Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)C1C=CC=CC=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[Li+].[N-:27]([S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29].C(OCC)(=O)C>O>[N-:27]([S:28]([C:31]([F:34])([F:32])[F:33])(=[O:30])=[O:29])[S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36].[CH2:18]([SH+:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([OH:9])=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc(CSCc2ccc(O)cc2)cc1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCc1ccccc1
Product: Oc1ccc(C[SH+]Cc2ccccc2)cc1
Temperature: 7.5 °C
Reaction time: 2 h

Procedure:
30 g (0.11 mol) of benzyl-4-hydroxyphenylmethylsulfonium chloride obtained by reacting benzyl chloride with 4-hydroxyphenylmethyl sulfide was dissolved in 500 mL of water, 33.9 g (0.118 mol) of bis(trifluoromethane sulfonyl)imide lithium and 500 mL of ethyl acetate were added thereto, and then stirred at 5 to 10° C. for two hours. The water layer was removed, the organic layer was dried, and then the reaction solution was concentrated under reduced pressure and dried under vacuum. The resulting oily matter was treated with hexane, and then dried under vacuum again. Then, 44.1 g of benzyl-4-hydroxyphenylmethylsulfonium bis(trifluoromethane sulfonyl)imide was obtained in a white crystal (yield: 76.7%). The melting point was 76 to 80° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([OH:30])[CH2:19][S:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[NH:23][CH:24]=[N:25]4)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[CH3:38]I>CN(C=O)C>[OH2:30].[CH3:38][N:25]1[CH:24]=[N:23][C:22]2[C:26]1=[N:27][CH:28]=[N:29][C:21]=2[S:20][CH2:19][CH:18]([OH:30])[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([CH:10]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:16][CH2:15]1.[CH3:38][N:25]1[CH:24]=[N:23][C:22]2[C:26]1=[N:27][CH:28]=[N:29][C:21]=2[S:20][CH2:19][CH:18]([OH:30])[CH2:17][N:14]1[CH2:13][CH2:12][N:11]([CH:10]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:16][CH2:15]1
Reactant: CI
Reactant: OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2c(SCC(O)CN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)ncnc21
Product: O
Reaction time: 1 h

Procedure:
To NaH (5 mmol, 240 mg, 50% in oil, pentane washed and decanted), in DMF (7 mL) was added at -15° C. 6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine (5 mol, 2.48 g) in DMF (15 mL) over 5 min. After stirring 1 h, methyl iodide (5 mmol, 0.32 mL) in one portion was added at 0° C. under nitrogen. After one hour, the reaction mixture was concentrated under reduced pressure (1 mm Hg, 60° C.) and the crude solid passed through silica gel using 15% MeOH: CH2Cl2 to give the desired product contaminated with DMF. The product was dissolved in CH2Cl2 (50 mL) and washed with H2O (2×50 mL), saturated brine (1×50 mL), dried over Na2SO4 and conconcentrated in vacuo to give pure product (490 mg, 19.2%) as a white glass. mp 68°-70° C. DCI/MS (M+1)=511. (300 MHz) 1H NMR (CDCl3) δ: 8.7 (s, 1H), 7.95 (s, 1H), 7.3 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 4.1 (m, 1H), 3.85 (s, 3H), 3.55 (octet, 2H), 2.6 (m, 2H), 2.6 (m, 4H), 2.35 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1COCC1>[CH:1]1([CH:4]([C:15](=[O:17])[CH3:16])[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C(C#N)C1CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of argon, was placed a solution of 2-cyclopropylacetonitrile (3.70 mL, 40.1 mmol) in THF (20 mL). The solution was cooled to −78° C., then LDA (2 M in THF, 30 mL, 60 mmol) was added drop-wise and the mixture was stirred for 1 h at −78° C. A solution of acetic anhydride (4.54 mL, 48.0 mmol) in tetrahydrofuran (10 mL) was added drop-wise at −78° C. The mixture was stirred for 1 h at 15° C., then carefully quenched with citric acid (10% aq, 200 mL). The mixture was extracted with diethyl ether (2×70 mL) and the combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound, which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:20][O:30]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-N-isobutyl-4-vinylbenzenesulfonamide (1.27 g, 3.70 mmol) in dichloromethane (DCM) (30 mL) stirred under nitrogen at 0° C., was added meta-chloroperoxybenzoic acid (mCPBA) (2.55 g, 14.79 mmol), portionwise. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was then stirred for 16 hours at 20° C. DCM (20 mL) was added to the mixture. The organic phase was washed with 0.1M sodium hydroxide solution (2×50 mL), dried using a hydrophobic frit and evaporated in vacuo to give the crude product. The sample was loaded in dichloromethane and purified on silica (Si) using a 0-50% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product, 935 mg, as an off-white oil which solidified on standing. LCMS [LCMS1] Rt 1.35 min, m/z (ES+) 360 (M+H).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:13])=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[O:3].[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25])[C:18]([OH:20])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:61][C:62](=[O:75])[C@H:63]([OH:74])[C@H:64]([NH2:73])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[Cl:72])C>CN(C=O)C>[Cl:72][C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=1[CH2:65][C@@H:64]([NH:73][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:23]([CH2:24][CH3:25])=[C:15]([N:14]2[C:9](=[O:11])[C:8]3[CH:7]=[C:6]([CH3:13])[S:5][C:4]=3[NH:1][C:2]2=[O:3])[CH:16]=1)[C@@H:63]([OH:74])[C:62]([OH:75])=[O:61]
Reactant: COC(=O)c1cc(C)sc1N=C=O
Reactant: CCc1ccc(C(=O)O)cc1N
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C(=O)N[C@H](Cc2ccccc2Cl)[C@@H](O)C(=O)O)cc1-n1c(=O)[nH]c2sc(C)cc2c1=O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
Methyl 2-isocyanato-5-methylthiophene-3-carboxylate (116 mg, 588 μmol, 1.5 eq.) was dissolved in DMF (1000 μL) then combined with 3-amino-4-ethyl-benzoic acid (64.8 mg, 392 μmol, 1.0 eq.) and DIPEA (137 μL, 2.0 eq.). The mixture was heated at 70° C. overnight. The solvent was removed and the product was combined with DMF (500 μL) and HATU (298 mg, 784 μmol, 2.0 eq.). The mixture was stirred at room temperature for 15 minutes before adding (2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (TFA salt, 146 mg, 392 μmol, 1.0 eq.) in DIPEA (137 μL, 2.0 eq.) and DMF (500 μL). The mixture was stirred overnight at room temperature. The solvent was removed and the product was dissolved in THF (600 μL) and 2 M aqueous NaOH (600 μL). The mixture was heated at 80° C. overnight. The product was purified by preparative HPLC to yield the title compound (12.3 mg, 100% purity). MS m/z [M+H]+ calc'd for C26H24ClN3O6S, 542.11. found 542.0.
Reaction SMILES: [I:1][CH2:2][C@H:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:4].[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[I-:1].[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C@H:3]([CH3:4])[CH2:2][P+:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H](CI)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC#N
Product: C[C@H](C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Product: [I-]
Yield: 72.7 %

Procedure:
A solution of 1.56 g (4.4 mmol) of 1-iodo-2-(S)-((t-butoxycarbonyl)piperidin-4-yl)propane (from EXAMPLE 30, Step E) and 1.31 g (5.0 mmol) of triphenylphosphine in 5 mL of CH3CN was heated at reflux for 48 h. The mixture was cooled and concentrated. The residue was triturated with ether and CH2Cl2 and the resulting solid filtered and dried to afford 1.97 g (72%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CCO2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCO2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
2,3-dihydrobenzofuran (5 g, 41.6 mmol) was dissolved in 35 mL of acetic acid, and ¼ HNO3 (0.9 mL, 45.4 mmol) was added dropwise. At the beginning of reaction, it was heated to 70° C., then the residual HNO3 was added. After 0.5 hour, the reaction was cooled, added into ice-water, and then neutralized with Na2CO3. The water layer was extracted with ethyl acetate. The organic layers were combined and dried, concentrated under vacuum, purified by column chromatography to obtain a product (1 g, 14.6%).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[C-:18]#[N:19].[K+]>CO.O>[N:2]1([C:14]2([C:18]#[N:19])[CH2:15][CH2:16][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [C-]#N
Reactant: C1CCNC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC1(N2CCCC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 55 ml water, 33 ml hydrochloric acid (32 per cent by weight), 50 ml methanol, 127 ml pyrrolidine, 50.0 g 1,4-dioxaspiro[4.5]decan-8-one and 50.0 g potassium cyanide was stirred for 65 hours at room temperature. The pale brown suspension obtained was extracted four times with 50 ml diethyl ether each time, the combined extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 76.7 g 8-pyrrolidin-1-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile were obtained as a pale brown liquid.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br-:16].[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N+:4]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:3][CH2:2]2)=[N:8]1
Reactant: BrCCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: [Br-]
Product: c1ccc2c(N3CC[N+]4(CCCC4)CC3)nsc2c1
Yield: 69.1 %

Procedure:
Method B--A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (5.0 g., 0.0228 mole), 1,4-dibromobutane (9.8 g., 0.0456 mole) and finely powdered anhydrous potassium carbonate (7.9 g., 0.057 mole) in 100 ml. of ethanol is stirred and refluxed for a 16 hr. period. The cooled reaction mixture is filtered and the filtrate concentrated in vacuo. Residual solid heated to reflux with 70 ml. of isopropanol and filtered. Concentration of the filtrate to about one-half volume and refrigeration affords 5.58 g. (69.1% yield) of 8-(1,2-benzisothiazol-3-yl)-8-aza-5-azoniaspiro[4.5]decane bromide, m.p. 246.5°-253° C.
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:14][N:13](C(OC(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25].[C:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)#[N:27]>CN(C=O)C>[ClH:25].[C:1]([NH:9][C@H:10]1[CH2:14][NH:13][C@H:12]([C:22]([N:29]2[CH2:30][CH2:31][CH2:32][C@H:28]2[C:26]#[N:27])=[O:24])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@@H](NC(=O)c2ccccc2)CN1

Procedure:
(2S,4R)-4-Benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (title compound of Reference Example 8, 1.6 g) and (S)-2-cyanopyrrolidine hydrochloride (0.63 g) were dissolved in DMF (10 mL), and triethylamine (1.32 mL), HOBT (0.79 g) and EDC hydrochloride (0.99 g) were successively added. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-((2S,4R)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (1.2 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(NC2CCCCC2)CCCCC1.Cl.[CH2:27]([O:34][C:35](=[O:42])[CH2:36][NH:37][C:38](=[O:41])[CH2:39][NH2:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)(Cl)Cl.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.C(Cl)Cl.C(OCC)(=O)C>[CH2:27]([O:34][C:35](=[O:42])[CH2:36][NH:37][C:38](=[O:41])[CH2:39][NH:40][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NCC(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Yield: 85.9 %

Procedure:
In 380 ml of a chloroform/methylene chloride/ethyl acetate (7:5:1 by volume) mixed solvent were dissolved 7.13 g (20 mmol) of t-butyloxycarbonylglycine-dicyclohexylamine and 5.18 g (20 mmol) of glycylglycine benzyl ester hydrochloride obtained in Example 1. To this solution, 50 ml of a chloroform solution containing 4.22 g (20 mmol) of EDAC were added at -5° C. with stirring. The resulting mixture was stirred for 24 hours. The resulting chloroform solution was successively washed twice with a 10% by weight aqueous citric acid solution, then twice with water, then twice with a 4% by weight aqueous sodium hydrogen carbonate solution and finally twice with water. Thereafter, the organic phase was dried over anhydrous sodium sulfate. The solvent was then completely removed in vacuo to obtain a white oily material. This was crystallized from hexane to obtain 6.52 g (yield: 86%) of t-butyloxycarbonylglycylglycylglycine benzyl ester as a white solid. This benzyl ester was dispersed, to which 130 ml of 4N HCl/ethyl acetate were added. The mixture was stirred for 4 hours and then the solvent was removed in vacuo to obtain white precipitates. The precipitates were washed well with diethyl ether to obtain 4.63 g (yield: 85%) of glycylglycylglycine benzyl ester hydrochloride as a white solid having the following physical properties:
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]([NH:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[O:15])[CH:7]=1.C(Cl)(=O)C([Cl:30])=O>C1(C)C=CC=CC=1>[ClH:30].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]([NH:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([Cl:30])=[O:23])=[CH:20][CH:19]=2)=[O:15])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1cccnc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cl
Product: O=C(NCc1ccc(C(=O)Cl)cc1)OCc1cccnc1
Reaction time: 4 h

Procedure:
0.8 ml of N,N-dimethylformamide was added to a toluene suspension (2000 ml) including 40 g (0.14 mole) of 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic acid. Then, 24 ml of oxalyl chloride were added dropwise to the resultant mixture, followed by stirring for 4 hours. A deposited white solid was collected by filtration to obtain 47.7 g (quantitative) of 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoyl chloride hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[S:12][C:11]([C:13](O)=[O:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].[N-:19]=[N+:20]=[N-:21].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:7][C:8]1[S:12][C:11]([C:13]([N:19]=[N+:20]=[N-:21])=[O:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
oxalyl chloride (460 mg, 3.62 mmol) followed by N,N-dimethylformide (0.05 mL) was added to a solution of 5-chloro-4-nitrothiophene-2-carboxylic acid (1.0 g, 14.0 mmol) in dichloromethane (20 mL) under nitrogen atmosphere and the resulting mixture was stirred at ambient temperature for 4 hours. TLC analysis showed no acid remaining so the mixture was allowed to be concentrated in vacuo. The resulting acid chloride was dissolved in dry tetrahydrofuran (10 mL). Sodium azide (190 mg, 2.89 mmol) was added to the above solution. The resulting mixture was stirred at ambient temperature for 10 hours. After this time, TLC analysis showed no acid chloride remaining so the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent was removed to afford the title product as a brown solid (400 mg, 59% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.23 (2H, s).
Reaction SMILES: CC([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])CO.C(C(CCCCCCCCCC)[CH2:19][OH:20])C>>[CH2:12]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:19][OH:20])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC(CC)CO
Reactant: CCCCCCCCCCCC(C)CO
Product: CCCCCCC(CO)CCCC

Procedure:
2-methyl-1-tridecanol; 2-ethyl-1-dodecanol;
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2)[CH3:2].[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[OH-].[Na+]>C(O)(=O)C.P(=O)(O)(O)O>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2)[CH3:2]
Reactant: O=C1CCNCC1
Reactant: CCc1cc2cc(F)ccc2[nH]1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1[nH]c2ccc(F)cc2c1C1=CCNCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
2.83 g 2-ethyl-5-fluoro-1H-indole are suspended in 50 ml acetic acid and heated to 90° C. A suspension of 6.66 g 4-piperidone in 15 ml phosphoric acid 2N is added. The reaction mixture is stirred for 3 hours at 90° C., combined with sodium hydroxide solution and the product is extracted with ethyl acetate. 2.85 g product are obtained as a solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:21]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:21].[CH:14](=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C(=C1CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: C(=C1CCNCC1)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.7 %

Procedure:
There was dissolved 24.6 g (96 mmol) of 1-benzyl-4-benzylidenepiperidine in 200 ml of dichloroethane and thereto 11.1 ml (102 mmol) of 1-chloroethyl chloroformate was added dropwise under cooling with ice. The reaction solution was refluxed with heating for 30 minutes and then stirred at room temperature for 1.5 hours. The reaction solution was concentrated to 80 ml by removing the solvent under reduced pressure, thereto was added 209 ml of methanol and the obtained mixture was refluxed with heating for 12 hours. The solvent was removed under reduced pressure and to the obtained residue was added 100 ml of isopropyl ether and the precipitate was separated by filtration to obtain 8.6 g of the titled compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH3:47])[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][NH2:46])=[CH:40][CH:39]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:46][CH2:45][CH2:44][C:41]4[CH:42]=[CH:43][C:38]([CH3:47])=[CH:39][CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: Cc1ccc(CCN)cc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(C)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-(p-tolyl)-ethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound, m.p. 190-192° C. MS [(+)ESI, m/z]: 570 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)[OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
A microwave tube was charged with rac-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-ylmethanol (Stage 1.1, 1.12 g, 3.60 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (789 mg, 3.60 mmol), tetrakis-(triphenylphosphine)palladium (210 mg), 2M Na2CO3 (6.5 mL) and DME (11 mL). It was heated at 150° C. under microwave irradiation for 10 min. The RM was taken up with EtOAc and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The reside was purified by MPLC eluting with a DCM/MeOH gradient to afford the title compound as a brown solid (tR 1.0 min(conditions 1), MH+=357).