Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:28].S(Cl)([Cl:32])(=O)=O.O>C(Cl)Cl>[Cl:32][C:4]1[CH:5]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:25])([F:26])[F:27])[CH:9]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:28]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)cc(Cl)c1O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a stirred solution of 2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol (0.332 g, 0.8. mmol) in CH2Cl2 (10 ml) was added sulfuryl chloride (0.113 g, 0.84 mmol) at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, and the whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with CH2Cl2-hexane to give the subtitle compound (0.318 g, 88.6% yield).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=O.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[N:24][N:25]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH:26]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[NH:33][C:30]1[CH:31]=[N:32][C:27]([N:25]2[CH:26]=[C:22]([C:21]([F:35])([F:34])[F:20])[CH:23]=[N:24]2)=[CH:28][CH:29]=1
Reactant: Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1
Reactant: CCOC(=O)c1ccc(C(=O)CCC(F)(F)F)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43921 %

Procedure:
To a solution of crude ethyl 4-(4,4,4-trifluorobutanoyl)benzoate (0.060 g, 0.22 mmol) and 6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-amine (0.050 g, 0.22 mmol) in methanol (2.2 ml) was added decaborane (8.0 mg, 0.066 mmol). The reaction was stirred for 12 hours at ambient temperature. The reaction mixture was quenched with aqueous 1.0M hydrochloric acid and concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO2, 0-100% ethyl acetate in heptane) to yield the product (47 g, 42%) as an oil. 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.38-7.45 (m, 2H), 6.96 (dd, J=8.8, 2.7 Hz, 1H), 4.50 (t, J=6.2 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H), 2.07-2.32 (m, 4H), 1.39 (t, J=7.2 Hz, 3H). MS (M+1): 487.3.
Reaction SMILES: C([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:47]2[N:48]=[C:49]([NH:52]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:50][CH:51]=2)\[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:29]([O:31]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:30])=[C:22]([CH:25]=[CH:26][CH2:27]I)[CH2:23][S:24][C@H:19]23)=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.[NH2:72][C:73]1[S:74][C:75]2[CH:80]=[CH:79][N:78]=[CH:77][C:76]=2[N:81]=1>CS(C)=O.C(OCC)(=O)C>[NH2:52][C:49]1[S:50][CH:51]=[C:47](/[C:14](=[N:13]/[O:12][C:8]2([C:6]([OH:7])=[O:5])[CH2:11][CH2:10][CH2:9]2)/[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:29]([O-:31])=[O:30])=[C:22](/[CH:25]=[CH:26]/[CH2:27][N+:78]4[CH:79]=[CH:80][C:75]5[S:74][C:73]([NH2:72])=[N:81][C:76]=5[CH:77]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:48]=1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=CCI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Reactant: Nc1nc2cnccc2s1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/OC2(C(=O)O)CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(/C=C/C[n+]4ccc5sc(N)nc5c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-5', 641 mg, 0.58 mmole) and 2-aminothiazolo[4,5-c]pyridine (97 mg, 0.64 mmole) in dimethylsulfoxide (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2×150 ml), dried over sodium sulfate and concentrated under reduced pressure. The oily residue was triturated with diisopropyl ether and the resulting precipitate (558 mg) was treated with a mixture of 90% trifluoroacetic acid (10 ml) and anisole (2 ml) at room temperature for 1 hour. Concentration of the mixture followed by trituration of the residue with ether gave 313 mg of crude I-5C, which was purified by column chromatography [HP-20, eluted with 30% and 50% CH3OH: the packing in the PrepPAK-500/C18 (Waters), eluted with 10% CH3OH] to give 40 mg (11%) of I-5C. M.p. >150° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].ClC1C=CC(S(O)=O)=CC=1C(O)=O.N1C[CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:12]2[CH2:30][CH2:31][O:32][CH2:33][CH2:13]2)(=[O:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C1COCCN1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: O=C(O)c1cc(S(=O)O)ccc1Cl
Product: O=C(O)c1cc(S(=O)(=O)N2CCOCC2)ccc1Cl
Yield: 100 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and morpholine and obtained in 100% yield. MS (m/e): 304.0 (MH−, 100%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([Cl:18])[N:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:18][C:13]1[N:12]=[N:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[CH:14]=1
Reactant: Clc1cc2c(nn1)CN(Cc1ccccc1)CC2
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1cc2c(nn1)CNCC2

Procedure:
A mixture of 7-benzyl-3-chloro-5,6,7,8-tetrahydropyrido[3,4-c]pyridazine (1.3 g, 5.0 mmol) and 1-chloroethyl chloroformate (0.86 g, 10.0 mmol) in dichloroethane (30 ml) is heated at refluxing temperature overnight. The solvent is removed in vacuo and MeOH (30 ml) is added to the residue. The resulting mixture is refluxed for 30 min. The solvent is removed in vacuo to give the title compound as a hydrogen chloride salt, which is used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[PH2:25]([O-:27])=[O:26].[Na+]>O>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[PH:25](=[O:26])[OH:27])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[PH](=O)O

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (1.8 g, 4.97 mmol), sodium hypophosphite (0.88 g, 9.94 mmol) and cupric sulfate (180 mg) in 20 ml of methyl nitrile/water (4:1) is heated under reflux for 24 hours. The reaction is poured into water, extracted with methylene chloride, dired and chromatographed (silica gel, eluting with 10% methanol/chloroform) to yield 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.[CH2:33](N)[CH2:34][CH3:35].C(OCC)(=O)C>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:33][CH2:34][CH3:35])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: CCCN
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCNC1
Yield: 65 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and propylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-50% ethyl acetate in DCM) afforded the title compound as glass (100 mg, 65%); LCMS (method B): RT=3.89 min, M+H+=488.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][S:7](=[O:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27](I)[S:28][C:21]=12)[NH2:15]>>[NH2:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]4[CH2:9][CH2:8][S:7](=[O:10])[CH2:6][CH2:5]4)[S:28][C:21]=23)=[C:12]([F:11])[CH:13]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCS(=O)CC1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCS(=O)CC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 83.3 %

Procedure:
Prepared from N-propargyl S-oxo-4-thiapiperidine (30.5 mg, 0.194 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (45 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6 Hz, 1H), 7.61 (s, 1H), 7.03 (m, 1H), 6.53 (m, 2H), 6.47 (m, 1H), 3.89 (br s, 2H), 3.64 (s, 2H), 3.25 (m, 2H), 2.92 (m, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)=[C:19]([Cl:33])[CH:18]=1)(=[O:3])[NH2:2].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.O.C(O)C>CN(C)C=O>[Cl:33][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:37][CH:34]1[CH2:36][CH2:35]1)=[O:25])[O:16][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: NC1CC1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)c2cc1C(N)=O
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), followed by stirring. Precipitated crude crystals were collected by filtration, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was collected by filtration and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g, 80.2%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[NH:17][C:16]5[N:24]=[CH:25][CH:26]=[CH:27][C:15]=5[N:14]4[C:28]=3[C:29]3[CH:34]=[CH:33][C:32]([C:35]4([NH:39]C(=O)OC(C)(C)C)[CH2:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[ClH:47].O1CCOCC1>CO>[ClH:47].[ClH:47].[ClH:47].[ClH:47].[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:12]=[C:13]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[NH:17][C:16]5[N:24]=[CH:25][CH:26]=[CH:27][C:15]=5[N:14]4[C:28]=3[C:29]3[CH:30]=[CH:31][C:32]([C:35]4([NH2:39])[CH2:38][CH2:37][CH2:36]4)=[CH:33][CH:34]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc5cnccc5c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccc5cnccc5c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 90 %

Procedure:
tert-Butyl {1-[4-(2-isoquinolin-6-yl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (40 mg, 0.066 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 19 hours. The mixture was concentrated to afford the desired product (40 mg, 90%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.76 (br s, 2H), 8.69 (s, 1H), 8.60 (d, J=6.3 Hz, 1H), 8.36 (s, 1H), 8.33-8.28 (m, 2H), 8.14 (dd, J=4.6 Hz and 1.7 Hz, 1H), 8.04 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.92 (d, J=7.4 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.45-7.40 (m, 2H), 7.33 (d, J=8.6 Hz, 1H), 7.18 (td, J=7.4 Hz and 1.1 Hz, 1H), 6.98 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.77 (dd, J=8.0 Hz and 4.6 Hz, 1H), 2.65-2.58 (m, 3H), 2.26-2.19 (m, 2H), 1.90-1.81 (m, 2H). LCMS: 507 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34](OC(C)(C)C)=[O:35])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:62]([N:69]1[CH:72](C(O)=O)[CH2:71][CH2:70]1)([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([CH:71]2[CH2:70][N:69]([C:62]([O:64][C:65]([CH3:66])([CH3:67])[CH3:68])=[O:63])[CH2:72]2)=[O:35])[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)C1
Yield: 71.3 %

Procedure:
The title compound was prepared according to the procedure described in Example 11 (Step c) using N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl](tert-butoxy)carboxamide (Example 11 Step b) (450 mg, 0.76 mmol) and 50% TFA in CH2Cl2 (6 mL) followed by EDC (Aldrich) (259 mg, 1.35 mmol), HOBT (Aldrich) (270 mg, 2.0 mmol) and N-Boc-azetidine-4-carboxylic acid (PepTech Corporation) (220 mg, 1.1 mmol) in THF (20 mL). Purification by silica gel chromatography (10:25:65 MeOH:EtOAc:hexane) provided the title compound as a white foam (365 mg). MS (ESI, pos. ion) m/z: 673 (M+1); (ESI, neg. ion) m/z: 671 (M−1). Calc'd for C34H45ClN4O6S: 673.26.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@@H:14]2[C:18]([OH:20])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[S:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>C(Cl)Cl>[CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@@H:14]2[C:18]([N:35]2[CH2:36][CH2:37][S:33][CH2:34]2)=[O:20])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1CSCN1
Reactant: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
0.60 g .COPYRGT.f 3-(2-indanylacetyl)-L-thioproline was suspended in 5 ml of methylene chloride. To the suspension was added 0.46 g of WSC HCl with stirring at room temperature. After 5 minutes, 0.18 g of thiazolidine dissolved in 5 ml of methylene chloride was added to the mixture, and the mixture was stirred for 17 hours at room temperature. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to produce 0.40 g of 3-[3-(2-indanylacetyl)-L-thioprolyl]thiazolidine as a colorless oil (yield: 55%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.[N:19]1([S:24](N2C=C[N+](C)=C2)(=[O:26])=[O:25])[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][N:7]([CH3:8])[S:24]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)(=[O:26])=[O:25])=[CH:4][CH:3]=1
Reactant: CNCc1ccc(F)cc1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: CN(Cc1ccc(F)cc1)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 39.8 %

Procedure:
A solution of 4-fluoro-N-methylbenzylamine (420 μL, 3.19 mmol) in acetonitrile (10 mL) was treated with 3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (1.50 g, 4.14 mmol) and stirred at ambient temperature for 5 days. The mixture was concentrated under vacuum and purified by silica gel chromatography to afford the title compound (342 mg, 40%) as a pale yellow/orange oil. 1H NMR (400 MHz, DMSO) δ 7.98 (br s, 1H), 7.25 (m, 4H), 7.08 (m, 2H), 4.26 (s, 2H), 2.75 (s, 3H). LCMS (m/z, Method A) ES+ 270.0 [M+1]+.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[NH:7][NH2:8].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:11]([O:10][C:6]([NH:7][NH:8][CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NNC1CCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24.9 %

Procedure:
Cyclobutanone (8.19 g, 116.85 mmol) was dissolved in ethanol (60 mL). tert-Butyl carbazate (15.64 g, 118.34 mmol) was added. The reaction was stirred at 25° C. for 2.5 h before it was concentrated in vacuo. The residue was re-dissolved in ethanol (60 mL). Acetic acid (14.09 mL, 246.14 mmol) and sodium cyanoborohydride (15.46 g, 246.02 mmol) were added. The reaction was stirred at 25° C. for 48 h. The reaction was quenched via slow addition of saturated aqueous sodium bicarbonate solution (until pH 8 was reached). The resulting mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes) afforded the desired product, N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (5.42 g, 29.10 mmol, 25%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.62-1.70 (1H, m), 1.73-1.82 (1H, m), 1.84-1.94 (2H, m), 2.07-2.15 (2H, m), 3.56-3.63 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C@H:13]2[C@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14]2)=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C@@H:19]2[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14][C@H:13]2[CH2:12][NH:11][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:37][N:36]=[N:35][N:2]=3)[CH:4]=2)=[O:10])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cccc(C#N)c2)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cccc(-c3nnn[nH]3)c2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[(3-cyanophenyl)carbonyl]amino}methyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in DMF (4 mL) were added sodium azide (38.7 mg) and ammonium chloride (37.1 mg) at room temperature, and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (32 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(OCC)(=O)C.CCCCCCC>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: O=C(CCl)CCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Temperature: 25 °C

Procedure:
At 120° C., 31 g (123 mmol) of p-fluorobenzamide and 33 g (123 mmol) of 1,3-dichloroacetone were stirred in the absence of a solvent for 2 hours. After cooling to room temperature, the product was dissolved in 250 ml of ethyl acetate. This solution was diluted with 400 ml of n-heptane and washed 3 times with saturated NaCl solution. The organic phase was filtered through 250 ml of silica gel, and the filter pad was then washed with 200 ml of n-heptane/ethyl acetate (4:1). The solvent was distilled off, giving 4-chloromethyl-2-(4-fluorophenyl)oxazole 1 as crude product. This was dissolved in 650 ml of acetone, and 90 g of NaI were then added. The mixture was then heated at reflux for 16 hours, most of the solvent was then removed and the solid residue was suspended in 200 ml of n-heptane/ethyl acetate (1:1) and filtered through 200 ml of silica gel. The precipitate was washed with 500 ml of n-heptane/ethyl acetate (1:1), and the organic phase was concentrated. On concentration, the iodide 2 began to crystallize as white crystals. TLC n-heptane/ethyl acetate (6:1) Rf=0.4 for 2 and Rf=0.35 for 1. C10H7FINO (303.08) MS(ESI): 304 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]3[C:21]=2[C:16](=[C:17]2[CH:33]=[CH:32][CH:31]=[CH:30][C:18]2=[CH:19]3)[C:15]1=[O:34])[CH3:11])(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][CH2:9][N:10]([CH3:11])[CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]3[C:21]=2[C:16](=[C:17]2[CH:33]=[CH:32][CH:31]=[CH:30][C:18]2=[CH:19]3)[C:15]1=[O:34]
Reactant: COc1ccc2c3c(c4ccccc4cc13)C(=O)N(CCN(C)CCNC(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c3c(c4ccccc4cc13)C(=O)N(CCN(C)CCN)C2=O

Procedure:
Method (i)—Removing Boc protection by Preparing Hydrochloride Salt: The hydrochloric salt of 2-{2-[(2-aminoethyl)methylamino]ethyl}-6-methoxy-1,2-dihydro-3H-dibenzo[de,h]isoquinoline-1,3-dione was prepared by stirring (2-{[2-(6-Methoxy-1,3-dioxo-1H,3H-dibenzo[de,h]isoquinolin-2-yl)-ethyl]-methyl-amino}-ethyl)-carbamic acid tert-butyl ester with 4M HCl in dry dioxane for 40 minutes. The reaction was quantitative.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH:33]=O>>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:33][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 416.22 g/mol.