Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=O)=[CH:18][CH:17]=2)=[C:12]([O:26][CH3:27])[CH:11]=1)(C(C)(C)C)(C)C.[Li+].[OH-].[N+:30]([C:33]1[CH:34]=[C:35]([S:49]([NH2:52])(=[O:51])=[O:50])[CH:36]=[CH:37][C:38]=1[NH:39][CH2:40][CH2:41][S:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O-:32])=[O:31].CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:52][S:49]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][CH2:40][CH2:41][S:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=3)(=[O:50])=[O:51])=[O:24])=[CH:20][CH:21]=2)=[C:12]([O:26][CH3:27])[CH:11]=1
Reactant: NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CO)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCCSc3ccccc3)c([N+](=O)[O-])c2)cc1
Reaction time: 3 h

Procedure:
A mixture of Example 438A (0.50 mmol) and 1M LiOH (0.60 mL) in THF (2 mL) was heated to 50° C., stirred for 3 hours, concentrated, dissolved in DMF (5 mL), and treated with a mixture of Example 77B (211 mg, 0.60 mmol), EDCI (193 mg, 1.0 mmol), and DMAP (50 mg). The mixture was stirred for 16 hours, treated with 1M HF (3 mL), stirred for 3 hours, diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl (10 mL), water (20 mL), and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50-100% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 592 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.79 (t, 1H), 8.62 (d, 1H), 7.92 (dd, 1H), 7.89 (d, 2H), 7.54 (d, 2H), 7.37 (m, 2H), 7.28 (r, 3H), 7.18 (tt, 1H), 7.06 (s, 1H), 6.97 (d, 1H), 4.54 (s, 2H), 3.76 (s, 3H), 3.66 (q, 2H), 3.20 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:5]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:4][C:3]=1N.COCCOCCOCCOC1C=C([N+:48]([O-])=O)C([N+]([O-])=O)=CC=1OCCOCCOCCOC.O.NN.C(Cl)Cl.CO>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:7]=1[NH2:48]
Reactant: COCCOCCOCCOc1cc(N)c(N)cc1OCCOCCOCCOC
Reactant: COCCOCCOCCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OCCOCCOCCOC
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COCCOCCOCCOc1ccc(N)c(N)c1OCCOCCOCCOC
Yield: 89 %

Procedure:
Synthesis of 1,2-diamino-4,5-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzene, IF, FIG. 1B. In an oven dried 500 mL round bottom flask, equipped with a Claisen adapter, pressure equalizing dropping funnel, and reflux condenser, 1,2-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4,5-dinitrobenzene 1E (20 g, 0.04 mol) was dissolved in absolute ethanol (200 mL). To this clear solution, 10% palladium on carbon (4 g) was added and the dark black suspension was heated to reflux under an argon atmosphere. Hydrazine hydrate (20 mL) in EtOH (20 mL) was added dropwise over 10 min to avoid bumping. The resulting brown suspension was heated at reflux for 1.5 h at which time the reaction mixture was colorless and TLC analysis (95/5; CH2Cl2 /MeOH) displayed a low RfUV active spot corresponding to the diamine. Therefore, the mixture was hot filtered through Celite and the pad rinsed with absolute ethanol (50 mL). The solvent was removed under reduced pressure and the resulting light brown oil was dried in vacuo (in the dark) for 24 h to yield 15.55 g (89%) of 1,2-diamino-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzene 1F. For 1F:FAB MS, M+ : m/e 432; HRMS, M+ : 432.2471 (calcd. for C20H36N2O8, 432.2482). This material was taken to the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:46]([C:48]1[N:53]2[N:54]=[CH:55][N:56]=[C:52]2[CH:51]=[CH:50][N:49]=1)[NH2:47].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11](=[O:13])[NH:47][NH:46][C:48]1[N:53]2[N:54]=[CH:55][N:56]=[C:52]2[CH:51]=[CH:50][N:49]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NNc1nccc2ncnn12
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2ncnn12)Cc1cc(F)c(F)cc1F
Reaction time: 0.25 h

Procedure:
A solution of 133 mg (0.4 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3), 84.5 mg (0.44 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 71 mg (0.5 mmol based on 95% purity) of 1-hydroxybenzotriazole (HOBT) in 1.5 mL of anhydrous DMF was stirred at room temperature in a stoppered flask. After 15 min, this solution was added dropwise by syringe through a septum to a stirred suspension of 72.1 mg (0.48 mmol) of 5-hydrazino[1,2,4]triazolo[1,5-c]pyrimidine (Intermediate 20) 0.209 mL (155 mg, 1.2 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF. Stirring under nitrogen was continued for 17 h. The mixture was then filtered and concentrated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The organic phase was washed with more 5% citric acid, then with water, and finally with saturated aqueous sodium carbonate solution. The organic solution was dried over magnesium sulfate, filtered and concentrated to yield the title compound as an off-white solid, mp 207.5-209.5° C. LC-MS 488 (M+Na), 366 (M+1-Boc).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][N+:24]([O-])=O)=[CH:18][CH:17]=1>C(N)CCC>[CH2:9]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[CH:23]1)[CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCCCN
Product: CCCCn1cc(-c2ccc(C)cc2)c2c1CCNC2
Yield: 77.6 %

Procedure:
The title compound (292.8 mg) was prepared from 0.56 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 260 μL of butylamine, and 0.45 g of 1-methyl-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C18H24N2, 268.19; found, m/z 269.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.20-7.14 (m, 4H), 6.93 (s, 1H), 4.32 (s, 2H), 3.88 (t, J=7.1 Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 3.00 (t, J=6.0 Hz, 2H), 2.32 (s, 3H), 1.77-1.70 (m, 2H), 1.41-1.33 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N=Nc2ccc(OCCCC(=O)O)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
6.30 g (0.019 mol) of ethyl 4-[4-(4-cyanophenylazo)phenoxy]-butyrate was dissolved in a mixture of 150 mL of dimethylformamide and 40 mL of water in a 500 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 3.8 g (0.095 mol) of NaOH was added through the condenser. Stirring and heating were continued for 1 h after which the reaction mixture was left for cooling to room temperature. The reaction mixture was then poured onto 200 of ice and acidified with 8N HCl until pH 2. The precipitated crude product was recovered by filtration. The precipitate was washed with 100 mL of hot ethanol and left overnight. After filtration and vacuum drying at 50° C. for 22 h. 5.49 g (yield 93%) of 4-[4-(4-cyanophenylazo)phenoxy]-butanoic acid was obtained
Reaction SMILES: [N+:1]([C:4]1[N:18]=[C:7]2[O:8][CH2:9][CH2:10][CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:6]2[N:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[C:12]1([CH:11]2[CH2:10][CH2:9][O:8][C:7]3=[N:18][C:4]([NH2:1])=[N:5][N:6]23)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1nc2n(n1)C(c1ccccc1)CCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1nc2n(n1)C(c1ccccc1)CCO2

Procedure:
To a solution of 2-nitro-7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazine (174 mg, 707 μmol) in ethyl acetate (7 mL) was added 10% Pd on carbon (17.4 mg, 164 μmol). The reaction was hydrogenated at room temperature under an atmosphere of hydrogen over night. The catalyst was filtered off and washed with ethyl acetate. The title compound was obtained as a white solid (143.3 mg, 94%) after stirring with diethyl ether.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[C:10]([O-:12])=[O:11])=O)(C)(C)C>Cl>[NH2:8][C@H:9]([C@@H:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CC(C)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: Cl
Product: CC(C)[C@H](O)[C@@H](N)C(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 283.1 %

Procedure:
In a 35 ml microwave vial, the diastereomeric mixture containing ethyl (2R*,3R*)- and (2R*,3S*)-2-(tert-butoxy-carbonylamino)-3-hydroxy-4-methyl-pentanoate (0.1 g, 0.36 mmol) was dissolved in a 6.0 M HCl solution (15 mL) and stirred at 130° C. for 1 h. The reaction mixture was extracted with Et2O (3×10 ml), and the aqueous phase concentrated under reduced pressure giving a white crude solid (0.15 g). The resulting diastereoisomeric mixture (anti:syn=8:2) was used without further purification in the following step. MS (ESI) m/z: 148 [M−H]+; (ESI) m/z: 146 [M−H]−. 1H NMR (DMSO-d6) δ 0.91 (dd, J=6.56, 10.18 Hz, 6H), 1.92 (p, J=7.10 Hz, 1H), 3.42 (d, J=8.47 Hz, 1H), 3.79-3.99 (m, 1H), 5.71 (s, 1H), 7.69-8.64 (m, 3H), 13.54 (s, 1H) (reported data refer to the major anti diastereoisomer) [see also Tetrahedron 2001, 57, 8267-8276].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1>>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 1-bromo-4-nitrobenzene (404 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 340 mg (90% isolated yield) of the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:19]Br>CC(O)=O>[Br:19][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:18]
Reactant: BrBr
Reactant: O=C(CCc1ccc(Cl)cc1)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: O=C(c1cccc(Cl)c1)C(Br)Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-(4-chlorophenyl)propan-1-one (1.39 g, 5 mmol) in HOAc (15 mL) at 0° C. was added Br2 (800 mg, 5 mmol) dropwise. The reaction was refluxed for 8 h, cooled to RT, concentrated then diluted with EA (25 mL) and water (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to give a residue which was purified by chromatography eluted with PE/EA (50:1) to give 2-bromo-1-(3-chlorophenyl)-3-(4-chlorophenyl)propan-1-one (358 mg, 20% yield) as a brown solid. LCMS: MH+ 359 and TR=2.029 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]2[O:15][CH:3]12)=[N:10][O:11][N:12]=3.CCO.[NH3:20]>>[CH3:1][C:2]1([CH3:16])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:20])[CH:3]1[OH:15])=[N:10][O:11][N:12]=3
Reactant: N
Reactant: CC1(C)Oc2cc3nonc3cc2C2OC21
Solvent: CCO
Product: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Yield: 87 %

Procedure:
0.82 g of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole (3.8 m mols) dissolved in 25 ml of 16.7% NH3 --EtOH solution was reacted in a pressure glass tube at 60° C. for 48 hours. The reaction solution was distilled off and the residue was subjected to a silica gel column chromatography using a developing solvent of ethyl acetate-methanol (5:1 (v/v)) to obtain 0.77 g (yield: 87%) of the intended compound as a brown solid. A part of the obtained compound was recrystallized from ethanol to obtain pure intended compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:30][CH:31]=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:30]/[CH:31]=[O:32])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C/C=C/c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
Solution of 6-bromo-2-carboxypyridine (3 g, 16.1 mmol) was dissolved in dichloromethane (100 mL). (Triphenylphosphoranylidene) acetaldehyde (4.9 g, 16.1 mmol) was added and obtained mixture was stirred at room temperature for 5 hrs. Dichloromethane was partially evaporated (to the volume about 50 mL) and reaction mixture was applied on chromatography column (SilicaGel 60) Products were eluted with dichloromethane. Fractions containing product were combined and evaporated to give 2.3 g of white powder (Yield 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A mixture of 4-nitro-1H-indazole (200 g, 1.22 moles) and 10% palladium on carbon (20.0 g,) in EtOH (3000 ml) was hydrogenated at ambient temperature (reaction was exothermic and temperature increased to 50° C.). After completion of reaction, the catalyst was removed by filtration. The solvent was evaporated under vacuum at below 80° C. and cooled to room temperature and n-hexane (1000 ml) was added to the residue and stirred for 30 min. Isolated solid was filtered and washed with n-hexane (200 ml). Product was dried under vacuum at 70-80° C. for 10-12 h to give 4-amino-1H-indazole as a brown solid (114 g, 70%), m. p.: 136-143° C. 1H NMR (200 MHz, CDCl3) δ 12 (br, 1H), 8.0 (s, 1H), 7.1-7.0 (dd, 2H), 6.5 (d, 1H), 3.9 (m, 2H). ESMS m/z 134 (M+1). Purity: 90-95% (HPLC)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Sn]([N:26]=[N+:27]=[N-:28])(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:26]=[N:27][NH:28][N:21]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nn[nH]n3)cc2)CC1
Temperature: 110 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
The intermediate 1A (6.0 g; 20.8 mmol) in solution in xylene (76 ml), under nitrogen, is treated with trimethyltin azide (6.25 g; 31.3 mmol). After stirring for 24 h at 110° C., the reaction medium is brought to room temperature and the precipitate formed is filtered on sintered glass and then washed with toluene and with petroleum ether. This solid is purified by chromatography on a silica gel column eluted with a dichloromethane/methanol/ammonium hydroxide mixture in the proportions 80/19/1 to give compound 1B (5.75 g; 87%) in the form of a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:18])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8].N1C=CN=C1.[H][H]>[Pd]>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:5]2[C:6]([CH:7]=[O:8])=[CH:2][N:3]=[C:4]2[CH3:18])=[CH:11][CH:12]=1)#[N:17]
Reactant: Cc1nc(Br)c(C=O)n1Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: c1c[nH]cn1
Product: Cc1ncc(C=O)n1Cc1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
A solution of 4-bromo-1-(4-cyanobenzyl)-2-methylimidazole-5-carboxaldehyde (1.33 g, 4.37 mmol) and imidazole (0.600 g, 8.74 mmol) in 1:1 ethyl acetate-alcohol (150 mL) was stirred with 10% palladium on carbon (0.020 g) under 1 atm hydrogen. After 2 h, the reaction was filtered through celite and concentrated to give the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.62 (1H, s), 7.90 (1H, s), 7.81 (2H, d, J=8 Hz), 7.20 (2H, d, J=8 Hz), 5.64 (2H, s), 2.33 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[CH:3][CH:2]=1.[NH3:17]>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:17])=[O:12])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(Nc2ccncc2)c1
Reactant: N
Product: NC(=O)c1cccc(Nc2ccncc2)c1
Yield: 50 %

Procedure:
3-(4-Pyridinylamino)benzamide was prepared from 3-(4-pyridinylamino)benzoic acid and ammonia according to the procedure of Example 48, part (b), and was obtained in 50% yield as a colorless powder, m.p. 201°-203° C. when recrystallized from methanol.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C[O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:38][C@@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[C:27]([OH:26])=[O:39])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid was coupled to (S)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.98 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 585.87; m/z found, 583/585 [M−H]−. H NMR (500 MHz, CDCl3): 11.35 (s, 1H), 8.36 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.8, 1H), 7.74-7.69 (m, 1H), 7.34 (d, J=8.2, 1H), 7.21 (d, J=2.0, 1H), 7.15 (d, J=8.4, 1H), 6.97 (dd, J=8.2, 2.0, 1H), 6.93 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=7.0, 1H), 4.95-5.00 (m, 1H), 3.32-3.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH:6]([C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:16]=[C:15]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=1)[CH3:2]>CCO>[CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH:6]([C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:16]=[C:15]([NH:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCc1cc(NC(=O)C(C)(C)C)nc(NC(=O)C(C)(C)C)n1)c1cnc2ccccc2c1
Solvent: CCO
Product: CCOC(=O)CC(CCCCCCc1cc(NC(=O)C(C)(C)C)nc(NC(=O)C(C)(C)C)n1)c1cnc2ccccc2c1
Reaction time: 3 h

Procedure:
The alkene 7-7 (1.02 g, 1.74 mmol) was dissolved in EtOH (50 mL) and degassed with argon. Palladium on carbon (10%; 100 mg) was added and the mixture stirred under an atmosphere of hydrogen gas (balloon) for 3 hours. The mixture was filtered through celite and the solvent removed to give the title compound 7-8 which was used as such in the next step.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([C:9]1[S:13][C:12]([NH:14][N:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][NH:2][C:3](=[O:4])[N:14]([C:12]1[S:13][C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])=[N:10][N:11]=1)[N:15]=[CH:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)c1nnc(NN=Cc2ccccc2)s1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)N(N=Cc1ccccc1)c1nnc(C(C)(C)C)s1
Reaction time: 2 h
Yield: 22.1 %

Procedure:
Methyl isocyanate (1.88 g) was added to a stirred suspension of benzaldehyde 5-t-butyl-1,3,4-thiadiazolyl hydrazone (7.8 g) in ethyl acetate (60 ml). Triethylamine (3 drops) was then added and the mixture was stirred for 2 hours. The solvent was evaporated to give a white solid, purified by chromatography. The pure fractions were combined and recrystallised from a mixture of ethyl acetate and hexane to give benzaldehyde 4-methyl-2-(5-t-butyl-1,3,4-thiadiazol-2-yl)semicarbazone (2.1 g, 22%) as a white powder, mp 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.N1C2C(=CC=CC=2)CCC1.[CH3:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH2:34][CH2:33][CH2:32]2>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[C:7]([C:8]([N:35]2[C:36]3[C:31](=[CH:30][C:29]([CH3:28])=[CH:38][CH:37]=3)[CH2:32][CH2:33][CH2:34]2)=[O:10])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C(O)c1cccnc1Oc1cccc(Cl)c1
Reactant: Cc1ccc2c(c1)CCCN2
Agent: c1ccc2c(c1)CCCN2
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 1, Step 2, replacing 2-(3-trifluoromethyl-phenoxy)-nicotinic acid with 2-(3-chloro-phenoxy)-nicotinic acid (Example 3, Step 1) and 1,2,3,4-tetrahydro-quinoline with 6-methyl-1,2,3,4-tetrahydro-quinoline ([CAS RN 91-61-2]). MS (ISP): 379.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C@H:3]([CH3:6])[CH2:4][OH:5].N1C=CN=C1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>CN(C)C=O>[Br:1][CH2:2][C@H:3]([CH3:6])[CH2:4][O:5][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CO)CBr
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an N,N-dimethylformamide solution (50.0 ml) of (2R)-3-bromo-2-methyl-1-propanol (7.63 g) were added under ice cooling imidazole (7.13 g) and tert-butylchlorodiphenylsilane (14.8 ml), followed by stirring at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford {[(2R)-3-bromo-2-methylpropyl]oxy}(tert-butyl)diphenylsilane (19.2 g).