Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>C(Cl)Cl>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (50 mg, 0.11 mmol) were added methanesulfonyl chloride (18 μL, 0.23 mmol) and DIPEA (59 μL, 0.34 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature for 15 min and diluted with CH2Cl2. The organic phase was then washed with 1M Na2CO3 and water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 28 mg (47%) of the title compound, m/z 517.7 [M−1]+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH:13]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:12]3[CH2:16][CH2:15][CH2:14][CH:13]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=CC1=CCCC1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/C1=CCCC1
Yield: 30.7 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2.51 g, 15 mmol) (Alfa) was reacted with cyclopent-1-enecarbaldehyde (1.45 g, 15 mmol) (Aldrich) and piperidine (1.49 mL, 15 mmol) in methanol to give E/Z-6-chloro-3-cyclopent-1-enylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.13 g, 30%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]1(N=C=NC2CCCCC2)CCCCC1.CO>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromophenylacetic acid (1.0 g, 4.65 mmol), 1,3-dicyclohexylcarbodiimide (1.44 g, 6.98 mmol) and MeOH (149 mg, 4.65 mmol) in dichloromethane (40 ml) was added 4-dimethylaminopyridine (57 mg, 0.465 mmol). The reaction mixture was stirred at RT for 1 hr. The white solid was precipitated out which was removed with filtration. The reaction solution was concentrated to give a crude product which was purified on silica gel column with dichloromethane. The product was collected which contain a little amount of DCU (1.36 g). NMR (CDCl3): □ 7.20-7.46 (4H, m), 3.72 (3H, s), 3.621(2H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)[C@H](C)Nc1ccc(F)c(F)c1

Procedure:
Following General Procedure AA above and using 3,4-difluoroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:21])=[CH:8][C:9]=1[CH2:10][CH2:11]2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:8][C:9]=1[CH2:10][CH2:11]2
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: c1ccncc1
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(OS(C)(=O)=O)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28.84 g of 11β-fluoro-1,3,5(10)-estratrien-3-ol-17-one (100 mmol) is dissolved in 200 ml of pyridine, cooled in an ice bath, 20 ml of methanesulfonic acid chloride is added in drops, and it is stirred for 2 hours at room temperature. Then, it is stirred into 2.5 liters of ice water, and after two hours of stirring, it is filtered off. The solid residue is dissolved in dichloromethane, the solution is shaken out with 1N hydrochloric acid, water and saturated common salt solution and dried with Na2SO4. After the solvent is drawn off, the residue is 37 g, and after crystallization from methanol, 33.6 g of 11β-fluoro-3-mesyloxy-estra-1,3,5(10)-trien-17-one (91% of theory), flash point, is obtained.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C:14]#[N:15])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24]Br>CS(C)=O>[CH2:1]([O:3][P:4]([C:13]1([C:14]#[N:15])[CH2:24][CH2:23]1)([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCCBr
Reactant: CCOP(=O)(CC#N)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOP(=O)(c1ccc(F)cc1)C1(C#N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.470 g of ethyl(cyanomethyl)(4-fluorophenyl)phosphinate was initially charged in 20 ml of DMSO, and 0.572 g (4.138 mmol) of potassium carbonate and then 0.388 g of 1,2-dibromoethane were added. The mixture was stirred at room temperature for 4 h and then at 50° C. for 2 h. The reaction mixture was concentrated, taken up in dichloromethane and washed with H2O.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CN1CCNCC1
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N3CCN(C)CC3)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 60.4 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (17 mg, 0.034 mmol) in DCM (2 mL) was added 1-methylpiperazine (0.011 mL, 0.10 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (11 mg, 60%). LC-MS m/z 536 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.66 (m, 2 H), 2.28 (s, 3H), 2.31 (s, 3H), 2.42 (m, 4H), 3.37 (m, 2H), 3.57 (m, 4H), 4.13 (m, 2H), 7.16 (m, 2H), 7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9].CCN(CC)CC.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:8][C:7]1[C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)=[C:3]([NH2:9])[CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1cccc(N)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cccc(N)c1B1OC(C)(C)C(C)(C)O1
Yield: 40 %

Procedure:
The procedure described in Example 3: step b was followed using 2-bromo-3-methyl-phenylamine (185 mg, 1.0 mmol, Example 25: step a), PdCl2(PPh3)2 (70.2 mg, 0.1 mmol), dioxane (3 mL), and Et3N (729 μL, 6 mmol), 4,4,5,5,-tetramethyl-[1,3,2]-dioxaborolane (453 μL, 3 mmol). Purification by preparative SiO2 TLC (25% EtOAc in hexanes) of the residue yielded the title compound (94 mg, 40%) as a yellow solid. ESI-MS (m/z): Calcd. for C13H20BNO2: 234.1 (M+H) found: 234.1.
Reaction SMILES: [Li+].[OH-:2].[CH2:3]([N:9]([CH3:20])[C:10]([CH:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[C:14](=[O:19])[O:15]2)=[O:11])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].Cl>>[CH2:3]([N:9]([CH3:20])[C:10]([CH:12]1[CH2:17][CH:16]([OH:15])[CH2:18][CH:13]1[C:14]([OH:2])=[O:19])=[O:11])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCN(C)C(=O)C1CC2CC1C(=O)O2
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)O
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of LiOH (105 mg in 4 mL, of water) was added at 0° C. to the lactone amide (65). After 1 h, the conversion was completed (HPLC). The mixture was acidified to pH 2-3 with 1N HCl, extracted with EtOAc, dried (MgSO4), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give the title compound (520 mg, 88%), m/z=270 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](O)=[O:27])[C:20]=2[O:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:26]([C:25]2[C:20]3[O:19][CH2:18][CH2:17][O:16][C:21]=3[CH:22]=[CH:23][CH:24]=2)=[O:27])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3c2OCCO3)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid. LC-MS (acidic): tR=0.97 min; [M+H]+=375.1. 1H-NMR (CDCl3): δ=0.61 (bs, 1H); 0.76-0.82 (m, 1H); 1.47-1.52 (m, 1H); 1.51 (s, 9H); 1.89 (bd, J=13.2 Hz, 1H); 2.42-2.47 (m, 1H); 3.34-3.74 (m, 3H); 4.30-4.35 (m, 1H); 4.32 (bs, 2H); 4.44 (bs, 2H); 6.91-7.05 (m, 2H); 7.67-7.73 (m, 1H); 8.43 (bs, NH).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Into a 250-mL round-bottom flask, was placed 1-(bromomethyl)-4-nitrobenzene (15 g, 69.77 mmol, 1.00 equiv), triethyl phosphite (70 mL). The resulting solution was stirred for 2 h at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:1). This resulted in 17 g (89%) of the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[C:15]1([CH2:14][N:1]2[C:5](=[O:6])[CH2:4][CH2:3][C:2]2=[O:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1Cc1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To 2,5-pyrrolidinedione (2.5 g, 25.2 mmol) in DMF (50 mL) was added K2CO3 (4.18 g, 30.3 mmol) followed by benzyl bromide (3.00 mL, 25.2 mmol), and the reaction mixture was stirred overnight at 55° C. Water was added to the reaction mixture (˜200 mL) and a precipitate was immediately observed. The precipitate was filtered, and the white solid was washed with water and dried to afford the title compound (2.7 g, 57%). 1H NMR (400 MHz, CDCl3): δ 2.73 (s, 4H), 4.68 (s, 2H), 7.28-7.37 (m, 3H), 7.39-7.44 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CS(O)(=O)=O.C1C(=O)N([Br:42])C(=O)C1>C(#N)C>[Br:42][CH2:21][C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)=[O:22]
Reactant: CC(=O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(CBr)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a warm (90° C.) and stirred solution of ketone 57 (5 g, 0.016 mol) in a mixture of 4:1 toluene and acetonitrile (125 ml) was added methane sulfonic acid (2.64 ml, 0.041 mole) and stirred for 1 hour. The reaction mixture was cooled to 68° C., NBS (3.19 g, 0.018 mol) was added at once and stirred the contents at 65° C. for 4 hour followed by stirring at RT for 18 hour. The solid from the reaction mixture was collected by filtration and dissolved in dichloromethane (100 ml). dichloromethane layer was washed with 10% aq. sodium carbonate and subjected to usual workup and concentration to obtain alpha bromo-ketone 58 (3.0 g, 48%) as an off-white solid.
Reaction SMILES: ClC1C=C(C[CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40]CC(O)=O)=[CH:35][CH:34]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][CH:28]1[CH2:29][CH2:30][CH:25]([N:11]([CH2:10][CH2:9][CH2:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccc(CCCC(=O)O)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: Cc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-methyl-phenyl)-butyric-acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[OH:26])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([O:26][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: OC(c1cccc(F)c1)c1cc(F)cc(F)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1cccc(F)c1)c1cc(F)cc(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3,5-difluoro-phenyl)-(3-fluoro-phenyl)-methanol. 1H NMR analysis (300 MHz, DMSO-d6)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9]([O:11]CC)=O)=O.[CH2:19]([NH:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[NH:27][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9](=[O:11])[CH2:8]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(Cc3ccccc3)N2)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.4 %

Procedure:
6.6 g of ethyl 3,4-dimethoxybenzoylacetate were suspended in ethanol, and 3.5 g of benzylhydrazine were added dropwise with ice cooling over the course of 1.5 hours. The reaction mixture was stirred at room temperature for 12 hours. Then the precipitated product was filtered out and washed first with ethanol and then with tert-butyl methyl ether. 4.36 g of 5-(3,4-dimethoxyphenyl)-2-benzylpyrazolin-3-one were obtained. Melting point: 164°-166° C.
Reaction SMILES: [C:1](OC(=O)NC(C1C=C(F)C=C(F)C=1)(C)C=O)(C)(C)C.[ClH:21].[NH2:22][C:23]1([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.NC1(C(O)=O)CCCCC1>>[ClH:21].[NH2:22][C:23]1([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:1]1
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1cc(F)cc(F)c1
Agent: Cl
Agent: NC1(C(=O)O)CCCCC1
Product: COC(=O)C1(N)CCCCC1

Procedure:
Essentially following the procedures described in Intermediate 1 for methyl 1-aminocyclopentanecarboxylate hydrochloride, but using 1-aminocyclohexanecarboxylic acid in place of 1-aminocyclopentanecarboxylic acid, the title compound was obtained. MS: m/z=158 (M+1).
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:14]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[NH:17][CH2:16][CH2:15]2>>[C:4]1([NH:1][C:2]([N:17]2[CH:18]3[CH2:21][CH2:22][N:14]([CH2:20][CH2:19]3)[CH2:15][CH2:16]2)=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1CN2CCC(CC2)N1
Reactant: O=C=Nc1cccc2ccccc12
Product: O=C(Nc1cccc2ccccc12)N1CCN2CCC1CC2
Yield: 48 %

Procedure:
Using general procedure A, 1-isocyanatonaphthalene (208 mg, 1.23 mmol) and 1,4-diazabicyclo[3.2.2]nonane gave the title compound as a white solid (150 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 7.80-7.72 (m, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.44-7.35 (m, 3H), 6.65 (br s, 1H), 4.18 (br s, 1H), 3.64 (t, J=8.0 Hz, 2H), 3.09-2.91 (m, 6H), 2.08-1.93 (m, 2H) 1.74-1.66 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 155.3, 134.4, 134.3, 128.9, 128.2, 126.2, 126.1, 126.0, 125.1, 121.2, 121.0, 57.6, 48.7, 46.4, 46.4, 42.2, 27.6, 27.6 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.53 min; (M+1) 296.
Reaction SMILES: NC1C([N+]([O-])=O)=C(N2CCN(CC(NC3SC=CN=3)=O)CC2)C(Br)=CN=1.Cl[C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=1[N+:36]([O-:38])=[O:37].CCN(C(C)C)C(C)C.[N:48]1[CH:53]=[CH:52][C:51]([CH:54]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH3:55])=[CH:50][CH:49]=1.Cl>CC(O)C>[Cl:34][C:33]1[C:28]([N:59]2[CH2:60][CH2:61][N:56]([CH:54]([C:51]3[CH:50]=[CH:49][N:48]=[CH:53][CH:52]=3)[CH3:55])[CH2:57][CH2:58]2)=[C:29]([N+:36]([O-:38])=[O:37])[C:30]([NH2:35])=[N:31][CH:32]=1
Reactant: CC(c1ccncc1)N1CCNCC1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(c1ccncc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Yield: 73 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 4,5-dichloro-3-nitropyridin-2-amine (22 mg, 0.106 mmol), iPrOH (1 mL), DIPEA (0.2 mL) and 1-(1-(pyridin-4-yl)ethyl)piperazine.3×HCl (1.1 eq, 0.116 mmol, 35 mg). Filtration and washing as previously described gave the product (28 mg, 73%) as a yellow solid; δH (500 MHz, DMSO-d6) 1.30 (d, J=6.7 Hz, 3H, CHCH3), 2.42 (s, br, 2H, piperazine NCH2), 2.53 (s, br, 2H, piperazine NCH2), 3.05 (s, br, 4H, piperazine N(CH2)2), 3.54 (q, J=6.8 Hz, 1H, CHCH3), 6.94 (s, br, 2H, NH2), 7.34 (d, J=6.0 Hz, 2H, pyridine H-2 & H-6), 8.04 (s, 1H, chloropyridine H-6), 8.51 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5);
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13](=[O:15])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:10]([CH3:11])[CH3:12]
Reactant: CNOC
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-Boc-L-valine (3.72 g, 17.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.84 g, 18.86 mmol) were dissolved in anhydrous methylene chloride (50 mL) under nitrogen. Triethylamine (2.09 g, 20.64 mmol) was added to the mixture, followed by dropwise addition of diethyl cyanophosphonate (3.09 g, 18.92 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction was then diluted with methylene chloride (150 mL) and washed with water (100 mL). The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed successively with aqueous sodium bicarbonate (2×100 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was carried forward without further purification. 1H NMR (CDCl3): 5.28 (d, 1H), 4.61 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 2.09-1.85 (m, 1H), 1.43 (s, 9H), 0.99 (d, 3H), 0.90 ppm (d, 3H).
Reaction SMILES: [F:1][C:2]1([F:15])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.Cl.Cl[CH:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]=1)[CH3:19].[OH-].[Na+].O>C(O)C>[F:15][C:2]1([F:1])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([S:12][CH:18]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][N:21]=4)[CH3:19])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Reactant: COc1ccnc(C(C)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccnc(C(C)Sc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c1
Yield: 68 %

Procedure:
4 g of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol, 3.6 g of (±)-2-(1-chloroethyl)-4-methoxy-pyridine hydrochloride, 1.4 g of sodium hydroxide, 3 ml of water and 50 ml of ethanol are stirred for 4 h at 65° C. The reaction mixture is concentrated to dryness, the residue is dissolved in 100 ml of 2N hydrochloric acid, impurities are extracted by shaking with ethyl acetate, and the aqueous phase is adjusted with sodium hydroxide solution to pH 10 and extracted with ethyl acetate. The organic phase is dried and concentrated. Recrystallisation from toluene gives 4.3 g (80.5%) of the title compound of m.p. 173°-175° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:32])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH:29]([OH:31])[CH3:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:32][C:17]1([CH3:16])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH:29]([O:31][C:11]([C:10]3[CH:14]=[CH:15][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:8][CH:9]=3)=[O:12])[CH3:30])[CH:20]=[CH:19][C:18]1=2
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: C=CCOC(=O)c1ccc(C(=O)OC(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2.1 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.3 g (10 mmol) of 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanol, 3.2 g (76%) of the expected allyl ester are obtained in the form of a colorless oil.