Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:4]([CH2:7][Li])(=[O:6])=[O:5])[CH3:3].[CH2:9]([Sn:13](Cl)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>CCCCCC.C1COCC1.C1COCC1>[CH3:1][N:2]([S:4]([CH2:7][Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][CH2:10][CH2:11][CH3:12])(=[O:6])=[O:5])[CH3:3]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [Li]CS(=O)(=O)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)CS(=O)(=O)N(C)C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Employing the apparatus and procedure of Example I, 100 ml. of an approximately one-molar solution of (N,N-dimethylaminosulfonylmethyl)lithium in hexane-THF solvent was added slowly over a period of 30 minutes to 0.1 mole of tri-n-butyltin chloride dissolved in THF. The temperature at addition was -60° C provided by a dry ice-acetone bath and rose through the addition period to 0° C. Following the complete addition, the reaction mixture was stirred for 2 hours at room temperature (20° C) and hydrolyzed by pouring into an aqueous one-molar ammonium chloride solution. Extraction from the hydrolyzate with ether solvent and purification by vacuum distillation yielded the desired compound, (N,N-dimethylaminosulfonylmethyl)tributyltin. The product, a pale-yellow liquid, had a boiling point of from 158°-160° C/0.1 mm. Hg. Analysis gave 43.8% Carbon and 8.5% Hydrogen compared to the calculated values, respectively, of 43.7% and 8.5%. The assigned structure was confirmed by infrared and proton nuclear magnetic resonance spectral analyses.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([Cl:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([Cl:12])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(Cl)sc2ncnc(Cl)c12
Product: Cc1c(Cl)sc2ncnc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12

Procedure:
The title compound was prepared (611 mg, 82%) from 4,6-dichloro-5-methylthieno[2,3-d]pyrimidine (425 mg, 1.94 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (582 mg, 2.9 mmol) by following the general procedure described for Preparation 9. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 5.25 (d, 1H), 4.35 (m, 1H), 4.30 (m, 2H), 3.00 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.45 (s, 9H), 1.35-1.55 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O.CN(C)C=O>C1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([Cl:16])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1cnccc1C(F)(F)F
Yield: 90.1 %

Procedure:
4-Trifluoromethylnicotinic acid (50.09 g, 0.262 mol) was suspended in benzene (250 ml), and thionyl chloride (38.2 ml, 0.524 mol) and N,N-dimethylformamide (0.1 ml) were added. The mixture was refluxed for 3 hours. The reaction mixture was concentrated, and the residue was distilled under reduced pressure to obtain 49.45 g (yield 90.1%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][C:32]1=[O:41]>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][C:32]1=[O:41]
Reactant: CC(C)(N)CCN1C(=O)CCc2ccccc21
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Product: CC(C)(CCN1C(=O)CCc2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
Prepared from 357 mg (1 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 232 mg (1 mmol) of 1-(3-amino-3-methylbutyl)-3,4-dihydroquinolin-2-one analogously to the method described for Example 5c). The final purification of the product is carried out by preparative HPLC (reverse phase, acetonitrile/water gradient with 0.1% trifluoroacetic acid). Yield: 94 mg (17%, trifluoroacetate); mass spectroscopy: [M]+=440.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:42](Cl)=[O:43])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:42]([N:39]2[CH2:38][CH2:37][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:41][CH2:40]2)=[O:43])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 67.1 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (130 mg, 0.376 mmol) in CH2Cl2 (5 ml) was added ethyl-diisopropyl-amine (0.10 ml, 0.56 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (94 mg, 0.41 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 3:1) afforded 135 mg (66%) of the title compound as a white solid. ES-MS m/e: 535.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:9])[C:6]=1[CH2:7]Br.[C-:10]#[N:11].[K+]>CCO.O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([Br:9])[C:6]=1[CH2:7][C:10]#[N:11]
Reactant: BrCc1c(Br)csc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(Br)csc1Br
Yield: 85.4 %

Procedure:
To a solution of 2,4-dibromo-3-(bromomethyl)thiophene (1.00 g, 3.00 mmol) in EtOH (10 mL) was added a solution of potassium cyanide (0.29 g, 4.5 mmol) in H2O (0.5 mL). The mixture was heated to reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and H2O. The EtOAc was dried (MgSO4) and the solvent removed. The residue was recrystalized from EtOH to yield (2,4-dibromothien-3-yl)acetonitrile (0.72 g, 86%). mp 75.5-77° C.; 1H NMR (500 MHz, DMSO-d6) δ: 3.94 (s, 2H), 7.94 (s, 1H). MS (EI) m/z 279/281/283 (M+.). Anal. Calcd for C6H3Br2NS: C, 25.65; H, 1.08; N, 4.99. Found: C, 26.04; H, 1.18; N, 4.86.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:40])[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[N:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[C:38]([C:34]1[CH:33]=[C:32]([C:30]2[N:31]=[C:22]([CH:19]3[CH2:18][CH2:17][CH:16]([O:15][CH2:14][C:13]([OH:40])=[O:12])[CH2:21][CH2:20]3)[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:37]=[CH:36][CH:35]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)COC1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(-c2nc(C3CCC(OCC(=O)O)CC3)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (TFA) (2 ml) is added to a solution of {4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexyloxy}-acetic acid tert-butyl ester (182 mg, 0.41 mmol) in CH2Cl2 (2 ml) at 0° C. The solution is stirred at room temperature for 1 hour, concentrated, and azeotroped with toluene (×3). Purification by chromatography on silica gel, eluting with 7% methanol in CH2Cl2 gives the product. MS (ES+) [M+H]+ 388.04
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.[H-].[Na+]>CN(C)C=O.O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][N:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]1=[O:10]
Reactant: O=c1[nH]ccc2ccsc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCn1ccc2ccsc2c1=O
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a solution of thieno[2,3-c]pyridin-7(6H)one (2.92 g, 19.3 mmol) in dry dimethylformamide (20 ml) under a nitrogen atmosphere was added 2-(dimethylamino)ethyl chloride hydrochloride (3.15 g, 21.8 mmol). This mixture was warmed to 80° C. and sodium hydride in mineral oil (60%, 2.6 g, 65 mmol) was added carefully and rapidly. After 1.5 hours additional 2-(dimethylamino)ethyl chloride hydrochloride (1.45 g, 10 mmol) was added. After two hours the reaction mixture was cooled and diluted with water. The crude product was extracted into chloroform and then into dilute hydrochloric acid. The acidic solution was made basic with sodium hydroxide and the product extracted into diethyl ether. This was dried over anhydrous sodium sulfate, filtered and evaporated to give an oily product (3.8 g, 89% yield) which contained less than 10% of the by-product resulting from O-alkylation.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCC1OCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CNCC1OCCO1)OCC

Procedure:
2,2-Diethoxyethylamine (23.3 grams), 2-bromomethyl-1,3-dioxolane (29.2 grams), triethylamine (25 ml) and toluene (150 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux overnight. After this time the mixture was cooled and filtered. The filtrate was then distilled under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine having a boiling point of 125° C at 0.1 mm of Hg pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:27]4[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28]4)[CH:22]=[CH:23][CH:24]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: O=C(O)C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CN2CCC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (100 mg, 0.258 mmol) (D11) in Ethanol (10 mL) stirred at room temperature was added 3-pyrrolidinecarboxylic acid (119 mg, 1.034 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA/THF for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, and dissolved in THF. The residue was purified by Mass Directed AutoPrep to afford 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-pyrrolidinecarboxylic acid (E44) (58 mg) as a TFA salt (off-white solid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17](=O)[CH3:18]>CC(C)=O.ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:16]=[C:17]([CH3:18])[C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: CC(C)=O
Product: Cc1csc2ccc(Br)cc12
Yield: 52 %

Procedure:
A mixture of 4-bromothiophenol (3.9 g, 20 mmol), K2CO3 (5.5 g, 40 mmol) and chloroacetone (6.6 mL, 82 mmol) in acetone (50 mL) was heated at reflux over night. The reaction mixture was filtered and the solvent was evaporated giving 5.0 g crude product. The intermediate thioether was dissolved in chlorobenzene (50 mL) and polyphosphoric acid (PPA, 2.5 g) was added (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). After reflux for 24 h, the solvent was decanted and the PPA residue was treated with CH2Cl2. The combined organic extracts were washed with water and dried. Evaporation of the solvents afforded the crude product which was purified on silica (heptane as eluent) to give the title compound (2.36 g, 50% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.41 (d, J=1.20 Hz, 3 H) 7.11 (qd, J=1.20, 0.54 Hz, 1 H) 7.44 (ddd, J=8.53, 1.90, 0.54 Hz, 1 H) 7.70 (dd, J=8.53, 0.54 Hz, 1 H) 7.85 (dd, J=1.90, 0.54 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23]([NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:30]2[CH2:31][CH2:32][CH:27]([CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:21])[CH3:19])[CH2:28][CH2:29]2)=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CN2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Yield: 15.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (110 mg, 0.31 mmol) was reacted with 4-({4-[(tert-butoxycarbonylamino)methyl]piperidin-1-yl}methyl)phenylboronic acid (80 mg, 0.26 mol) to afford the desired product (25 mg, 20%) as a yellow glass: 1H NMR (500 MHz, CD3OD) δ 7.69-7.66 (m, 2H), 7.57-7.54 (m, 2H), 7.41-7.38 (m, 3H), 5.96-5.95 (m, 1H), 4.48-4.44 (m, 2H), 3.75 (s, 3H), 3.70-3.64 (m, 2H), 3.27-2.91 (m, 4H), 2.25-1.95 (m, 2H), 1.57 (s, 1H), 1.52-1.42 (m, 10H); ESI MS m/z 534 [C30H35N3O4S+H]+; HPLC 97.6% (AUC), tR=14.10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].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.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][CH3:78])([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([NH:65][CH2:66][C:67]5[CH:68]=[CH:69][C:70]6[C:74]([CH2:75][CH3:76])([CH2:77][CH3:78])[O:73][B:72]([OH:79])[C:71]=6[CH:80]=5)=[O:26])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(F)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.23 mmol) and DIPEA (118 mg, 0.92 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (175 mg, 0.46 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]-oxaborol-1(3H)-ol hydrochloride (118 mg, 0.46 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title compound.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([C:34]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]([C:48]3[C:49]4[C:54]([C:55]([N:62]([C:71]5[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=5[CH3:77])[C:63]5[CH:68]=[CH:67][C:66]([CH:69]=O)=[CH:65][CH:64]=5)=[C:56]5[C:61]=3[CH:60]=[CH:59][CH:58]=[CH:57]5)=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]3[C:35]=2[CH:36]=[CH:37][CH:38]=[CH:39]3)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:22][CH:21]=1)=O>CS(C)=O>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([C:34]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]([C:48]3[C:49]4[C:54]([C:55]([N:62]([C:71]5[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=5[CH3:77])[C:63]5[CH:68]=[CH:67][C:66]([CH:69]=[CH:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)=[CH:65][CH:64]=5)=[C:56]5[C:61]=3[CH:60]=[CH:59][CH:58]=[CH:57]5)=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]3[C:35]=2[CH:36]=[CH:37][CH:38]=[CH:39]3)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:22][CH:21]=1)=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1N(c1ccc(C=O)cc1)c1c2ccccc2c(-c2c3ccccc3c(N(c3ccc(C=O)cc3)c3ccccc3C)c3ccccc23)c2ccccc12
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccccc1N(c1ccc(C=Cc2ccccc2)cc1)c1c2ccccc2c(-c2c3ccccc3c(N(c3ccc(C=Cc4ccccc4)cc3)c3ccccc3C)c3ccccc23)c2ccccc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
10,10′-Bis(p-tolylphenylamino)-9,9′-bianthryl(19 g; yield 54%) was prepared as described in Preparation Example 3, except that 20 g of diphenylamine was replaced with 22 g of p-tolylphenylamine. Then, 7 g of 10,10′-bis(p-tolylphenylamino)-9,9′-bianthryl was dissolved in 50 mL of toluene, to which 3.7 g of phosphorus oxychloride was then added, and the mixture was stirred at room temperature. To the mixture was added dropwise 2.7 g of N-methylformanilide, and the mixture was stirred at 50° C. for 5 hours. After completion of the reaction, the mixture was slowly poured into 100 mL of cold water. The mixture was transferred into a separatory funnel and the toluene layer was washed several times until pH of the washing become neutral. The organic layer was dried over magnesium sulfate and evaporated to give 4.5 g (yield 60%) of 10,10′-bis(N-p-formylphenyl-N-tolylamino)-9,9′-bianthryl. To 50 mL of dimethylsulfoxide were added 2.9 g of diethyl benzylphosphonate and 0.6 g of sodium hydride. To the stirred mixture was added dropwise 4.5 g of 10,10′-bis(N-p-formylphenyl-N-tolylamino)-9,9′-bianthryl in 50 mL of dimethylsulfoxide, and the reaction mixture was stirred at 50° C. for 3 hours. After completion of the reaction, the solution was poured into 50 mL of ice-water. The mixture was neutralized with an acid and extracted with ethyl acetate. After evaporating the solvent under a reduced pressure, the residue was purified by column chromatography on silica gel eluting with chloroform, and the product was recrystallized from ethanol to give 3.8 g (yield 70%) of 10,10′-bis(N-p-styrylphenyl-N-tolylamino)-9,9′-bianthryl.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Br)(=[O:30])=[O:29].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1)(=[O:30])=[O:29]
Reactant: COc1ccccc1S(=O)(=O)Br
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1OC)C2

Procedure:
Prepared analogously to Example 5 from methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride and o-methoxybenzenesulphonyl bromide in chloroform in the presence of triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:30][OH:31]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][O:15][N:16]=2)=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)CCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reactant: NO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)CCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
Ethyl 3-(4-[(3-chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propanoate (27 mg, 0.079 mmol) was suspended in benzene (1 mL) under an atmosphere of nitrogen and phosphorus pentachloride (18.0 mg, 0.086 mmol) was added. The solution was heated to reflux for 2.5 h. The solvent was removed in vacuo. The residue was dissolved in EtOH (1.0 mL) and hydroxylamine (100 μL, 2 mmol) (50% solution in water) was added to the reaction. After stirring 1 h, the solution was diluted with MeOH and purified by preparative LCMS to give the desired product (8.5 mg, 30%). 1H NMR (400 MHz, CD3OD): δ 7.03 (t, J=8.9 Hz, 1 H), 6.95 (dd, J=6.4, 2.7 Hz, 1 H), 6.71 (m, 1 H), 4.12 (q, J=7.2 Hz, 2 H), 3.11 (t, J=7.2 Hz, 2 H), 2.80 (t, J=7.2 Hz, 2 H), 1.23 (t, J=7.2 Hz, 3 H); LCMS for C14H15ClFN4O1(M+H)+: m/z=357.1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:30][N:31]([CH3:35])[C:32](=[O:33])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 108 %

Procedure:
A suspension of 2.00 g (0.006 mol) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol in 160 ml of toluene was treated with 2 ml (0.014 mol) of triethylamine, 0.88 g (0.007 mol) of 4-dimethylaminopyridine and 0.7 ml (0.007 mol) of dimethylcarbamoyl chloride and then boiled under reflux for 4 hours. After cooling the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. After extraction with methylene chloride and chromatography over silica gel with ethyl acetate/hexane 1:2 there were obtained 2.40 g of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl dimethylcarbamate as an oil.