Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([C:23](=[O:25])[CH3:24])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][N:18]([CH3:1])[C:17]=2[CH:16]=[C:15]([C:23](=[O:25])[CH3:24])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
Potassium carbonate (2.43 g, 17.6 mmol) and methyl iodide (1.3 ml, 20.9 mmol) were added to a solution of the 1-[8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (3.73 g, 16.0 mmol) in dimethylformamide (35 ml) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue and the mixture was washed with water (twice) and brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel-C200,60 g) and then fractionated with 2% ethyl acetate-toluene to yield the title compound (2.61 g, 66.0% yield) as bright golden yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:17][C:13](=[O:16])/[CH:14]=[CH:15]/[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:6]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(O)c1cc(Br)cnc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c(C(C)(C)O)c1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-(2-Amino-5-bromo-pyridin-3-yl)-propan-2-ol (200 mg, 0.86 mmol), tert-butyl acrylate (628 μL, 4.3 mmol) and (i-Pr)2EtN (452 μL, 2.6 mmol) in DMF (10 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (19.4 mg, 0.09 mmol) and P(o-tol)3 (51.7 mg, 0.18 mmol) then heated to 110° C. for 20 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with H2O (100 mL) then extracted with ethyl acetate (2×100 mL). The combined organic fractions were dried over MgSO4, and subjected to flash chromatography on silica gel using 50% ethyl acetate:hexanes. The appropriate fractions were collected and concentrated to yield a yellow crystalline solid. Yield: 153 mg (64%); 1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J=2.1 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.45 (d, J=15.8 Hz, 1H), 6.69 (s, 2H), 6.32 (d, J=15.8 Hz, 1H), 5.53 (s, 1H), 1.52 (s, 6H), 1.48 (s, 9H); ESI MS m/z 279 [C15H22N2O3+H]+
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.CO.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>O1CCCC1>[C:18]([O:17][C:15](=[O:14])[NH:7][CH2:6][C:5]1[CH:8]=[C:9]([F:10])[C:2]([NH2:1])=[CH:3][C:4]=1[F:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: N#Cc1cc(F)c(N)cc1F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cc(F)c(N)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A dried 50 ml two-neck round bottom flask was filled with argon gas. The solution of 4-amino-2,5-difluorobenzonitrile (0.5 g, 3.24 mmol) in tetrahydrofuran was put into the flask and cooled to 0° C. To the solution was added Borane-THF complex (2 eq, 6.49 mmol, 6.49 ml) slowly. The temperature of the mixture was raised and heated to reflux for 18 hours. After confirming the completion of the reaction with TLC, to the solution was added methanol slowly (generation of bubbles) and stirred for 2 hours. The methanol was removed under reduced pressure and the residue was extracted with ethylacetate. The ethylacetate layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to yield yellow syrup. The above obtained liquid was dissolved in tetrahydrofuran and added BOC2O (1.0 eq, 0.71 g) slowly and stirred for 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction solution was extracted with ethylacetate, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=4/1) to yield a white solid (0.43 g, 51.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
95 g (0.30 M) of rac-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 1 liter of absolute acetone and treated with 60 g of powdered potassium carbonate and 43 g of dimethyl sulphate. The mixture is stirred at room temperature for 4 hours and left to stand in a refrigerator for 48 hours. The mixture is then concentrated, treated with ice-water and extracted several times with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is crystallised from ethyl acetate/petroleum ether, there being obtained rac-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 154°-156° C.
Reaction SMILES: [OH:1][CH:2]([C@@H:6]([NH:11][C:12]([C:14]1([NH:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10])[C:3](O)=[O:4].ClC1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37].C1(CN)CCCC1>>[CH:35]1([CH2:36][NH:37][C:3](=[O:4])[C:2](=[O:1])[C@@H:6]([NH:11][C:12]([C:14]2([NH:20][C:21]([N:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]3)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:34][CH2:40][CH2:39][CH2:38]1
Reactant: NCc1cccc(Cl)c1
Reactant: CCCC[C@H](NC(=O)C1(NC(=O)N2CCN(C(C)=O)CC2)CCCCC1)C(O)C(=O)O
Agent: NCC1CCCC1
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCN(C(C)=O)CC2)CCCCC1)C(=O)C(=O)NCC1CCCC1
Yield: 11 %

Procedure:
The same procedure as in Example 28 was repeated except that the (2RS,3S)-2-hydroxy-3-[1-[N-[N-(morpholine-4-carbonyl)amino]cyclohexanecarbonyl]amino]heptanoic acid was replaced by 881 mg of (2RS,3S)-2-hydroxy-3-[N-[1-[N-(4-acetylpiperazine-1-carbonyl)amino]cyclohexanecarbonyl]amino]heptanoic acid synthesized in Reference Example 28 and the 3-chlorobenzylamine was replaced by 496 mg of cyclopentylmethylamine, whereby 64 mg of the captioned N-[(S)-1-(N-cyclopentylmethylamino)-1,2-dioxo-3-heptyl]-1-[N-(4-acetylpiperazine-1-carbonyl) amino]cyclohexanecarboxamide was obtained in a yield of 11%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:16]=1
Reactant: Cc1cc(O)nc(/C=C/c2ccc(Cl)c(Cl)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2ccc(Cl)c(Cl)c2)n1
Yield: 57.6 %

Procedure:
In analogy to example 12c), by heating (E)-2-[2-(3,4-dichloro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (0.56 g, 2 mmol) in POCl3 (3.66 ml, 40 mmol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(3,4-dichloro-phenyl)-vinyl]-6-methyl-pyrimidine (0.345 g, 58%) as a pink solid. EI mass spectrum, m/e: 298 (M calculated for C13H9Cl3N2: 298).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:5]([CH3:16])[CH:4]=1.C(N(CC)CC)C.[CH:24]1([C:29](Cl)=[O:30])[CH2:28][CH:27]=[CH:26][CH2:25]1.O>ClCCl>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:29]([CH:24]3[CH2:28][CH:27]=[CH:26][CH2:25]3)=[O:30])[CH2:12][CH2:13]2)=[C:5]([CH3:16])[CH:4]=1
Reactant: O=C(Cl)C1CC=CC1
Reactant: Cc1cc(Cl)ccc1OC1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1OC1CCN(C(=O)C2CC=CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
4-(4-Chloro-2-methylphenoxy)piperidine hydrochloride (28.6 g) and triethylamine (45.5 mL) were stirred in dichloromethane (100 mL) and cyclopent-3-ene-1-carbonyl chloride (14.26 g) in dichloromethane (100 mL) was added dropwise. When addition was complete, the reaction mixture was stirred at room temperature for 2 h. Water (250 mL) was added to the reaction mixture and product was extracted with dichloromethane. The dichloromethane was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was filtered through a plug of silica eluting with diethyl ether to give the subtitle compound (29.5 g).
Reaction SMILES: C([O-])=O.[NH4+].[OH:5][C:6]1[CH:29]=[CH:28][C:9](/[CH:10]=[CH:11]\[C:12]([O:14][CH:15]2[CH2:20][CH2:19][C:18]([CH3:27])([C:21]([O:23]CC=C)=[O:22])[CH2:17][CH2:16]2)=[O:13])=[CH:8][C:7]=1[O:30][CH3:31].[Cl-].[Na+]>C1COCC1.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>[OH:5][C:6]1[CH:29]=[CH:28][C:9](/[CH:10]=[CH:11]\[C:12]([O:14][CH:15]2[CH2:20][CH2:19][C:18]([CH3:27])([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]2)=[O:13])=[CH:8][C:7]=1[O:30][CH3:31]
Reactant: C=CCOC(=O)C1(C)CCC(OC(=O)/C=C\c2ccc(O)c(OC)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc(/C=C\C(=O)OC2CCC(C)(C(=O)O)CC2)ccc1O
Yield: 14.4 %

Procedure:
0.2 g of bis(triphenylphosphine)palladium dichloride and 4 g of ammonium formate were added to a solution of 6.2 g of allyl cis-4-(4-hydroxy-3-methoxycinnamoyloxy)-1-methyl-1-cyclohexanecarboxylate (Example 10) in 80 ml of THF. The solution was reacted for 20 hours under an argon stream, while it was refluxed. After reaction, 150 ml of an aqueous sodium chloride solution was added to the reaction solution. The solution was extracted three times with 70 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution and dried over magnesium sulfate. Then, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=1:2, the solvent was removed in vacuo, yielding 0.8 g of cis-4-(4-hydroxy-3-methoxy-cinnamoyloxy)-1-methyl-1-cyclohexanecarboxylic acid (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[NH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Brc1ccc(I)nc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1ccc(Br)cn1
Temperature: 170 °C
Reaction time: 3 h

Procedure:
A mixture of 8.86 g (31.20 mmol) of 5-bromo-2-iodopyridine and 10.00 g (62.42 mmol) of tert-butyl (2-aminoethyl)carbamate was stirred for 3 hours at 170° C. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by chromatography (silica gel, cyc/EtOAc 4:1). Yield: 2.37 g (24% of theoretical); C12H18BrN3O2 (M=316.194); calc.: molpeak (M+H)+:316/318 (Br); found: molpeak (M+H)+:316/318 (Br); Rf value: 0.22 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([C:20]4[O:21][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C)[CH:26]=5)=[N:23][N:24]=4)[CH:17]=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(=O)=O.CC(C)=O>ClCCl>[CH:10]1[C:11]2[N:12]([C:14]3[CH:15]=[C:16]([C:20]4[O:21][C:22]([C:25]5[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=5)=[N:23][N:24]=4)[CH:17]=[CH:18][CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(-c2nnc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1cccc(-c2nnc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(3-carbazol-9-ylphenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (3.0 g, 72 mmol) in dichloromethane (20.0 ml) was dropwise added BBr3 (30.0 ml, 1M in dichloromethane) at −78° C. (dry-ice/acetone) under nitrogen. After addition of BBr3 solution, the reaction was taken to room temperature and kept at room temperature for 6 h. The reaction mixture was poured into ice-water (100.0 ml). Dichloromethane was evaporated under reduced pressure. The white solid was collected by filtration. After drying under vacuum, product as white solid was obtained in 2.9 g (100%) yield. 1H NMR (400 MHz, acetone-d6, δ): 8.89 (s, br, 1H, OH), 8.41 (m, 1H), 8.34 (m, 1H), 8.26 (m, 2H), 7.92 (m, 2H), 7.66 (m, 2H), 7.53-7.41 (m, 5H), 7.33 (m, 2H), 7.10 (m, 1H). MS-EI (m/z): [M]+ calcd for C26H17N3O2, 403.1. found 403.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:6][C:5]2=[O:20].[CH2:21](C([Sn])=C(CCCC)CCCC)[CH2:22]CC>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:20])[CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)=[CH:3][C:2]=1[CH:21]=[CH2:22]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: C=Cc1cc2c(=O)cc(-c3ccccc3)[nH]c2cc1OC
Temperature: 100 °C
Yield: 79.7 %

Procedure:
To a solution of 6-bromo-7-methoxy-2-phenylquinolin-4(1H)-one (1.0 g, 3.03 mmol) in DMSO (35 mL) was added tri(n-butyl)vinyltin (1.06 mL, 3.63 mmol) and finally tetrakis(triphenylphosphine)palladium (88 mg, 0.076 mmol). The mixture was then degassed using a freeze/pump/thaw cycle (2×). The mixture was then heated to 100° C. in a sealed tube for 22 h. At this time, LC-MS revealed complete consumption of the bromoquinoline). The reaction mixture was then poured into a mixture of water (200 mL) and EtOAc (200 mL) which caused solid to crash out. The solid was filtered off, washed with CH3CN, EtOAc, DCM, and then hexanes to give 7-methoxy-2-phenyl-6-vinylquinolin-4(1H)-one as a light greenish solid (670 mg, 80%). 1H NMR (400 MHz, DMSO-d6) ppm: 11.58 (s, 1H), 8.16 (s, 1H), 7.83 (m, 2H), 7.58 (m, 3H), 7.25 (s, 1H), 6.99 (dd, J=11 Hz, 17.5 Hz, 1H), 6.28 (s, 1H), 5.85 (d, J=17.5 Hz, 1H), 5.31 (d, J=11 Hz, 1H), 3.92 (s, 3H). LRMS (CI, [M+H]) Calc'd=278.1. found=278.2.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].CCN(CC)CC.C[O:29][C:30](=O)[C:31]1[C:36]([NH:37][C:38]([CH:40]2[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:43]Br>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:16]2[C:30](=[O:29])[C:31]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[CH2:43]2)[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Temperature: 90 °C
Yield: 25.5 %

Procedure:
To the DMF solution (20 ml) of 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.80 g, 2.7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.2 mmol). The mixture was heated at 90° C. for 12 hours then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.35 g, 30%): mp 115-117° C.; 1H NMR (CDCl3) δ 0.83-0.92 (m, 2H, c-CH2), 1.09-1.13 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.66-1.70 (m, 1H, c-CH), 2.98 (s, 3H, SO2CH3), 3.64 (dd, J=3.8, 14 Hz, 1H, CH2), 4.10 (q, J=6.8 Hz, 2H, OCH2), 4.33 (dd, J=10, 14 Hz, 1H, CH2), 4.37 (dd, J=5, 50 Hz, 2H, CH2N), 5.69-5.74 (m, 1H, NCH), 6.57 (t, JH-F=75 Hz, 1H, CF2H), 6.94-7.04 (m, 3H, Ar), 7.18 (d, J=7.5 Hz, 1H, Ar), 7.47 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8.5 Hz, 1H, Ar), 10.42 (s, 1H, NH); 13C NMR (CDCl3) δ 9.06, 15.3, 16.9, 42.4, 49.0, 52.5, 56.3, 65.6, 112.4, 113.9, 116.6, 117.5, 117.6, 118.7, 119.9, 120.7, 123.8, 134.5, 136.5, 138.9, 141.1, 141.9, 151.9, 170.9, 173.4; Anal Calcd for C24H26F2N2O6S: C, 56.68; H, 5.15; N, 5.51. Found: C, 56.72; H, 5.15; N, 5.38.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].Cl.Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:13][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([O-:3])=[O:2]
Reactant: ClCCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCCN2CCCCC2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 102.3 %

Procedure:
To a stirred solution of 3,4-dinitrophenol (2 g, 10.9 mmol, 1 eq) in dimethyl formamide (40 ml), chloropropyl piperidine hydrochloride (2.8 g, 14.2 mmol, 1.3 eq) and potassium carbonate (3.2 g, 22.9 mmol, 2.1 eq) were added. The mixture was heated to 100° C. for 4 hours and the reaction was cooled to room temperature. The mixture was passed through a SCX column and eluted with 7N ammonia in methanol, the eluent was concentrated and the residue was subjected to chromatography on silica gel (100 g) to yield 1-[3-(3,4-dinitro-phenoxy)-propyl]-piperidine [3.45 g] as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]([N:19]3[CH2:24][CH2:23][C:22]4([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]4)[O:21][C:20]3=[O:31])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)=[O:4]>CO.O>[CH3:32][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:19]3[CH2:24][CH2:23][C:22]4([CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]4)[O:21][C:20]3=[O:31])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nc2)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Solvent: O
Solvent: CO
Product: CC(c1ccc(-c2ccc(C(=O)N(C)C)nc2)cc1)N1CCC2(CCC(O)CC2)OC1=O

Procedure:
The title compound is prepared from 5-{4-[(S)-1-(2,9-dioxo-1-oxa-3-aza-spiro[5.5]undec-3-yl)-ethyl]-phenyl}-pyridine-2-carboxylic acid dimethylamide following a procedure analogous to that described in Example 22; after HPLC on reversed phase (methanol/water) the title compound is obtained in a ca. 1:1 mixture of cis- and trans-isomer. Yield: 53% of theory; LC (method 2): tR=1.58 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:22])[C:16]=1[CH3:32].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:62][C:63]([F:73])([F:72])[C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[C:66]([NH2:71])[CH:65]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:70][C:67]2[CH:68]=[CH:69][C:64]([C:63]([F:62])([F:72])[F:73])=[CH:65][C:66]=2[NH2:71])=[O:30])=[O:22])[C:16]=1[CH3:32]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)Nc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (441 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-trifluoromethyl-o-phenylenediamine (211 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (390 mg, 65% yield) as a red solid. LC-MS (m/z) 600 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:9].O.[OH-].[Li+]>O1CCCC1.O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)NCCOCCO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round bottom flask, was placed a solution of methyl 3-((2-(2-hydroxyethoxyl)ethyl)carbamoyl)benzoate (10 g, 37.45 mmol, 1.00 equiv) in tetrahydrofuran (40 mL), and a solution of lithium hydroxide hydrate (23.4 g, 558.33 mmol, 15.00 equiv) in water (30 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 3-4 with hydrochloric acid (2 mol/L), extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (50:1). This resulted in 5 g (53%) of 3-((2-(2-hydroxyethoxyl)ethyl)carbamoyl)benzoic acid as a yellowish solid. 1H-NMR (300 MHz, DMSO, ppm): δ 13.25(s, 1H), 8.71(m, 1H), 8.48(d, J=8.5 Hz 1H), 8.06(m, 2H), 7.62(m, 1H), 4.59(s, 1H), 3.41-3.60 (m, 8H). MS (ES, m/z): 254 [M+H]+.