Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14]([C:18]([NH:20][C:21]4[CH:28]=[CH:27][C:24]([CH2:25][Cl:26])=[CH:23][CH:22]=4)=[O:19])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[Cl-:26].[CH3:29][N+:30]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([NH:20][C:18]([N:14]3[CH2:13][CH2:12][C:11]4[C:16](=[CH:17][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[CH:9][CH:10]=4)[CH2:15]3)=[O:19])=[CH:22][CH:23]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CN1CCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)CN(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)CN(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CC3)cc1
Product: [Cl-]

Procedure:
A solution of 4-(7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-ylcarbonylamino)benzyl chloride (0.2 g) and 1-methyl piperidine (0.19 ml) in dimethylformamide (5 ml) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent and was mixed with ethyl acetate, and the precipitate was collected by filtration. The precipitate was recrystallized from ethanol to obtain 1-methyl-1-(4-((7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonylamino)benzyl)piperidinium chloride (compound 29) (0.23 g) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[N:13][C:14]([C@@H:24]([NH2:26])[CH3:25])=[C:15]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=3)[CH:16]=2)[CH:11]=[CH:10]1.[Cl:27][C:28]1[N:33]=[C:32](Cl)[C:31]([C:35]#[N:36])=[CH:30][N:29]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:27][C:28]1[N:33]=[C:32]([NH:26][C@H:24]([C:14]2[N:13]=[C:12]3[CH:11]=[CH:10][N:9]([CH3:8])[C:17]3=[CH:16][C:15]=2[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=2)[CH3:25])[C:31]([C:35]#[N:36])=[CH:30][N:29]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C[C@H](Nc1nc(Cl)ncc1C#N)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 28.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine 2,2,2-trifluoroacetate (100 mg, 0.271 mmol), 2,4-dichloropyrimidine-5-carbonitrile (70.7 mg, 0.406 mmol) and N-ethyl-N-isopropylpropan-2-amine (146 μL, 0.812 mmol) were combined in acetonitrile (1725 μL), and the resulting mixture was heated to 120° C. in a microwave reactor for 1 hour. The mixture was concentrated and purified on a silica gel column, eluting with EtOAc. The fractions were collected and concentrated in vacuo to give the title compound as a yellow solid (30 mg, 28%). ESI-MS m/z [M+H]+ calc'd for C19H17ClN8, 393.13; found 393.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:12]>CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:12])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)cc1
Solvent: CCOCC
Product: COc1ccc(CBr)cc1

Procedure:
A solution of 4-methoxybenzyl alcohol (6.2 ml, 50 mmol) in dry ether (120 ml) was treated dropwise with phosphorus tribromide (2.07 ml, 22 mmol), refluxed for 1 hour, cooled, washed twice with water, dried and the solvent evaporated. The 4-methoxybenzyl bromide thus produced was added to a mixture of 4-bromo-1,2-dihydro-3,6-pyridazinedione (for a preparation, see B. Kasnar et al, Nucleosides & Nucleotides (1994), 13(1-3), 459-79 or Example 30(a)) (4 g, 21 mmol) and potassium carbonate (8.28 g, 60 mmol) in dry DMF (60 ml) and stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed 3 times with water, dried over magnesium sulfate and evaporated to low volume. Some solid was filtered off and washed with ethyl acetate. The filtrate was evaporated to dryness and the residue chromatographed on silica gel, eluting with 20% ethyl acetate/hexane and then 100% ethyl acetate. This gave the less polar of the 2 desired products (3.233 g), the more polar of the 2 desired products (1.626 g) and a mixture of these (1.351 g). Total yield 6.30 g, 70%.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[C:20](/[CH3:25])=[CH:21]\[C:22]([OH:24])=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOC[CH2:27]1>[Ni]>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:20]([CH3:25])[CH2:21][C:22]([O:24][CH3:27])=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C/C(=C/C(=O)O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reactant: C1COCCO1
Agent: [Ni]
Product: COC(=O)CC(C)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reaction time: 8 h

Procedure:
3.2 g (8.95 mmol) of 3-(2-benzenesulphonamido-indan-5-yl)-crotonic acid in 50 ml of dioxan are hydrogenated in the presence of Raney nickel at room temperature under a hydrogen pressure of 3.5 bar. The mixture is filtered, the filtrate is evaporated, the residue is dissolved in 20 ml of methanol, and 1.5 ml of thionyl chloride are added dropwise at -50° C. The mixture is allowed to stand overnight at room temperature and is evaporated again, and the residue is chromatographed over silica gel using ethylene chloride. The fractions having an Rf-value of 0.6 are combined and evaporated. This gives a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH:34]4[CH2:36][CH2:35]4)(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH:34]4[CH2:35][CH2:36]4)(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(=O)(=O)C3CC3)CC2)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(=O)(=O)C4CC4)CC3)n[nH]c12
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
A 10 ml round-bottomed flask equipped with a magnetic stirrer is charged with 57 mg of 5-(2,6-difluorophenyl)-3-{[1-(cyclopropylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 5 ml of DCM. After cooling to 0° C. using an ice bath, 0.3 ml of TFA is added and the mixture is stirred at RT for 3 h. It is concentrated under RP and the solid obtained is taken up in 20 ml of water and extracted with three times 20 ml of AcOEt, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of cyclohexane and AcOEt (80/20 by vol.), to give 16 mg of 5-(2,6-difluorophenyl)-3-{[1-(cyclopropylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89-1.04 (m, 4 H) 1.67 (m, 2 H) 2.10 (m, 2 H) 2.58 (m, 1 H) 3.00 (m, 2 H) 3.62 (m, 2 H) 3.82 (m, 1 H) 6.21 (d, J=7.8 Hz, 1 H) 7.34 (t, J=7.8 Hz, 2 H) 7.70 (m, 1 H), 8.19 (broad s, 1 H) 8.27 (dd, J=8.5, 1.5 Hz, 1 H) 8.56 (d, J=8.5 Hz, 1 H) 13.07 (s, 1 H) LC-MS-DAD-ELSD: 509 (+)=(M+H)(+).
Reaction SMILES: Br[CH:2]([C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(C)C.[NH2:22][C:23]([NH2:25])=[S:24]>>[NH2:25][C:23]1[S:24][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:22]=1
Reactant: CCOC(=O)C(Br)C(=O)Cc1ccc(Cl)cc1
Reactant: NC(N)=S
Solvent: CC(C)O
Product: CCOC(=O)c1sc(N)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
In a 100 mL round bottomed flask, to a solution of ethyl 2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (990 mg, 3.1 mmol) in isopropyl alcohol (20 mL, 300 mmol) was added thiourea (590 mg, 7.8 mmol) and the resulting mixture was stirred at reflux for 16 hours. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was suspended in EtOAc (50 mL) and then washed with a saturated aqueous solution of NaHCO3 (50 mL), brine (50 mL). The resulting organic layer was dried over anhydrous MgSO4, filtered, and concentrated to afford ethyl 2-amino-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (900 mg, yield >99%) as a yellowish solid that was used without further purification. LC/MS (FA) ES+ 297, 299.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:47][CH2:48][CH3:49])[N:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[C:19](=[O:31])[C:20]=1[C:21]1[CH:22]=[N:23][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:47][CH2:48][CH3:49])[N:18]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:3][C:4](=[O:7])[O:5][N:46]=3)=[CH:37][CH:38]=2)[C:19](=[O:31])[C:20]=1[C:21]1[CH:22]=[N:23][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)c(-c2ccc(OC(C)C)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)nc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogen carbonate (0.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(6-isopropoxypyridin-3-yl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.57 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.48 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.CC#N>[CH2:31]([NH:38][C:39]([NH:30][C:29]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[N:13][C:12]=2[N:28]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CO
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)NCc4ccccc4)nc3n2)CC1
Yield: 63.4 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.08 g) from Example 36 was reacted with 0.298 g of benzyl isocyanate according to the general procedure of Example 37 to give 0.822 g of 1-benzyl-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=579; mp 144°-148.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][Br:32])=[CH:29][CH:30]=3)[CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Reactant: BrCCCCCCCCCCBr
Product: BrCCCCCCCCCCOc1ccc(C2c3ccc(OCc4ccccc4)cc3OCC2c2ccccc2)cc1

Procedure:
From (+,-) cis 7-Benzyloxy-4-(4-hydroxy-phenyl)-3-phenyl-chroman (2 g, 4.9 mmol) and 1,10-Dibromodecane (7.4 g, 24.5 mmol). The product was purified by flash chromatography using petrol ether-ethyl acetate-toluene-methylene chloride 10+0.5+0.5+0.1 as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](Cl)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]([Cl:22])([Cl:21])[C:14]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)=[O:15].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:22][C:13]([Cl:12])([Cl:21])[C:14]([C:16]1[NH:17][CH:18]=[C:19]([C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:20]=1)=[O:15]
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1cccc(Cl)c1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h

Procedure:
In a dry flask, 3-chlorophenylacetyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided the title compound 1. HPLC Method A, Rt=15 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[CH3:23][C:24]1[CH:29]=[C:28]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)[CH:27]=[CH:26][C:25]=1[C:36]1[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=1>>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[C:10]([NH:12][C:42]([C:39]2[CH:38]=[CH:37][C:36]([C:25]3[CH:26]=[CH:27][C:28]([C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:29][C:24]=3[CH3:23])=[CH:41][CH:40]=2)=[O:43])[CH:9]=[CH:8][C:7]=1[O:13][CH3:14])[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: COc1ccc(N)cc1N(CCN(C)C)C(=O)OC(C)(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1N(CCN(C)C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from N,N-dimethyl-N'-t-butyloxycarbonyl-N'-(5-amino-2-methoxyphenyl)ethylenediamine (D21, 0.37 g, 0.0012 mole) and 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carboxylic acid (EP 0533268 A1) (0.34 g, 0.0012 mol) using the method of Example 1 (0.40 g, 57%)
Reaction SMILES: C(Cl)CCl.C(N(CC)CC)C.[C:12]1([CH2:22][OH:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[C:24]([NH:31][C@H:32]([C:40](O)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C1C=CN=CC=1)C.ClCCl>[C:12]1([CH2:22][O:23][C:40](=[O:41])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1cccc2ccccc12
Reaction time: 8 h

Procedure:
1192 mg (6.2 mmol) of EDC, 578 μl (4.1 mmol) of triethylamine, 345 mg (2.8 mmol) of DMAP, and 328 mg (2.1 mmol) of 1-naphthylmethanol were added at RT to a solution of 500 mg (1.89 mmol) of N-Boc-L-phenylalanine in 25 ml dichlormethane. The reaction composition was stirred overnight, then diluted with 50 ml Dichlormethane and successively washed in a solution of 10% of aqueous citric acid, water, and saturated saline. The organic phase was dried over magnesium sulphate and then evaporated, and the residue purified with preparative HPLC. The yield was 501 mg (66% o. th.) of the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4](Cl)=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2.C(N(CCCC)CCCC)CCC.[H][H]>[Pd].C(O)CC>[CH:2]1[S:3][CH:4]=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2
Reactant: [H][H]
Reactant: O=c1[nH]c2c(Cl)sc(Cl)c2c(=O)c2cscc12
Agent: [Pd]
Solvent: CCCO
Solvent: CCCCN(CCCC)CCCC
Product: O=c1[nH]c2cscc2c(=O)c2cscc12
Yield: 75.2 %

Procedure:
A mixture of 5.0 g (0.0164 mole) of 1,3-dichloro-4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione, 4 g of 5% strength Pd/C, 6.3 g (0.034 mole) of tributylamine and 300 ml of propanol was stirred in a hydrogen atmosphere at 80° C. When absorption of hydrogen was complete (after 5 hours), the hot mixture was filtered and the filtrate was poured onto ice water. The resulting suspension was acidified with concentrated hydrochloric acid, and the mixture was then stirred for a short time and filtered under suction. The residue from filtration of the crude reaction mixture was washed several times with hot dimethylformamide. The dimethylformamide used for washing was poured onto ice water, and the precipitate formed was filtered off under suction. The solid thus obtained was combined with the solid product obtained from the propanol filtrate. The total solid product was washed with water and then dried at 50° C. in a drying oven under reduced pressure. 2.9 g (75%) of 4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione were obtained in the form of beige crystals of melting point 268°-271° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.CN(C1NC=NN=1)C.CN1CCOCC1.CN(C(O[N:56]1[N:64]=[N:63][C:58]2C=[CH:60][CH:61]=[N:62][C:57]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:63][CH2:58][C:57]1[NH:62][C:61]([CH3:60])=[N:64][N:56]=1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1nnc[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)[nH]1
Reaction time: 1 h
Yield: 52.2 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), methyl-4H-1,2,4 triazole-3-yl-methylamine hydrogen chloride (7.80 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12.6 mg, 0.024 mmol, 51.2% yield): LCMS=526.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (2 H, d, J=8.28 Hz), 7.49-7.76 (8 H, m), 5.18 (1 H, s), 4.35-4.61 (2 H, m), 4.26 (1 H, s), 2.41 (3 H, br. s.); HPLC peak RT=2.3 min (Method E).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:6]([CH:7]=O)=[C:5]([OH:13])[CH:4]=1.[C:14]([NH:18][OH:19])([CH3:17])([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:6]([CH:7]=[N+:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[O-:19])=[C:5]([OH:13])[CH:4]=1
Reactant: COc1cc(O)c(C=O)c(OC)c1
Reactant: CC(C)(C)NO
Product: COc1cc(O)c(C=[N+]([O-])C(C)(C)C)c(OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 4,6-dimethoxy-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 60.7% yield as a yellow crystalline solid, m.p. 97.3° C. (Rf=0.38 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:36]([I:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C.O>[Cl:39][C:38]1[C:30]2[N:29]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:32](=[O:33])[C:31]=2[CH:35]=[C:36]([I:40])[CH:37]=1
Reactant: Nc1c(Cl)cc(I)cc1C(=O)O
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc(I)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methanesulfonyl chloride (0.31 mL, 4.07 mmol) in acetonitrile (10 mL) was added dropwise a mixture of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 3, Step D) (1.0 g, 3.87 mmol) and triethylamine (0.54 mL, 3.87 mmol) in acetonitrile (5 mL) at 0° C. The reaction mixture was then stirred for 15 minutes at 0° C. Then, 2-amino-3-chloro-5-iodobenzoic acid (i.e. the product from Step A) (1.15 g, 3.87 mmol) was added, and stirring was continued for an additional 5 minutes. A solution of triethylamine (1.08 mL, 7.74 mmol) in acetonitrile (5 mL) was then added dropwise while keeping the temperature below 5° C. The reaction mixture was stirred 40 minutes at 0° C., and then methanesulfonyl chloride (0.31 mL, 4.07 mmol) was added. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were washed successively with 10% aqueous sodium bicarbonate (1×20 mL) and brine (1×20 mL), dried (MgSO4) and concentrated under reduced pressure. The residual solid was purified by chromatography on silica gel to afford 575 mg of the title compound as a crude yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:28])[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][Br:27])=[CH:22][CH:21]=1)[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:13]([OH:28])=[O:12])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(CBr)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.635 ml (2.420 g, 21.228 mmol) of trifluoroacetic acid were added to a solution of 500 mg (1.415 mmol) of tert-butyl[4-(bromomethyl)phenyl](cyclopentyl)acetate (Example 10A) in 5 ml of dichloromethane. The mixture was stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate solution was then added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gave 364 mg (87% of theory) of the title compound.