Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]3[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38](=[O:44])[NH:39][CH:40]4[CH2:43][CH2:42][CH2:41]4)=[O:32])[N:26]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:25]=3)=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1.[CH2:52](Cl)CCl.CO>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]3[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38](=[O:44])[NH:39][CH:40]4[CH2:43][CH2:42][CH2:41]4)=[O:32])[N:26]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:25]=3)=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH3:52])=[O:19])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OC2CCC2)CC1

Procedure:
To a solution of 150 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid cyclobutyl ester in 3 ml DMF were added 42 mg EDC, 27 mg DMAP and 37 μl methanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 45 mg MS (ES+): m/e=722.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15](OS(C(F)(F)F)(=O)=O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:31]([O:34][Si](C)(C)C)[C:32]#[CH:33].[Cl-].[Li+].C(N(CC)CC)C>CN(C=O)C.[Cu](I)I.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]([C:33]#[C:32][CH2:31][OH:34])=[C:10]3[CH:9]=[CH:8]2)=[CH:29][CH:30]=1
Reactant: C#CCO[Si](C)(C)C
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1C#CCO
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
To a solution of ethyl 1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (1.50 g, 3.36 mmol) in DMF (4 mL) was added propargyloxytrimethylsilane (0.73 g, 5.72 mmol), lithium chloride (0.214 g, 5.1 mmol), copper iodide (0.028 g ml, 0.15 mmol), triethylamine (7 ml, 50.4 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.052 g, 0.074 mmol). The resulting mixture was stirred for 20 min at 140° C. in a microwave reactor (Personal Chemistry). The solvent was evaporated and 10 mL ethyl acetate was added. After stirring for 10 min, the mixture was filtered through Celite and the filtrate was concentrated. Purification by flash chromatography (Biotage) over silica gel (1:3, hexane/ethyl acetate) afforded the title product as yellow oil (0.46 g, 46% yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.69 (s, 1H) 7.36 (d, J=3.28 Hz, 1H) 7.06-7.14 (m, 2H) 6.98-7.06 (m, 2H) 6.84 (d, J=2.53 Hz, 1H) 5.40 (s, 2H) 4.67 (s, 2H) 4.48 (q, J=7.07 Hz, 2H) 1.46 (t, J=7.20 Hz, 3H). LC-MS (APCI, M+H+): 353.1. HPLC: 96% purity.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH:9]=[CH:8][C@H:7]2[O:11][C:12]([NH2:14])=[N:13][C@@H:6]12)=[O:4]>CN(C=O)C>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH:9]=[CH:8][C@H:7]2[NH:14][C:12](=[O:11])[NH:13][C@@H:6]12)=[O:4]
Reactant: COC(=O)N1CC=C[C@H]2OC(N)=N[C@H]21
Solvent: CN(C)C=O
Product: COC(=O)N1CC=C[C@H]2NC(=O)N[C@H]21

Procedure:
A solution of 5 (200 mg, 1 mmol) in DMF (10 ml) is brought to reflux for 1 h. After evaporating the solvent, the crude product (280 mg) is purified by chromatography on silica gel (Et2O/MeOH, 93:7). Product 19 (Rf=0.36, Et2O/MeOH, 92:8) is obtained in the form of a yellow solid (81 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)=[O:8].[Br:24]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:24][C:11]1[N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:2]([Cl:1])[CH:3]=2)=[O:8])[C:18]([OH:19])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1ncc2cccnc2c1O
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Br)c2cccnc2c1O
Reaction time: 4 h

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide from Example 1, Step 3 (1.28 g, 3.69 mmol) in CH2Cl2 (100 ml) at room temperature was added N-bromosuccinimide (0.689 g, 3.87 mmol). The reaction was stirred for 4 hrs and then poured into water. The organic phase was washed with water (3×100 ml), and dried (Na2SO4). The solvent was evaporated in vacuo and the residue triturated with CH2Cl2 to afford the title compound as an off white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC.[CH2:53]([OH:56])[CH:54]=[CH2:55].C(N(CC)CC)C.Cl>CC([O-])=O.CC([O-])=O.[Pd+2].C([O-])([O-])=O.[Na+].[Na+]>[Br:8][C:6]1[CH:7]=[C:2]([C:54](=[CH2:55])[CH2:53][OH:56])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Solvent: CCN(CC)CC
Product: C=C(CO)c1cncc(Br)c1
Temperature: 125 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A microwave vial was charged with 3,5-dibromo pyridine (5.00 g, 21.1 mmol), Pd(OAc)2, (0.185 g, 0.820 mmol), 1,3-Bis(diphenylphosphino)propane (0.7 g 1.7 mmol), and 1-butyl-3-methylimidazolium tetrafluoroborate (25 mL) under nitrogen at room temperature. The reaction mixture was degassed three times and allyl alcohol (2.85 g, 49.1 mmol) and triethylamine (4.7 ml, 3.6 mmol) were added. The reaction mixture was heated in microwave reactor at 125° C. for 2 h. After cooling to room temperature, aqueous HCl (20 mL, 10%) was added and the mixture stirred for 1 h. The reaction mixture was treated with saturated Na2CO3 (20 mL) and the aqueous portion extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (SiO2, hexane/EtOAc=8/2) to yield 2-(5-bromopyridin-3-yl)prop-2-en-1-ol (1.6 g, 36%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (d, 1H, J=2 Hz), 8.62 (d, 1H, J=2.4 Hz), 8.13 (s, 1H), 5.66 (s, 1H), 5.45 (s, 1H), 5.15 (t, 1H, J=5.2 Hz), 4.35 (d, 2H, J=5.2 Hz). LCMS Method T: retention time 0.96 min; [M+1]=216.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:30])[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>>[C:21]1([CH3:30])[C:22]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccccc1C)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and o-toluoyl chloride, there is obtained ethyl N-(o-toluoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum: m/e: M+ 384 (5), 355 (10), 194 (100), 119 (31);
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][C:12](=[O:14])[OH:13])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41](ON1C(=O)CCC1=O)=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1.C(N(CC)CC)C>CN(C=O)C>[NH:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:30]([C:41]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:42])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1
Reactant: CCCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 97.5 %

Procedure:
1.57 g (3.78 mmoles of H-Nle-Asp-D-Phg-NH2.HCl are reacted with 1.52 g (3.78 mmoles) of BOC-Trp-OSu in 50 ml of DMF in the presence of 1.06 ml (7.6 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the residue is admixed with water, and the suspension is filtered. 2.45 g (97.5%) of BOC-Trp-Nle-Asp-D-Phg-NH2 are obtained; m.p.: 217° C. (decomposition), Rf5 :0.35, [α]D -32.7° (c: 1.0, in dimethyl formamide).
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([CH3:36])[C:28]=1[S:29]([CH2:32][N+:33]([O-:35])=[O:34])(=[O:31])=[O:30])[NH2:25].Cl>O1CCCC1.O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:25][C:24]1[CH:23]=[C:22]([CH3:21])[C:28]([S:29]([CH2:32][N+:33]([O-:35])=[O:34])(=[O:31])=[O:30])=[C:27]([CH3:36])[CH:26]=1)(=[O:19])=[O:18]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(F)cc2F)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
0.65 g (8.22 mmol) of pyridine, dried over potassium hydroxide, and 1.3 g (6.11 mmol) of 2,4-difluorobenzenesulphonyl chloride are successively added to a solution, cooled to about 10° C., of 1.0 g (4.09 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 20 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 2 h at 10° C. and then for 20 h at room temperature, after which it is poured into 100 ml of water. The mixture is brought to pH 3 by addition of concentrated hydrochloric acid and then extracted with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and by recrystallization from toluene, to give 0.38 g (22%) of 2,4-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH3:22]OC(=O)OC.CN(C)C=O>O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH3:22])[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NCc2cccnc2N1c1cccc(C(F)(F)F)c1
Reactant: COC(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Yield: 76.3 %

Procedure:
A mixture of 0.5 g 1-(m-trifluoromethylphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 0.8 g of dimethylcarbonate and 10 ml of dimethylformamide was reacted at 160° - 170° C in sealed-tube for 20 hours. After the reaction was finished, the solvent was distilled off from the mixture to leave a residue, to which was added water. This residue was extracted with ether and then dehydrated. The ether solution was applied on a column of alumina, and then eluted with ether. The ether was evaporated from the eluate and left to give 0.4 g of 1-(m-trifluoromethylphenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 122° - 124° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]([CH3:15])[CH2:10][CH:11]2[CH2:13][CH:12]2[CH3:14])[N:6]=[C:5]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:4]=1.C(N(CC)CC)C>ClCCl.CS(C)=O.CCOC(C)=O>[CH:2]([C:3]1[CH:8]=[C:7]([N:9]([CH3:15])[CH2:10][CH:11]2[CH2:13][CH:12]2[CH3:14])[N:6]=[C:5]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:18])=[O:19])[CH:4]=1)=[O:1]
Reactant: CC1CC1CN(C)c1cc(CO)cc(N(C)S(C)(=O)=O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1CC1CN(C)c1cc(C=O)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-(hydroxymethyl)-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide (480 mg, 1.53 mmol) in dichloromethane (10 mL) and DMSO (2.5 mL) was added triethylamine (1.07 mL, 7.66 mmol) and SO3-pyridine (975 mg, 6.13 mmol). The reaction mixture was stirred at rt for 0.5 h, diluted with EtOAc, washed with 1N HCl, sat'd aq NaHCO3, brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica, 25-50% EtOAc/hexanes) to provide N-(4-formyl-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide. 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 6.92 (s, 1H), 6.72 (s, 1H), 3.53 (A of ABX, dd, J=14.8, 6.4 Hz, 1H), 3.40 (s, 3H), 3.36 (B of ABX, dd, J=14.8, 6.8 Hz, 1H), 3.15 (s, 3H), 3.13 (s, 3H), 1.04 (d, J=6.0 Hz, 3H), 0.78-0.62 (m, 2H), 0.45-0.37 (m, 1H), 0.31-0.24 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][CH:11]1[C:16](=[O:17])[N:15]2[CH:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH2:21][CH:14]2[N:13]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])(=[O:36])=[O:35])[CH2:12]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:18]2[N:15]3[C:16](=[O:17])[CH:11]([NH:10][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[CH2:12][N:13]([S:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])(=[O:36])=[O:35])[CH:14]3[CH2:21][N:20]([CH:22]([CH3:24])[CH3:23])[C:19]2=[O:25])=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: CC(C)N1CC2N(C(=O)C(NC(=O)c3cccnc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using nicotinoyl chloride *HCl and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=663.09 (calculated, monoisotopic); measured value (M+H)+: 664.11
Reaction SMILES: C(Cl)(=O)C.FC1C=CC(C(C)(C)CC(Cl)=O)=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:37])([CH3:36])[CH:27]=[C:28]=[C:29]([CH3:35])[C:30]([O:32]CC)=[O:31])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:37])([CH3:36])[CH:27]=[C:28]=[C:29]([CH3:35])[C:30]([OH:32])=[O:31])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C)=C=CC(C)(C)c1ccc(F)cc1
Agent: CC(C)(CC(=O)Cl)c1ccc(F)cc1
Solvent: CC(=O)Cl
Product: CC(=C=CC(C)(C)c1ccc(F)cc1)C(=O)O

Procedure:
Repeating the procedure of Example 1, step B, but replacing the p-thiomethylphenyl)-acetyl chloride, used therein, with an approximately equivalent amount of 3-(p-fluorophenyl)-3-methyl-butyryl chloride, there is accordingly obtained ethyl 5-(p-fluorophenyl)-2,5-dimethyl-hexa-2,3-dienoate, which upon treatment according to Example 2, yields 5-(p-fluorophenyl)-2,5-dimethyl-hexa-2,3-dienoic acid, m.p. (72.5° - 75.5°).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:13])[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].O>CN(C)C=O>[CH2:8]1[O:9][C:10]2[CH:11]=[CH:12][C:4]([CH2:3][O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]=2[O:7]1
Reactant: ClCCCCCBr
Reactant: OCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCOCc1ccc2c(c1)OCO2
Yield: 24.1 %

Procedure:
60% Sodium hydride (0.6 g) was suspended in dimethylformamide (10 ml), and piperonyl alcohol (1.5 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1-bromo-5-chloropentane(1.8 g) was added, which was followed by stirring at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 0.6 g of 5-((3,4-methylenedioxyphenyl)methoxy)pentyl chloride.
Reaction SMILES: C([N:8]1[C@@H:13]([CH:14]=[CH:15][CH3:16])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:17])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:17][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH:14]=[CH:15][CH3:16])[NH:8]1
Reactant: CC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(1-propenyl)piperidine (1.80 g, 7.65 mmol) in 15% trifloroacetic acid (38 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(1-propenyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid that was homogeneous by TLC analysis. mp 139.5-141.1° C.; 1H NMR (250 MHz) δ 9.39 (s, 2H), 5.84-5.86 (m, 2H), 4.23 (s, 1H), 3.54 (s, 1H), 1.9-1.44 (m, 12H); 13C NMR (62.7 MHz) 131 (s), 123 (s), 48 (s), 28.5 (s), 28 (s), 17.6 (s), 17.1 (s), 13.7 (s) ppm. FT-IR (neat): 3420, 3020, 2944, 1588, 1459, 1434, 1386, 821, 816, 804. Elemental Analysis for C9H18NCl: C, 61.52%; H, 10.35%; N, 7.97%. Found: C, 61.44%; H, 10.29%; N, 7.88%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][C@H:21]1[CH2:26][NH:25][CH2:24][C@@H:23]([CH3:27])[NH:22]1.N12CCC(CC1)CN2>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:25]4[CH2:24][CH:23]([CH3:27])[NH:22][CH:21]([CH3:20])[CH2:26]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: C1CN2CCC1CN2
Product: CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC(C)N1
Temperature: 140 °C
Yield: 20.9 %

Procedure:
A mixture of 2.8 g (0.01 mol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.14 g (0.01 mol) of cis-2,6-dimethylpiperazine and 2.2 g of diazabicyclo-[2,2,2]-octane is heated at 140° C. for 5 hours. The solvent is distilled off under a high vacuum, 30 ml of water are added to the residue, the suspension is adjusted to pH 8 with 2N hydrochloric acid and the precipitate which has separated out is boiled up with 30 ml of methanol. 0.75 g (21% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 234°-236° C. is obtained.
Reaction SMILES: COC1N=CC(N2CCC(N3CC[C@@H](NC(=O)C[NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27](C(F)(F)F)[CH:26]=4)C3)CC2)=CC=1.CSC1C=C(C=CC=1)N.COC1N=CC(N)=CC=1>>[C:24]([NH2:23])(=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: COc1ccc(N)cn1
Agent: CSc1cccc(N)c1
Product: NC(=O)c1ccccc1

Procedure:
N-{2-[((3R)-1-{1-[3-(methylsulfanyl)phenyl]piperidin-4-yl}pyrrolidin-3-yl)amino]-2-oxoethyl}-3-trifluoromethyl)benzamide was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, 3-(methylsulfanyl)aniline was substituted for 6-methoxypyridin-3-amine. The crude product was purified by preparative HPLC. MS m/z: 521 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:18]=[N:17][C:16]=2[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:29]([C:16]1[N:17]=[N:18][C:19]([O:21][CH:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 4-(4-benzyloxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine (Example 1, 14 mmol, 6.04 g) in methanol/ethyl acetate (100 mL, 1/1) was added 10% palladium on activated carbon (10% by weight, 0.60 g). The mixture was repeatedly de-gassed under vacuum, filled with hydrogen for 3 times. Then hydrogen balloons were attached to the reaction, which was stirred at room temperature for 2 hours. TLC/LCMS monitored to completion. The mixture was then filtered through celite, the celite cake was washed with 1/1 methanol/ethyl acetate for 3 times, and the organic layers were combined and condensed to give 4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-phenol as a white powder (4.06 g, 85% yield), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([NH:30]C(=O)OC(C)(C)C)[CH2:20][C:19]2[CH:21]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14][CH:13]=[CH:12][CH2:11][C:10]2=[CH:22][C:6](=[CH:7][C:8]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[N:9]2)[CH2:5][O:4][C:3]1=[O:29]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:30][C:2]1([CH3:1])[CH2:20][C:19]2[CH:21]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14][CH:13]=[CH:12][CH2:11][C:10]2=[CH:22][C:6](=[CH:7][C:8]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[N:9]2)[CH2:5][O:4][C:3]1=[O:29].[NH2:30][C:2]1([CH3:1])[CH2:20][C:19]2[CH:21]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14][CH:13]=[CH:12][CH2:11][C:10]2=[CH:22][C:6](=[CH:7][C:8]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[N:9]2)[CH2:5][O:4][C:3]1=[O:29]
Reactant: CN(c1cc2cc(n1)CC=CCc1cccc(c1)CC(C)(NC(=O)OC(C)(C)C)C(=O)OC2)S(C)(=O)=O
Agent: CN(c1cc2cc(n1)C/C=C/Cc1cccc(c1)CC(C)(N)C(=O)OC2)S(C)(=O)=O
Agent: CN(c1cc2cc(n1)C/C=C\Cc1cccc(c1)CC(C)(N)C(=O)OC2)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cc2cc(n1)CC=CCc1cccc(c1)CC(C)(N)C(=O)OC2)S(C)(=O)=O

Procedure:
A solution of tert-butyl [(3EZ)-14-methyl-8-[methyl(methylsulfonyl)amino]-13-oxo-12-oxa-7-azatricyclo[14.3.1.16,10]henicosa-1(20),3,6(21),7,9,16,18-heptaen-14-yl]carbamate (14 mg, 0.026 mmol) (Intermediate V.11.c.1) in DCM (0.5 mL) and TFA (1.5 mL) was stirred at rt for 1 h. Concentration, purification and separation of EZ isomers by reverse phase preparative HPLC (5-95% CH3CN in water containing 0.1% TFA) gave N-[(3E)-14-Amino-14-methyl-13-oxo-12-oxa-7-azatricyclo[14.3.1.16,10]henicosa-1(20),3,6(21),7,9,16,18-heptaen-8-yl]-N-methylmethanesulfonamide and N-[(3Z)-14-Amino-14-methyl-13-oxo-12-oxa-7-azatricyclo[14.3.1.16,10]henicosa-1(20),3,6(21),7,9,16,18-heptaen-8-yl]-N-methylmethanesulfonamide