Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=2[F:28])[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:19]=1[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[N:21]=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:19]=2[CH3:36])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(Br)cnc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-morpholinopyridin-3-amine (0.3282 g, 1.272 mmol) in dry DMF (10.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.125 g, 3.12 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.46 g, 1.57 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with MeOH and placed on the rotovap. (without vac.) in a 45° C. water bath. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=512.1 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])=[CH:10][CH:11]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(S(=O)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(S(=O)c3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(phenylsulfinyl)acetophenone (2.50 g, 10.24 mmol), lithium bis(trimethylsilyl)amide (2.57 g,15.36 mmol), chlorotrimethylsilane (1.94 mL,15.36 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 171-173° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 3.01 (t, 2 H), 6.83 (s, 1 H), 7.19 (m, 5 H), 7.54 (m, 3 H), 7.75 (d, 2 H), 7.86 (d, 2 H), 7.95 (d, 2 H), 12.05 (bs, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: COc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparations 78 and 79 using 4-fluoro-2-methoxy-1-nitrobenzene and 1-methylpiperazine. The residue was purified by silica gel column chromatography eluting with 0-20% MeOH in EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[C:9]([CH3:25])[S:8][C:7]=2[C:26]=1[O:27]S(C1C=CC(C)=CC=1)(=O)=O.CO.C(C(O)=O)(F)(F)F>C1COCC1.[OH-].[Na+]>[OH:27][C:26]1[C:7]2[S:8][C:9]([CH3:25])=[C:10]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)c2c(C)sc3c(OS(=O)(=O)c4ccc(C)cc4)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)c2c(C)sc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 30 °C
Reaction time: 8 h
Yield: 279.4 %

Procedure:
A mixture of the product of Example 41 (0.035 g; 0.00645 mmol) in THF (0.5 ml) and 1% NaOH in MeOH (0.52 ml; 0.0129 mmol) was stirred overnight at 30° C. under N2 and acidified with the drop of CF3CO2H. This was evaporated to dryness and diluted to 15 ml with diethyl ether, washed with 0.1 M HCl (2 ml), 5% NaHCO3 (2 ml), brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure title compound (0.007 g; 28%), as a colourless crystals.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[C:4](=[O:11])[CH2:3]1.N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19].C(O)C>ClCCl>[C:18]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]1=2)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC1CC(=O)c2sccc2N1
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)N1c2ccsc2C(=O)CC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
[Step 4] 123 mg (0.74 mmol) of the 5-methyl-5,6-dihydrothieno[3,2-b]pyridin-7(4H)-one were dissolved in 4 mL of anhydrous dichloromethane followed by sequentially adding 0.12 mL (1.5 mmol) of anhydrous pyridine and 0.078 mL (1.1 mmol) of acetyl chloride and stirring for 1 hour at room temperature. Following completion of the reaction, ethanol was added, the solution was concentrated under reduced pressure and then additionally boiled with toluene. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain 111 mg of 4-acetyl-5-methyl-5,6-dihydrothieno[3,2-b]pyridin-7(4H)-one in the form of a pale brown oil (72%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[N:11]#[C:12][NH2:13].[N+:14]([O-:17])([OH:16])=[O:15].NC(N)=N>>[N+:14]([O-:17])([OH:16])=[O:15].[NH:1]([C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1)[C:12]([NH2:13])=[NH:11]
Reactant: N#CN
Reactant: Nc1ccc2[nH]nnc2c1
Agent: N=C(N)N
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc2[nH]nnc2c1

Procedure:
5-Guanidinobenzotriazole nitrate was prepared from 5-aminobenzotriazole (790 mg, 5.89 mmol), cyanamide (371 mg, in 0.75 ml H2O, 8.83 mmol) and concentrated nitric acid (0.5 ml) following the method described for the guanidine of Example 1 to give the compound as a brown solid (248 mg). δH (d6DMSO) 9.71 (1H, s), 8.0 (1H, d, J 6.5 Hz), 7.80 (1H, s), 7.41 (4H, s) and 7.26 (1H, d, J 6.7 Hz). MS (ES+) 177 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1O[CH2:8]1)[CH:2]1[O:4][CH2:3]1.O[C:11]1[CH:26]=[CH:25][C:14]([C:15](NC2C=CC(O)=CC=2)=O)=[CH:13]C=1.S(N)(=O)([C:29]1[CH:34]=[CH:33][C:32](N)=[CH:31][CH:30]=1)=O>>[CH3:15][C:14]([C:25]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:11][CH:26]=1)([C:29]1[CH:34]=[CH:33][C:32]([O:5][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:31][CH:30]=1)[CH3:13]
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(O)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C(OCC1CO1)C1CO1
Product: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
Part of the diglycidyl ether of 4,4'-dihydroxybenzanilide prepared from B (4.3925 grams) is combined and mixed with an equivalent amount of a curing agent, sulfanilamide (1.0624 grams). This blend of solids is then placed in a 175° C. convection oven. After melt has occurred (approximately 10 minutes) the resinous mixture is poured into a mold (dimensions=7.5"×0.5"×0.021"; 190.5 mm×12.7 mm×0.53 mm) also located in the same convection oven. This mold is then placed in a mechanical press heated to 130° C. Pressure (approximately 2,000 psi, 13.8 MPa) is then applied to the mold within 5 minutes. After 1.5 hours at 130° C., the temperature of the press is increased and held for one hour at the following temperatures: 160° C., 180° C. and 200° C. After one hour at 200° C., the temperature of the press is raised to 225° C. where it is held for two hours before it is allowed to cool to room temperature. After cooling to room temperature an opaque casting is obtained from the mold. The flash from this casting, which results from excess resin being squeezed from the mold, exhibits a birefringent texture which is oriented in the direction of its flow formation. The apparent glass transition temperature for this polymer is 245° C. as determined by thermal mechanical analysis which is 65° C. higher than that obtained for the diglycidyl ether of bisphenol A in Comparative Experiment A-2. The average tensile strength and modulus for two cast films prepared using this procedure are 12,450 psi (85.8 MPa) (standard deviation=1,460 psi, 10.1 MPa) and 635,000 psi (4,378.2 MPa) (standard deviation=3,500 psi, 24.1 MPa), respectively. These values represent a 41 and 23 percent improvement for these respective properties when compared to those obtained for the diglycidyl ether of bisphenol A in Comparative Experiment A-2. The results are reported in Table VI.
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[N:15][C:14]([OH:17])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[N:15][C:14]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: Oc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 67.1 %

Procedure:
The process was carried out essentially like that of Example 5, using 0.8 g of sodium, 20 ml of methanol, 100 ml of dimethylsulfoxide, 8 g of 1-(3,4-dichlorophenyl)-3-hydroxy-1,2,4-1H-triazole and 6.3 g of ethyl 2-bromopropionate. The product was 7.7 g of the desired product, m.p. 69°-71°.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([NH:13][CH2:14][C@@H:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:13]2[CH2:14][C@H:15]([C:16]([O:18][CH3:19])=[O:17])[O:20][C:21]2=[O:22])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Temperature: 60 °C
Yield: 95.8 %

Procedure:
A mixture of methyl (2R)-3-[(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate (Step 8, 0.84 g, 2.96 mmol) and 1,1′-carbonyldiimidazole (0.48 g, 2.96 mmol) in acetonitrile is stirred and heated at 60° C. overnight. The reaction is diluted with ethyl acetate, washed with 2N HCl and saline, and evaporated under reduced pressure. The resulting solid is triturated with methanol to give pure product as a white solid (0.88 g, 96%); MS for C13H11FN2O6 m/z 311 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:22][C:11]3([O:16][C:15]4[CH:17]=[CH:18][CH:19]=[N:20][C:14]=4[NH:13][C:12]3=O)[CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[CH2:22][C:11]3([O:16][C:15]4[CH:17]=[CH:18][CH:19]=[N:20][C:14]=4[NH:13][C:12]3=[S:32])[CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ncccc2OC12Cc1cc([N+](=O)[O-])cnc1C2
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnc2c(c1)CC1(C2)Oc2cccnc2NC1=S

Procedure:
A solution of 3-nitro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,2′-pyrido[3,2-b][1,4]oxazin]-3′(4′H)-one from Step D (450 mg, 1.5 mmol) in toluene (3 mL) is treated with Lawesson's reagent (650 mg, 1.6 mmol) and the mixture heated at reflux for several hours. The solvent is removed in vacuo and the residue is purified by silica gel chromatography (gradient elution with 0-10% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][C@H:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][C@H:50]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:51][CH2:52][C:53](=[O:55])[OH:54].CCN(C(C)C)C(C)C>C1COCC1.O>[C:59]([O:58][C:56](=[O:57])[C@@H:50]([NH:49][C:9](=[O:8])[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:51][CH2:52][C:53]([OH:54])=[O:55])([CH3:62])([CH3:61])[CH3:60]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of (S)-2-(19-tert-butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester (prepared similarly as described in WO 2005/012347) (4.1 g) in THF (100 ml) was added a solution of H-Glu-OtBu (1.47 g) in water (20 ml). pH was adjusted to 8 with DIPEA. The mixture was concentrated after stirring for 1.5 h. The residue was recrystallized from DCM to give the title compound as a white solid (2.81 g, 61%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>C(#N)C.CN(C)C=O>[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:25]1
Reactant: NCC1CCCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(N2CCCC(CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
A suspension of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.48 g), 3-aminomethylpiperidine (1.14 g) and triethylamine (1.5 g) in acetonitrile (20 ml) and N,N-dimethylformamide (10 ml) was refluxed overnight. Concentration of the reaction mixture followed by purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=15:5:1) gave 7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, which was recrystallized from isopropanol-water to afford yellow prisms. m.p. 192°-193° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=1.[CH2:18]1[C@H:27]2[C@@H:22](CCCC2)[CH2:21][CH2:20][NH:19]1.[CH3:28]CN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([N:19]2[CH2:18][CH2:27][CH2:22][CH2:21][CH:20]2[CH3:28])=[O:17])[N:14]=1
Reactant: COc1cccc(F)c1-c1nc(C(=O)O)cs1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Reactant: CCN(C(C)C)C(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cccc(F)c1-c1nc(C(=O)N2CCCCC2C)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
2-(2-Fluoro-6-methoxy-phenyl)-thiazole-4-carboxylic acid (49.5 mg, 0.2 mmol) from the previous step, trans-decahydro-isoquinoline (TCI America, Portland, Oreg.; 27.8 mg, 0.2 mmol), DIPEA (0.1 mL, 0.57 mmol), and PyBrop (103 mg, 0.22 mmol) were mixed in dry DCM (1 mL) and the mixture was left stirring for overnight at room temperature. To the mixture was added water. The DCM layer was separated and the aqueous layer was extracted with DCM twice. The combined DCM layers were dried under vacuum and purified by C-18 reversed phase HPLC with a gradient of 10-100% Acetonitrile/water to give [2-(2-fluoro-6-methoxy-phenyl)-thiazol-4-yl]-(2-methyl-piperidin-1-yl)-methanone (12 mg, 16%).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([OH:23])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:3][C:2]#[CH:1])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 15 h

Procedure:
1.73 g (14.6 mmol) of propargyl bromide were added dropwise to a mixture of 3.00 g (9.74 mmol) of 3-chloro-2-(4-chloro-3-hydroxyphenyl)-5-trifluoromethylpyridine, 4.0 g (29 mmol) of potassium carbonate and 100 ml of anhydrous dimethylformamide. The mixture was stirred at 20°-25° C. for about 15 hours and then poured into 400 ml of water. The solution was kept cold for a few hours, and the resulting crystals were then separated off, washed with water and dried under reduced pressure. Yield: 3.1 g (92%) of colorless crystals of melting point 102°-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH2:12]([N:16]=[C:17]=[O:18])[CH:13]([CH3:15])[CH3:14].C(OCC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:17]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:18])=[O:6]
Reactant: NNC(=O)c1cccc(Br)c1
Reactant: CC(C)CN=C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CNC(=O)NNC(=O)c1cccc(Br)c1
Reaction time: 8 h

Procedure:
5.00 g (23.3 mmol) of 3-bromobenzoic acid hydrazide are placed in 50 ml tetrahydrofuran at room temperature. 2.70 g (27.2 mmol) of isobutyl isocyanate, dissolved in 10 ml tetrahydrofuran, are rapidly added dropwise with stirring to this suspension. The mixture is firstly further stirred at room temperature and then allowed to stand overnight. The precipitate formed after addition of 100 ml diethyl ether is filtered off and then washed with diethyl ether. An initial quantity of 1.42 g (19% of theory) of the target compound is thus obtained. The mother liquor is concentrated, and the residue again slurried in diethyl ether and filtered. After washing with diethyl ether and drying in vacuo, a further 5.62 g (77% of theory) of the target compound remain.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[F:22][C:23]([F:42])([F:41])[C:24]1[CH:25]=[C:26]([C@H:34]2[O:38][C:37](=[O:39])[NH:36][C@H:35]2[CH3:40])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:36]2[C@@H:35]([CH3:40])[C@@H:34]([C:26]3[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=[C:24]([C:23]([F:22])([F:41])[F:42])[CH:25]=3)[O:38][C:37]2=[O:39])[CH:6]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4S,5R)-5-(3,5-bis-trifluoromethyl-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc2nonc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2nonc2c1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
5-(2-Hydroxyethyl)benzofurazan (1.48 g, 9 mmol) was dissolved in dichloromethane (45 ml) and triethylamine (1.88 ml, 1.37 g, 13.5 mmol) was added. The mixture was cooled to -30° C. and methanesulfonyl chloride (0.84 ml, 1.24 g, 10.8 mmol) was added dropwise over 5 min. The mixture was stirred at -30° C. for 15 min. and dichloromethane (100 ml) was added. The mixture was washed with water (100 ml), dried (Na2SO4) and evaporated under reduced pressure to give the benzofurazan as a yellow solid (2.10 g, 96%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
5.19 (5), Tyr; 1.01 (1), Phe; 1.02 (1),
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18](=[O:20])[CH3:19])=O)C1C=CC=CC=1.[N:21]1[C:30]2[C:25](=[N:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.N1CCCCC1>CC(O)C>[N:26]1[C:25]2[C:30](=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:28][C:27]=1[CH:31]=[C:15]1[NH:11][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[N:13][C:14]1=[O:16]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: CC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C

Procedure:
To a mixture of 2-acetylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (47.1 mg, 0.17 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration to give N-(5-[1, 5]-naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-acetamide as a yellow solid, 15.3 mg (31.8%). HR-ES (+) m/e calcd. for C14H11N5O2: (M+H)+ 282.0986. Found: 282.0985.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][O:43][CH3:44]>>[CH3:36][O:37][CH2:38][CH2:39][N:40]([CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[O:23][N:22]=1)[CH2:41][CH2:42][O:43][CH3:44]
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: COCCNCCOC
Product: COCCN(CCOC)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and bis-(2-methoxyethyl)amine (280 μl, 1.98 mmol) as starting materials.