Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>FC(F)(F)C(O)=O>[C:4]([CH2:3][CH2:2][S:1][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:32]=1)[CH2:9][C:10]([OH:12])=[O:11])([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCS
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSC(CC(=O)O)c1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To trifluoroacetic acid (20 ml), cooled to 0° C., was added 3-mercaptopropionic acid (0.26 ml, 3 mmoles) followed by t-butyl 3-hydroxy-3-[2-(7-(3-trifluoromethylphenylthio)heptyl)phenyl]propanoate. The reaction mixture was stirred for 1 hour and evaporated. The resulting residue was diluted with carbon tetrachloride and washed with ice water. The organic layer was dried over sodium sulfate, filtered and evaporated. The resulting oil was flash chromatographed to give the desired product, -log KB value 6.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH2:12])[CH3:11].Cl[C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:41][C:24]2=[CH:25][C:26]3[C:27](=[O:40])[N:28]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[C:29](=[O:32])[C:30]=3[CH:31]=[C:23]2[N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:22][C:23]2=[CH:31][C:30]3[C:29](=[O:32])[N:28]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[C:27](=[O:40])[C:26]=3[CH:25]=[C:24]2[N:41]=1)[CH3:11]
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Reactant: CC(N)Cc1cc(F)ccc1F
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O

Procedure:
Racemic 1-(2,5-difluorophenyl)propan-2-amine and 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione were submitted to general procedure A. The isolated solid was triturated with water once and MeOH four times to give the title compound as an off-white solid, which was used directly in the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9]Cl.[I-].[K+].[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>CN(C)C(=O)C>[C:15]([C:14]1([C:13]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8]1)(=[O:16])[CH3:17]
Reactant: ClCCCl
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
A total of 662.4 g of potassium carbonate, 1161.2 g of 1,2-dichloroethane, 696.7 g of N,N-dimethylacetamide, 33.2 g of potassium iodide, and 464.5 g of methyl acetoacetate were mixed, followed by a reaction at 100° C. for 13 hours. The reaction mixture was cooled to room temperature and was filtrated, the resulting filtrate was washed with two portions of 5% by weight hydrochloric acid, and the organic layer was washed with water. The washing with the aqueous layer was extracted with 999.7 g of 1,2-dichloroethane. The extract with the organic layer was concentrated under a reduced pressure to distill off 1,2-dichloroethane, was subjected to distillation under a reduced pressure and thereby yielded 160.1 g of methyl 1-acetyl-1-cyclopropanecarboxylate as a colorless liquid as a fraction at 75° C./20 mmHg.
Reaction SMILES: [BH4-].[Na+].Br[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[O:6].C([O-])([O-])=O.[K+].[K+]>CO>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[CH:5]1[CH2:4][O:6]1
Reactant: O=C(CBr)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: Fc1ccc(C2CO2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (0.367 g, 10.85 mmol) was added to a stirred solution of 2-bromo-2′,4′-difluoroacetophenone ([CAS 102429-07-2], 5.1 g, 21.7 mmol) in MeOH (152 mL) at 10° C. The mixture was stirred at RT for 1 h. Then, K2CO3 (4.499 g, 32.55 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was treated with water and extracted with CH2Cl2/THF. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield I-19 (2.24 g, 66%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:4]=[N:3]1.[CH3:21][O:22][CH:23]([O:33][CH3:34])[CH2:24][NH:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(OCC)(=O)C>CCCC(C)C>[CH:26]1([N:25]([CH2:24][CH:23]([O:33][CH3:34])[O:22][CH3:21])[C:15](=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(CNC1CCCCCC1)OC
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCCC1)OC

Procedure:
The subtitled compound (1.2 g) was prepared from 3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 2a, Step i)] and N-(2,2-dimethoxyethyl)cycloheptanamine [Preparation 6], using a similar method to that described in Preparation 3 Step iii) and the elution gradient used was 50-80% ethyl acetate in isohexane. 1H NMR (400 MHz, DMSO-d6) δ 8.10 and 8.09 (2×s, 1H), 7.82 (s, 1H), 7.44-7.40 (m, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.26-7.21 (m, 1H), 7.06-7.02 (m, 1H), 4.51 and 4.39 (2×t, J=5.0 Hz, 1H), 3.85 (s, 3H), 3.86-3.66 (m, 1H), 3.68-3.56 (m, 4H), 3.31 (s, 3H), 3.30 and 3.16 (2×d, J=5.0 Hz, 2H), 3.25 (s, 3H), 2.81-2.76 (m, 2H), 2.61-2.51 (m, 2H), 1.79-1.23 (m, 12H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[CH3:21]O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([O:16][CH3:21])=[O:15])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(O)cccc2s1

Procedure:
4-(Methoxymethyloxy)benzo(b)thiophene-2-carboxylic acid (7 g) was dissolved in methanol (140 ml) and thionyl chloride (2.0 ml) was added under ice-cooling. The mixture was refluxed under heating for 2 hr and the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the solvent was evaporated under reduced pressure to give the title compound (6.0 g).
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:20][CH2:21][C:22](O)=[O:23])[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:36]1([NH:35][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]2[CH:5]=[C:6]([C:14]([F:16])([F:17])[F:15])[CH:7]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:9]=2)[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)Nc1ccccc1)Cc1c[nH]c2ccccc12
Reaction time: 16 h

Procedure:
A mixture consisting of 42.9 mg of 4[N'-methyl-N'-(3,5-bis-trifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pentanoic acid, 8.9 mg of aniline, 36.65 mg of propanephosphonic acid anhydride, 60 μl of triethylamine and 1.5 ml of methylene chloride is left to stand at room temperature for 16 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. In this way the title compound is obtained in the form of a white foam. Rf value=0.26 (ethyl acetate).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][CH:6]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O)[C:7](O)=[O:8]>CO>[CH3:4][O:5][CH:6]1[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[N:3][NH:2][C:7]1=[O:8]
Reactant: COC(CC(=O)c1ccc(C)cc1)C(=O)O
Reactant: NN
Solvent: CO
Solvent: O
Product: COC1CC(c2ccc(C)cc2)=NNC1=O
Reaction time: 8 h
Yield: 61.9 %

Procedure:
0.5 g of hydrazine hydrate (100%) was added, at room temperature, to a solution of 2.22 g of 2-methoxy-4-(4-methylphenyl)-4-oxobutyric acid (prepared as described in Preparation 2) in 20 ml of methanol, and the mixture was allowed to stand at room temperature overnight. The crystals which precipitated were collected by filtration and washed with methanol, to give 1.35 g of the title compound. The filtrate was concentrated by evaporation at 50° C. and the resulting residue was washed with methanol, giving a further 0.5 g of the pure title compound, melting at 167°-169.5° C. The total yield was 85%.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[CH:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)[CH:24]=2)[CH:19]=[CH:18]1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cn2nc(Oc3ccc4cc[nH]c4c3)ccc2n1)C1CC1
Temperature: 110 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (473 mg, 1.44 mmol), 1H-indole-6-ol (250 mg, 1.87 mmol), potassium carbonate (597 mg, 4.32 mmol) and N,N-dimethylformamide (4.0 mL) was stirred at 110° C. for 2 days. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→85/15), and precipitated from ethyl acetate/hexane to give the title compound (48 mg, 10%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:16])([CH3:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:39][N:40]([C:57](=[O:72])[C@H:58]([NH:70][CH3:71])[CH2:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[C@@H:41]([C:49]1[O:53][C:52]([C:54]([NH2:56])=[O:55])=[N:51][N:50]=1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(C(C)C)C(C)C)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:16])([CH3:15])/[CH:10]=[CH:11]/[C:12](=[O:14])[N:70]([C@@H:58]([C:57](=[O:72])[N:40]([C@@H:41]([C:49]1[O:53][C:52]([C:54](=[O:55])[NH2:56])=[N:51][N:50]=1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH3:39])[CH2:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[CH3:71])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)c1nnc(C(N)=O)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)/C=C/C(C)(C)NC(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)c1nnc(C(N)=O)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.2 %

Procedure:
(2E)-4-tert-Butoxycarbonylamino-4-methylpent-2-enoic acid (143 mg, 0.62 mmol) was dissolved in dichloromethane (4 ml). 1-Hydroxy-7-azabenzotriazole (85 mg, 0.62 mmol) and subsequently N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (119 mg, 0.62 mmol) were added. The solution was stirred for 15 min at room temp. 5-((1R)-1-(Methyl((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-2-phenylethyl)-[1,3,4]oxadiazol-2-carboxylic acid amide (230 mg, 0.52 mmol) was added. The solution was stirred for 5 min and ethyldiisopropylamine (0.11 ml, 0.62 mmol) was given to the reaction mixture. It was stirred for 16 h at room temp., diluted with ethyl acetate (20 ml) and extracted with water (20 ml). The phases were separated. The aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with a saturated solution of sodium hydrogencarbonate and dried over magnesium sulfate. The crude product was purified by flash-chromatography on silica (40 g) with dichloromethane/ethyl acetate 1:1 to give 126 mg of ((E)-3-(((1R)-1-(((1R)-1-(5-carbamoyl-[1,3,4]oxadiazol-2-yl)-2-phenylethyl)methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamoyl)-1,1-dimethylallyl)carbamic acid tert-butyl ester.
Reaction SMILES: F[C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14])=[O:5].[ClH:19].Cl.[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37]C4N=CC=CC=4C(NC4C=CC=CC=4C)=O)=[CH:33][C:32]=3[F:54])=[C:24]2[CH:23]=[CH:22]1>>[ClH:19].[ClH:19].[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:2]4[N:18]=[CH:17][CH:16]=[CH:15][C:3]=4[C:4]([NH:6][C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=4[CH3:14])=[O:5])=[CH:33][C:32]=3[F:54])=[C:24]2[CH:23]=[CH:22]1
Reactant: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Cc1cc(F)ccc1NC(=O)c1cccnc1F
Agent: Cl
Product: Cc1cc(F)ccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 42 %

Procedure:
2-Fluoro-N-(4-fluoro-2-methylphenyl)nicotinamide (0.050 g, 0.20 mmol) was converted to the title compound (0.043 g, 42%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide (Step B of Example 8). 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 10.87 (s, 1H), 10.28 (s, 1H), 8.10-8.40 (m, 4H), 6.96-7.60 (m, 7H), 6.72 (d, 1H, J=6.5 Hz), 6.45-6.53 (m, 1H), 2.20 (s, 3H); HRMS(ESI+), 472.1580 (M+H)+ calc, 472.1590 (M+H)+ found.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][O:14][C:15]([CH3:19])([CH3:18])[O:16][CH2:17][CH:10]2[O:9]1)C1C=CC=CC=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(Cl)(Cl)Cl>C(O)C.CO.[Pd]>[OH:9][CH:10]1[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[O:14][CH2:13][CH:11]1[CH2:12][NH:8][C:28](=[O:29])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)OCC2CN(Cc3ccccc3)OC2CO1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1(C)OCC(O)C(CNC(=O)OCc2ccccc2)CO1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
To a solution of (3aR/S,8aR/S)-2-benzyl-6,6-dimethylhexahydro-[1,3]dioxepino[5,6-d]isoxazole (10.4 g, 39.5 mmol) in ethanol (150 mL) was added 10% Pd/C (2.5 g) and the mixture was stirred under a hydrogen atmosphere. After 2 days the solids and solvent were removed. A solution of the residue in methanol (100 mL) and triethylamine (11.01 ml, 79 mmol) was cooled in an ice bath and benzyl chloroformate (7.30 ml, 51.3 mmol) was added, then the solution was allowed to warm to RT. Then chloroform was added and the solution was washed with water and processed normally. The crude residue was triturated with petroleum ether to give benzyl ((5R/S,6R/S)-6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)methylcarbamate (7.73 g, 24.99 mmol, 63.3% yield) as a white solid. 13C NMR (CDCl3) δ 157.3, 136.9, 128.9, 128.5, 128.5, 102.1, 69.1, 67.2, 64.6, 59.8, 46.4, 40.0, 25.2, 25.0.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]4[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=4)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[CH3:34][N:35]([CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27](=[O:28])[C:26]1[CH:32]=[CH:33][C:23]([CH:19]([NH:18][C:15]2[CH:16]=[N:17][C:12]([N:10]3[CH:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=[N:9]3)=[CH:13][CH:14]=2)[CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=1
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)OCC)cc1
Product: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)N(C)CCC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Steps B and C of Example 2, using ethyl 4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzoate and tert-butyl 3-(methylamino)propanoate. MS (M+1) 554.5.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl>Cl.CCO>[NH2:1][C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]([C:14]#[N:15])=[CH:6][CH:5]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c2ncccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: N#Cc1ccc(N)c2ncccc12
Yield: 86.9 %

Procedure:
In a similar fashion using route 19 general procedure 29, 8-nitroquinoline-5-carbonitrile 471 (350 mg, 1.7 mmol), SnCl2 (1.3 g, 7.0 mmol), 6N HCl (4 drops) and EtOH (10 ml) gave the title compound (250 mg, 86%) which was used in the next step without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:66]=[CH:65][C:64]([C:67](O)=[O:68])=[CH:63][CH:62]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:67]([C:64]1[CH:65]=[CH:66][C:61]([C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)=[CH:62][CH:63]=1)=[O:68]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 40.4 %

Procedure:
DIPEA (48 mg, 0.38 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (87 mg, 0.20 mmol) in DMF (1 mL). HOBT (19 mg, 0.15 mmol) and EDCI.HCl (29 mg, 0.15 mmol) were then added at room temperature. After 2 minutes, biphenyl-4-carboxylic acid (25 mg, 0.13 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 26 mg (42% yield) of biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 94.87%, HPLC Purity: 97.28%, 1H NMR (DMSO-d6): δ 8.6 (bs, 1H), 8.0-7.9 (d, 2H), 7.8-7.6 (m, 7H), 7.6-7.4 (m, 4H), 4.2 (d, 2H), 3.8-3.6 (m, 4H), 3.4 (m, 2H), 3.2-3.1 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.[OH-].[Na+]>[CH2:15]([O:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(OCc2ccccc2)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (2.55 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 5a) in THF is added at 0° C. subsequently 315 mg (2.80 mmol) potassium-tert-butylate, 47 mg (0.13 mmol) tetra-butylammonium-iodide and 0.45 mL (3.82 mmol) benzylbromide. The reaction mixture is stirred overnight at RT and is diluted with EtOAc and 1M aqueous sodium hydroxide solution. The organic phase is separated, washed with water and dried over MgSO4. After filtration, the solvent is evaporated and the residue is elutriated in tert-butylmethylether. The precipitate is collected and dried.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].Cl.ClCCN1CC[O:27]CC1>>[O:27]1[CH2:2][CH2:1][N:3]([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=2)[CH2:18][CH2:19]1
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CCCC(=O)c1ccc(OCCN2CCOCC2)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 21 except that N-(2-chloroethyl)morpholine hydrochloride was used instead of 2-(diethylamino)ethyl chloride hydrochloride. This produced a crude oil, which was purified by silica gel column chromatography, eluting with 1:1 hexanes/ethyl acetate, to give 24 (550 mg, quantitative) as a clear oil: MS (ES+) m/z 278.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:12][N+:13]([O-:15])=[O:14])=[NH:11])=[CH:4][N:3]=1.Cl[CH2:17][N:18]([CH2:20]Cl)[CH3:19].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:19][N:18]([CH3:20])[CH2:17][NH:11][C:10]2=[N:12][N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1
Reactant: CN(CCl)CCl
Reactant: N=C(NCc1ccc(Cl)nc1)N[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CNC(=N[N+](=O)[O-])N(Cc2ccc(Cl)nc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
0.6 g of 1-(2-chloro-5-pyridylmethyl)-3-nitroguanidine and 0.4 g of bis(chloromethyl)methylamine were suspended in dried THF. To the suspension, a solution of 0.52 g of triethylamine in THF was added dropwise with cooling. The reaction mixture was stirred for 1 hour, and then poured into ice water. The mixture was extracted with dichloromethane. After the extract was dried over anhydrous magnesium sulfate, dichloromethane was distilled off. The residue was recrystallized from methanol to obtain 0.78 g of the title compound. This compound is No. 1 in Table 1. m.p.: 150-154° C.
Reaction SMILES: [OH:1][CH:2]([CH2:30][OH:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]#[C:16][CH2:17][CH2:18][NH:19]C(=O)OCC1C=CC=CC=1)[CH:9]=[CH:8]2>CO.[Pd]>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:30][OH:31])[CH:14]=[CH:13]2
Reactant: O=C(NCCC#Cc1ccc2cc(OCC(O)CO)ccc2c1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccc2cc(OCC(O)CO)ccc2c1
Reaction time: 1 h
Yield: 85 %

Procedure:
A suspension of benzyl 4-[6-(2,3-dihydroxypropoxy)naphthalen-2-yl]but-3-ynylcarbamate (31, 236 mg, 0.5 mmole) and 10% Pd/C (96 mg) in MeOH (70 mL) was subjected to hydrogenation conditions (1 atm) for 1 h at room temperature. The reaction mixture was filtered through a plug of diatomaceous earth and the plug was washed with MeOH. The filtrate was then concentrated in vacuo to afford diol 32 (123 mg, 78%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=8.4 Hz, 2H), 7.56 (s, 1H), 7.30 (dd, J=8.4, 1.5 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.14 (dd, J=8.7, 2.4 Hz, 1H), 4.18-3.99 (m, 3H), 3.76-3.65 (m, 2H), 2.75 (dt, J=10.8, 7.2 Hz, 4H), 1.80-1.70 (m, 2H), 1.62-1.52 (m, 2H).