH2Cl2 (0.5 mL) was added trichloroacetyl isocyanate (4 μl, 0.031 mmol). After stirring at 0° C. for 30 min, K2CO3 (2 mg, 0.014 mmol) and MeOH (0.5 mL) were added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organic extracts were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to afford a colorless oil. The oil was dissolved in MeOH (3.0 mL) and water (3.0 mL) and K2CO3 (120 mg, 0.84 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and then partitioned between EtOAc and H2O. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (10 mg, 44%) as a white solid. 1H NMR (CD3OD, 1.5:1 mixture of amide rotamers) δ 8.73 (br s, 1H), 8.13-8.04 (m, 4.5H), 8.02-7.95 (m, 2H), 7.78-7.64 (m, 3H), 7.23-7.08 (m, 4H), 7.02-6.88 (m, 0.5H), 4.94-4.89 (m, 1H), 4.67-4.41 (m, 1H), 4.25 (t, J=6.5 Hz, 2H), 4.18-4.05 (m, 1.5H), 4.01-3.71 (m, 1.5H), 3.65-3.46 (m, 4H), 3.37-3.34 (m, 2H), 3.02 (t, J=6.5 Hz, 1.5H), 2.92-2.77 (m, 1.5H), 1.68-1.53 (m, 2H), 1.31-1.25 (m, 3H), 1.20-1.17 (m, 1H), 0.99 (t, J=7.4 Hz, 2H), 0.94-0.86 (m, 3H), 0.78-0.73 (m, 2H), 0.68 (t, J=6.4 Hz, 1H); MS(ESI+) m/z 813.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:23]([OH:25])=[O:24])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:6]=2[CH:33]=1.[N+](=[CH2:36])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:23]([O:25][CH3:36])=[O:24])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:6]=2[CH:33]=1
Reactant: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: CCN(CC)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)OC

Procedure:
In the manner given in Example 14, 7-chloro-2-[[1-carboxy-4-(diethylamino)butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-4-(diethylamino)butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=3[CH3:22])[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:22])[N:8]([CH2:11][CH2:12][CH3:13])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1C
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc2c(Cl)cccc2c1-c1ccc(O)cc1C
Yield: 58.8 %

Procedure:
Prepared according to Example 128 from 7-chloro-3-(4-methoxy-2-methylphenyl)-2-propyl-2H-indazole (0.04 g, 0.13 mmol), boron tribromide (0.20 mL, 2.10 mmol) and 1.0 mL of cyclohexene to give the product (0.023 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][C:10]1[C:11](F)=[C:12]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])=[O:7].CCN(CC)CC.[CH3:31][OH:32]>>[O:7]=[S:6]1(=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[C:10]1[C:11]([O:32][CH3:31])=[C:12]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(NS(=O)(=O)CCCCCl)c1F
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCCS2(=O)=O)c1OC
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of methyl 3-{[(4-chlorobutyl)sulfonyl]amino}-2-fluoro-5-nitrobenzoate (D146) (1.5 g, 4.1 mmol, 1 equiv) in MeOH (30 ml) was added NEt3 (1.2 ml 8.6 mmol, 2.1 equiv) and the resulting solution was refluxed for 15 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with AcOEt/Et2O to give methyl 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-2-(methyloxy)-5-nitrobenzoate (D149) (1.2 g, 55%) as a light brown solid which was used in the next step without further purification. [M+H]+=345.1, RT2.80 min.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:15]=[CH:14]C=[CH:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:3]=1[CH:23]([CH2:28][CH2:29][CH3:30])[C:24]([O:26]C)=[O:25].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:15][CH2:14][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:3]=1[CH:23]([CH2:28][CH2:29][CH3:30])[C:24]([OH:26])=[O:25]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CC=CC=C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Temperature: 60 °C
Yield: 81.8 %

Procedure:
To a solution of methyl [2-methyl-4-(3-chlorophenyl)-5H-cyclohepta[4,5]thieno [2,3-b]pyridin-3-yl]pentanoate (0.281 g; 0.65 mmol) in methanol (6.5 mL) was added a solution of sodium hydroxide 5 N (1.3 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.220 g (82%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N-]C(C)C)(C)C.[Li+].Br[CH2:17]/[CH:18]=[C:19](/[C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([Cl:38])=[CH:32][CH:31]=1)\[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O>O1CCCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20](/[C:19](/[C:30]2[CH:31]=[CH:32][C:33]([Cl:38])=[C:34]([O:36][CH3:37])[N:35]=2)=[CH:18]\[CH2:17][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:7])=[CH:25][CH:24]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: CN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(/C(=C/CC2CCN(C)C2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of N-methylpyrrolidone (0.7 mL) in tetrahydrofuran (3 mL) was stirred at −78° C. in a nitrogen atmosphere, during which a lithium diisopropylamide solution (2.2 M, 0.5 mL) was added dropwise thereto. The mixture was stirred at the same temperature for 30 minutes. A solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (182 mg) in tetrahydrofuran (2 mL) was slowly added dropwise thereto, and the mixture was stirred at −78° C. for one hour. Water was added to the reaction solution, which was then warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:10) to give 3-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-1-methylpyrrolidin-2-one as a colorless oil (176 mg, 93%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 74.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 180 mg (77%) of the title compound as an amorphous foam. mp 64°-87°. FDMS: m/e=373. α[D]589 =+64.42 (c=1.04, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[C:23]([CH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH2:35])=[NH:34])[CH:29]=[CH:30][CH:31]=1)#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:34]=[C:33]([NH:32][C:28]4[CH:27]=[C:26]([CH2:25][C:23]#[N:24])[CH:31]=[CH:30][CH:29]=4)[N:35]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N#CCc1cccc(NC(=N)N)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: N#CCc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-cyanomethyl-phenyl)-guanidine nitrate were converted to I-78 (6%): HRMS Calcd. for C20H14ClN5O: 376.0965, Found 376.0994.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][O:3][CH2:2]1.[C:9]([O:13][C:14](=[O:20])[NH:15][CH2:16][CH2:17][CH2:18][NH2:19])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1>CC(N(C)C)=O.CCOC(C)=O>[C:9]([O:13][C:14](=[O:20])[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:1](=[O:8])[CH2:2][O:3][CH2:4][C:5]1=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1COCC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCN1C(=O)COCC1=O
Temperature: 120 °C
Yield: 29.3 %

Procedure:
A mixture of diglycolic anhydride (22 g, 0.188 mol), tert-butyl-3-aminopropylcarbamate (65 g, 0.377 mol) and NMM (21 mL, 0.188 mol) in DMA (300 mL) was heated up to 120° C. for 48 h. The reaction mixture was cooled down to r.t and diluted with EtOAc (1.5 L). The solution was washed with brine (5×150 mL), dried with MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel (15% ethylacetate in chloroform) affording 15 g of the title compound (30%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14](O)=[O:15].[NH2:20][NH2:21]>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([NH:20][NH2:21])=[O:15]
Reactant: NN
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)O)c1Cl
Solvent: C1CCOC1
Product: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)NN)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
To a solution of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.050 g, 0.175 mmol) in anhydrous THF (2 mL), under N2, was added CDl (0.030 g, 0.184 mmol). The mixture was stirred at rt for 4 h and additional CDl (0.030 g, 0.184 mmol) was added. After 45 min, additional CDl (0.079 g, 0.49 mmol) was added. After 5 min, hydrazine (0.112 g, 3.5 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was partitioned between EtOAc and 0.2N NaOH. The organic phase was washed with 0.2N NaOH and sat'd brine. The combined aqueous phases were extracted with EtOAc (×2). The second EtOAc phases were washed with sat'd NaHCO3 solution and brine. The organic phases were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-10% MeOH—CH2Cl2 gradient) to afford the title compound (0.027 g, 52% yield): MS (ES) m/z 299 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:24]=[C:25]=[O:26])(=O)=O>ClCCl>[C:25]([C:14]1[NH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:26])[NH2:24]
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])cc1
Temperature: -24 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To 18 g (69.16 mmol) of ethyl 4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate suspended in 300 cm3 of dichloromethane are added, at a temperature in the region of −24° C. under an argon atmosphere, 8.1 cm3 (91.29 mmol) of chlorosulfonyl isocyanate dissolved in 100 cm3 of dichloromethane. After stirring for 30 minutes at a temperature in the region of −24° C., the reaction medium is allowed to warm to a temperature in the region of 20° C. over 2 hours. After initiating the crystallization using a glass rod, the reaction mixture is stirred at a temperature in the region of 20° C. for 30 minutes. The reaction mixture is then cooled to a temperature in the region of 5° C. and then filtered through a No 3 sinter funnel. The solid is washed with three times 40 cm3 of dichloromethane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. for 3 hours. The solid is then suspended in 500 cm3 of water; the resulting mixture is then heated at a temperature in the region of 40° C. for 3 hours and then cooled at a temperature in the region of 5° C. for 1 hour before filtering through a No 3 sinter funnel. The solid is successively washed with twice 50 cm3 of water and twice 30 cm3 of petroleum ether and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. for 16 hours to give 15.4 g of ethyl 5-carbamoyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate in the form of a beige-coloured solid; EI: m/z=303: M+; m/z=274 [M-CH2CH3]+; m/z=258 [M-OCH2CH3]+; m/z=241 [258-OH]+ base peak.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1.[CH2:35](N(CC)CC)C.CI.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH3:35])[CH2:19][CH2:20]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1
Reactant: CCN(CC)CC
Reactant: CON=C1C[C@@H](c2noc(CN3CCNCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Product: CON=C1C[C@@H](c2noc(CN3CCN(C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A solution containing 1 equivalent of (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime (Example 48), dissolved in dry DCM at 0° C. in presence of 1.5 equivalent of triethyl amine, was reacted with 1 equivalent of methyl iodide. The reaction mixture was stirred at room temperature for 12 hours. The reaction was hydrolyzed and then made basic with sodium carbonate solution (10%) and extracted with DCM. The organic phase was then dried with magnesium sulfate, and concentrated in vacuo to give a residue which was purified by flash-chromatography using dichloromethane/methanol as eluent to give the expected product, (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-{5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-3-pyrrolidinone O-methyloxime, as a mixture of E-/Z-isomers, in 50% yield (99.9% purity by HPLC). The pure Z-isomer could be separated by flash-chromatography, and was obtained in 31% yield (98.9% purity by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:22]=[C:21]([CH3:32])[C:20]=1[O:33][CH3:34].[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:22]=[C:21]([CH3:32])[C:20]=1[O:33][CH3:34]
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)OC(C)C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2-methyl-phenoxy]acetate (64 mg, 0.2 mmol, 1.0 eq) in THF (2 mL) was added LiOH (2M aqueous solution, 2.0 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The THF was removed and the pH of the aqueous solution that remained adjusted to pH 4-5 with diluted HCl. The aqueous layer was extracted with EtOAc, the organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (30 mg, 50%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[O:4]1.CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][C@H:3]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[O:4]1)(=[O:20])=[O:19]
Reactant: OC[C@H]1CCC2(CC2)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCC2(CC2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane (116 mg, 0.9 mmol) and Et3N (183.8 mg, 1.82 mmol, Shantou Xilong chemical factory) in dry CH2Cl2 (6 mL) at −10° C. under N2, was added MsCl (203 mg, 1.4 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe. After stirring for 2 hrs at rt, the reaction was quenched with water ice (3 mL), and the water phases were extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to give ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(B(CC)[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)C.[OH-].[K+].COCCOC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCB(CC)c1cccnc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: COCCOC
Solvent: O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccnc4)cc3CC[C@@H]12
Yield: 56.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (30 mg, 0.03 mmol), tetrabutylammonium bromide (17 mg, 0.05 mmol), diethyl(3-pyridyl)borane (148 mg, 0.98 mmol), powdered potassium hydroxide (85 mg, 1.4 mmol) and 3 mL of DME, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with water (15 mL), extracted with 10% methanol in dichloromethane (2×50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 112 mg (56%) of the title compound as a white solid. mp 135°. FDMS: m/e=306.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.Cl[CH2:9][CH:10]=O>O>[Br:1][C:2]1[S:6][C:5]2=[N:7][CH:9]=[CH:10][N:4]2[N:3]=1
Reactant: O=CCCl
Reactant: Nc1nnc(Br)s1
Solvent: O
Product: Brc1nn2ccnc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-bromo-1,3,4-thiadiazol-2-amine (60 g, 0.33 mol) in H2O (1.5 L), a solution of chloroacetaldehyde (50% wt in water, 64.5 mL, 0.50 mol) was added, and the mixture was stirred at reflux temperature for 5 h. A second portion of chloroacetaldehyde (20.6 mL, 0.5 eq) was added, and stirring was continued overnight. The starting material had been consumed completely, and the reaction mixture was cooled to RT. The solid was removed by filtration and washed with water. The mother liquor was neutralized with a sat. aq. solution of NaHCO3 and extracted with DCM (2×1 L). The organic layers were washed with brine (2×600 mL), dried and evaporated in vacuo. The brown residue obtained was triturated with a mixture of MeOH and MTBE (1:1, 70 mL) to afford the desired product as a pale yellow solid. The mother liquors were purified by chromatography (SiO2, DCM) to yield some more product. Combined yield: 9.4 g (14%). MS (ESI+): m/z=204 [M+H]+; 1H-NMR(CDCl3): 7.36 (d, 1H); 7.56 (d, 1H).