Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[C:11]([O:2][N:1]=[C:3]1[CH2:8][S:7][CH2:6][CH2:5][S:4]1)=[O:12]
Reactant: ON=C1CSCCS1
Reactant: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)ON=C1CSCCS1

Procedure:
2-[[O-[N-Methyl-N-(4-tert.butylphenylthiosulfenyl)carbamoyl]oximino]]-1,4-dithiane was prepared according to the procedure described in Example I, by reacting 1.09 g (0.0073 m) of 2-oximino-1,4-dithiane, 2.0 g (0.0073 m) of N-methyl-N-(4-tert.butylphenylthiosulfenyl)carbamoyl fluoride and 0.736 g (0.0073 m) of triethylamine in 25 ml of dioxane. Weight of the residual oil 1.95 g IR (Neat) 5.75μ (C=O). NMR (CDCl3) 1.28δ(s), 9H, t-butyl; 3.10δ(s), 4H, (CH2), 3.20δ(s), 3H, CH3N; 3.52δ(s) 2H, CH2 ; 7.37δ(d), JAB =8.5 Hz 2H and 7.54δ(d) JBA =85 Hz, 2H. Aromatic.
Reaction SMILES: CCC(CCCCC(N[C@H](C([NH:18][C@H:19]([C:23]([NH:25][C@H:26]([C:30]([NH:32][C@@H:33]1[C:61](=[O:62])[NH:60][C@H:59]([CH2:63][CH2:64][NH2:65])[C:57](=[O:58])[NH:56][C@H:55]([CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[C:53](=[O:54])[NH:52][C@@H:51]([CH2:73][CH:74]([CH3:76])[CH3:75])[C:49](=[O:50])[NH:48][C@@H:47]([CH2:77][CH2:78][NH2:79])[C:45](=[O:46])[NH:44][C@@H:43]([CH2:80][CH2:81][NH2:82])[C:41](=[O:42])[NH:40][C@@H:39]([C@H:83]([OH:85])[CH3:84])[C:37](=[O:38])[NH:36][CH2:35][CH2:34]1)=[O:31])[CH2:27][CH2:28][NH2:29])=[O:24])[C@H:20]([OH:22])[CH3:21])=O)CCN)=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[K+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.N[C@H](C(O)=O)CS>CO>[CH3:84][C@@H:83]([OH:85])[C@@H:39]1[NH:40][C:41](=[O:42])[C@H:43]([CH2:80][CH2:81][NH2:82])[NH:44][C:45](=[O:46])[C@H:47]([CH2:77][CH2:78][NH2:79])[NH:48][C:49](=[O:50])[C@H:51]([CH2:73][CH:74]([CH3:75])[CH3:76])[NH:52][C:53](=[O:54])[C@H:55]([CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[NH:56][C:57](=[O:58])[C@H:59]([CH2:63][CH2:64][NH2:65])[NH:60][C:61](=[O:62])[C@@H:33]([NH:32][C:30]([C@@H:26]([NH:25][C:23]([C@@H:19]([NH2:18])[C@H:20]([OH:22])[CH3:21])=[O:24])[CH2:27][CH2:28][NH2:29])=[O:31])[CH2:34][CH2:35][NH:36][C:37]1=[O:38]
Reactant: CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H](C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O
Agent: N[C@@H](CS)C(=O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: CC(C)C[C@@H]1NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@@H](N)[C@@H](C)O)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Reaction time: 18 h

Procedure:
A mixture of Polymyxin B (20 g), immobilised papain (185 ELU/g), potassium phosphate buffer (25 mM; pH 7, 1.25 L), potassium chloride (30 mM), EDTA (10 mM) and cysteine (1 mM) was incubated at 37° C. for 18 h with gentle agitation. The progress of the reaction was monitored by LC-MS using the conditions outlined in Table 1. The immobilized papain was removed by filtration and the filtrate was concentrated in vacuo to leave a solid residue which was re-suspended in 10% aqueous methanol and left at room temperature overnight. The supernatant was decanted and concentrated in vacuo. Polymyxin B nonapeptide was purified from the residue by SPE on C18 silica, eluting with 0-10% aqueous methanol. Evaporation of the appropriate fractions gave the product as a white solid. m/z 482, [M+2H]2+
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]([CH3:20])[CH:13]=[C:12]2[C:21]1[N:29]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH:22]=1)C1C=CC=CC=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]([CH3:20])[CH:13]=[C:12]2[C:21]1[N:29]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH:22]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2c(cc1O)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 40 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
A solution of 2-(5-benzyloxy-6-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [6.26 g, Reference Example 13(e)] in acetonitrile (500 mL) was treated with sodium iodide (4.38 g) followed by trimethylsilyl chloride (3.17 mL). The mixture stirred at 40° C. for 3 hours then treated with further portions of sodium iodide (4.38 g) and trimethylsilyl chloride (3.17 mL). After stirring at 40° C. for a further 12 hours the reaction mixture was evaporated. The residue was treated with water (200 mL) and the mixture was extracted three times with ethyl acetate (200 mL). The combined extracts were dried over magnesium sulfate then evaporated. The residual brown foam was triturated with ethyl acetate and diisopropyl ether to give the title compound (3.04 g) as a light brown solid, m.p. 211-214° C. HPLC (METHOD A): RT=9.30 minutes.
Reaction SMILES: Cl.CO[C:4]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([O:12]C)=[CH:6][C:5]=1[CH2:14][CH2:15][NH2:16].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(#N)C.C(OCC)(=O)C>[CH3:11][C:8]1[C:9]([CH3:10])=[C:4]2[C:5]([CH2:14][CH2:15][NH:16]2)=[CH:6][C:7]=1[OH:12]
Reactant: COc1cc(CCN)c(OC)c(C)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(O)cc2c(c1C)NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a suspension of 2,5-dimethoxy-3,4-dimethylbenzeneethaneamine hydrochloride (12.3 g, 0.05 mol) in water (50 mL) was added dropwise a solution of diammonium cerium (IV) nitrate (60.3 g, 0.11 mol) in acetonitrile (100 mL) and water (100 mL) under ice-cooling over 30 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added dropwise to a suspension of a sodium bicarbonate (65.6 g, 0.78 mol) in water (250 mL)-ethyl acetate (250 mL), and the mixture was stirred at room temperature for 10 minutes. This mixture was filtered, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate two times. The combined organic layers were washed with water, mixed with a 80% sodium hydrosulfite (21.8 g, 0.10 mol) solution in water (200 mL), shaken, and the aqueous layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol-diisopropyl ether to obtain 5.79 g of the title compound.
Reaction SMILES: [Br-:1].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1Cl)([OH:30])[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11].[OH:38][C:39](C1C=CC=CC=1OC)(C1C=CC=CC=1)C(O)=O>>[Br-:1].[OH:30][C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:38][CH3:39])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11]
Reactant: COc1ccccc1C(O)(C(=O)O)c1ccccc1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl)C2)Nc1ccon1
Agent: [Br-]
Product: COc1ccccc1C(O)(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)c1ccccc1

Procedure:
This compound is prepared analogously to (R)-3-[2,2-bis-(2-chloro-phenyl)-2-hydroxy-acetoxy]-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide [Example 1] by substituting bis-(2-chloro-phenyl)-hydroxy-acetic acid with Hydroxy-(2-methoxy-phenyl)-phenyl-acetic acid (Intermediate N).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:20][CH:21]=3)[C:8]=2[CH:9]=1)=O.[Br:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1.ClCCl.C([O-])(O)=O.[Na+]>CC(O)C>[Br:28][C:29]1[S:33][C:32]2=[N:34][C:3]([C:5]3[O:6][C:7]4[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]5[N:18]=[C:19]([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[S:20][CH:21]=5)[C:8]=4[CH:9]=3)=[CH:2][N:31]2[N:30]=1
Reactant: Nc1nnc(Br)s1
Reactant: O=C(CBr)c1cc2c(OCc3csc(-c4ccccc4)n3)cc(F)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: Fc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Temperature: 150 °C
Yield: 43.8 %

Procedure:
In a 2-5 mL microwave pressure vial was added 2-bromo-1-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone (Example 36E, 35 mgs, 0.078 mmol) in propan-2-ol (2 mL) followed by 5-bromo-1,3,4-thiadiazol-2-amine (16.2 mgs, 0.09 mmol). The reaction was heated to 80° C. overnight and to 150° C. for 1 h in microwave oven. The reaction mixture was then poured into a mixture of dichloromethane (8 mL) and saturated NaHCO3 (2 mL) and this was extracted twice with dichloromethane. The organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (ISCO 12 g gold column using 100% dichloromethane, then 1% ethyl acetate and then 2% ethyl acetate in dichloromethane) to give the title material (18 mgs, 43%) as a yellowish solid. LC (Method B): 2.754 min. LCMS (APCI) calcd for C22H13BrFN4O2S2 [M+H]+ m/z 526.96. found 527.0.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[SH:16])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[K].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][S:16][C:12]1[N:13]=[N:14][S:15][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:10][CH:9]=1)[CH3:24]
Reactant: CC(C)(C)c1ccc(-c2snnc2S)cc1
Reactant: CCOC(=O)CBr
Agent: [K]
Solvent: CCO
Product: CCOC(=O)CSc1nnsc1-c1ccc(C(C)(C)C)cc1
Yield: 83.2 %

Procedure:
A solution of 2.9 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassium salt in 50 ml of ethanol was stirred overnight with 1.67 g of ethyl bromoacetate, then concentrated in vacuo. The residue was taken up in ether, filtered and evaporated in vacuo. The oily residue was dissolved in dichloromethane and purified as described in Example 50, giving an oil which was crystallized from methylcyclohexane, giving 2.8 g of the desired compound as white needles, mp 62.5°-63.5° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 1.21 (t, 3H, J=7.0 Hz, CH3); 1.37 (s, 9H, t-butyl); 4.11 (s, 2H, SCH2); 4.15 (q, 2H, CH2O); 7.55 (s, 4H, C6H4). Infrared absorption spectrum (KBr pellet): 1739(s); 1606(w); 1520(w); 1480(w); 1445(w); 1385(w); 1365(w); 1305(s); 1175(s); 1040(w); 935(s); 840(s).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:38])([F:37])[C:12]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:13][NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:34]([N:33]([CH2:32][C:12]([OH:31])([CH2:13][NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([F:38])([F:37])[F:10])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:35][CH3:36]
Reactant: O=C(O)c1ccccc1
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 11 from benzoic acid and 1,1,1-trifluoro-3-[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-].[K+]>C(O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:14]1[O:16][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCC1CO1
Reactant: CC(C)(C)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccccc1OCC1CO1

Procedure:
To a solution of 40 parts of o-t-butylphenol, 75 parts of epichlorhydrin, and 40 parts of ethanol boiling under reflux with stirring was added dropwise over 10 minutes a solution of 17.6 parts of potassium hydroxide dissolved in 66 parts of ethanol and the minimum amount of water. The mixture was stirred and refluxed for 105 minutes, cooled, diluted with water, and well extracted with ether, which was then washed with water, dried over magnesium sulphate, and evaporated to an oil. Distillation at 144° /8 mm afforded 43 parts of 3-(2-t-butylphenoxy)-1,2-epoxypropane as a clear oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH:32]1([N:35]2[CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:37]=[N:36]2)[CH2:34][CH2:33]1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH:32]4[CH2:34][CH2:33]4)[CH:39]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Product: Cn1ncc(NC(=O)c2csc(-c3cnn(C4CC4)c3)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave 235. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 4.92-4.83 (m, 1H), 4.59-4.40 (m, 1H), 4.32 (dd, J=22.2, 15.0 Hz, 1H), 4.19-3.93 (m, 1H), 3.80 (dd, J=7.4, 3.7 Hz, 1H), 3.77 (s, 3H), 3.38-3.31 (m, 1H), 2.12-2.03 (m, 1H), 1.87-1.66 (m, 5H), 1.17-0.96 (m, 4H). LCMS (ES+) m/z 446 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:24]O)[CH:12]([CH2:13][OH:14])[C:11](=[O:15])[N:10]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:24][O:14][CH2:13][CH:12]1[C:11](=[O:15])[N:10]([C@@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:9]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)C(CO)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)COCC2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
To a cooled (0° C.) solution of (3S)-3,4-bis(hydroxymethyl)-5-oxo-1-[(R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (710 mg, 2.03 mmol) and triphenylphosphine (450 mg, 2.64 mmol) in tetrahydrofuran (10 mL) was added a solution of 40% diethyl azodicarboxylate in toluene (1.06 mL, 2.33 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 6 h. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40% AcOEt in hexane to afford the title compound (435 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25]>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([Cl:18])[C:3]=1[CH2:4][C:5]([CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])([C:6]#[N:7])[C:8]#[N:9]
Reactant: N#CC(C#N)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 52.7 %

Procedure:
Using 0.30 g of (2,6-dichloro-4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.20 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.21 g of 2-(2,6-dichloro-4-(trifluoromethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (7)).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=2)[C:6]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:5]=2[N:4]([CH3:22])[C:3]1=[O:23].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]=1[CH3:39])=[C:25]=[S:26]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:5]2[N:4]([CH3:22])[C:3](=[O:23])[CH:2]([NH:1][C:25]([NH:24][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:29][C:28]=3[CH3:39])=[S:26])[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[N:10]=3)[C:6]=2[CH:17]=1
Reactant: COc1cccc(C2=NC(N)C(=O)N(C)c3ccc(Cl)cc32)n1
Reactant: Cc1cc(N2CCOCC2)ccc1N=C=S
Product: COc1cccc(C2=NC(NC(=S)Nc3ccc(N4CCOCC4)cc3C)C(=O)N(C)c3ccc(Cl)cc32)n1
Temperature: 70 °C
Yield: 89.5 %

Procedure:
As illustrated in the scheme above, a solution of 3-amino-7-chloro-1,3-dihydro-5-(6-methoxy-2-pyridinyl)-1-methyl-2H-1,4-benzodiazepin-2-one (0.0113 g, 0.0342 mmol) and 4-(4-isothiocyanato-3-methylphenyl)morpholine (0.0080 g, 0.034 mmol) in (CH2Cl)2 (0.9 mL) was heated at 70° C. for 20 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (2:1 CH2Cl2:EtOAc) to provide the title compound (0.0172 g, 89%) as a slightly yellow solid. 1H-NMR (CDCl3): δ 7.79 (dd, J=0.8 Hz, J=7.2 Hz, 1H), 7.70-7.65 (m, 2H), 7.54 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.42 (br s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.28-7.25 (m partially hidden under CHCl3, 2H), 6.85-6.80 (m, 3H), 6.14 (m, 1H), 3.88-3.85 (m, 4H), 3.78 (s, 3H), 3.40 (s, 3H), 3.22-3.18 (m, 4H), 2.36 (s, 3H). MS (M+H+=565.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:34]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:30][C:29]1[CH:28]=[CH:27][C:26]([NH:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:34]=2)=[CH:25][C:24]=1[NH:23][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-morpholinobenzamide to give N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamide in 58% yield; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 2.1 (m, 2H), 2.18 (s, 3H), 3.18 (t, 4H), 3.35 (m, 1H), 3.41 (m, 2H), 3.75 (t, 4H), 5.1 (m, 1H), 7.12 (td, 1H), 7.21 (d, 1H), 7.37 (m, 3H), 7.41 (t, 2H), 7.5 (s, 1H), 7.57 (d, 1H), 7.78 (d, 1H), 9.83 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H+ 601.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=O)[CH2:22][CH2:21]4)[N:17]=2)=[CH:9][CH:8]=1.[NH2:35][OH:36]>C(O)C>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[N:35][OH:36])[CH2:22][CH2:21]4)[N:17]=2)=[CH:9][CH:8]=1
Reactant: CN(C)CCCOc1ccc(-c2nc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)[nH]2)cc1
Reactant: NO
Solvent: CCO
Product: CN(C)CCCOc1ccc(-c2nc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of the product of Example 14, Step 6 (0.07 g, 0.155 mmol) in ethanol (3 ml) at 80° C. was added aqueous hydroxylamine (1.5 ml, 50% in water). After 30 minutes the mixture was cooled to room temperature and concentrated in vacuo to give the title compound, (0.072 g, 100%) as a yellow solid; MS(AP+) m/e 468 [M+H]+.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[CH2:8]=[C:9]1[O:12][C:11](=[O:13])[CH2:10]1.Cl>C1COCC1>[NH2:4][C:3]1[O:12][C:9]([CH3:8])=[CH:10][C:11](=[O:13])[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: C=C1CC(=O)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(=O)c(C#N)c(N)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Malononitrile (110 g, 1.67 mol) was dissolved in dry THF (1000 ml) and cooled in ice-water bath. NaH (60% in mineral oil, 67 g, 1.67 mol) was added portionwise below 10° C. very carefully while the reaction flash was evacuated with N2 flow. After addition completed, the mixture was stirred at 0° C. for 30 min. Then 4-methyleneoxetan-2-one (140 g, 1.67 mol) was added dropwise below 0° C. After addition completed, the mixture was stirred at −10° C. for 1H. The reaction mixture was neutralized by 4 N HCl and concentrated under vacuum to give compound 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile as an orange oil. The crude product was used to next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1.CO.[CH2:39](NCC)C>C(=O)=O>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH3:39])=[O:32])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CCNCC
Agent: O=C=O
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)nc1

Procedure:
(+/−)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)butylamino)nicotinamido)propanoate (prepared as described in Example 1.29) was resolved via SFC (Column: Chiralcel OJ-H 250×4.6 mm×5 μm, Mobile phase: 5 to 40% methanol in CO2, modifier: 0.05% diethylamine, flow rate: 2.5 mL/min) to give methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)butylamino)nicotinamido)propanoate, Isomer 1 (retention time: 7.36 min) and methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)butylamino)nicotinamido)propanoate, Isomer 2 (retention time: 8.85 min).