Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[Cl:12])=[O:3].[N+:13]([O-])([OH:15])=[O:14]>>[CH3:1][C:2]([NH:4][C:5]1[C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[Cl:12])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(Cl)c1Cl
Product: CC(=O)Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nitric acid (30 ml) is cooled to -5°, and N-methylcarbonyl 2,3-dichloroaniline (9.8 g, 48 mmol) is added to the acid in small portions, with the temperature maintained at -5° or lower. After the addition is complete, the reaction is stirred for 1 hour at +5°. The reaction is then added dropwise to about 150 g of ice-water mixture. The resulting solid is collected by filtration and purified by prep. TLC (developing with 30% ethyl acetate/hexane). The least polar component is isolated to give N-methylcarbonyl 2,3-dichloro-6-nitroaniline.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[N:20]1[C:25](=[O:26])[CH2:24][O:23][C:22]2[CH:27]=[C:28]([S:31]([N:34](CC3C=CC(OC)=CC=3)[C:35]3[S:36][CH:37]=[CH:38][N:39]=3)(=[O:33])=[O:32])[CH:29]=[CH:30][C:21]1=2>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[N:20]1[C:25](=[O:26])[CH2:24][O:23][C:22]2[CH:27]=[C:28]([S:31]([NH:34][C:35]3[S:36][CH:37]=[CH:38][N:39]=3)(=[O:32])=[O:33])[CH:29]=[CH:30][C:21]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(=O)N3c2ccc(C(F)(F)F)cc2OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc(S(=O)(=O)Nc3nccs3)ccc21
Yield: 83 %

Procedure:
In a 25-mL round bottom flask was dissolved 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide in 4 mL of DCM then treated with TFA (2.384 mL, 30.9 mmol). After 30 min the reaction mixture was concentrated under reduced pressure and purified by MPLC (ISCO) with DCM:MeOH 100:0 to 90:10 to afforded 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H benzo[b][1,4]oxazine-7-sulfonamide (250 mg, 0.515 mmol, 83.0% yield from INTERMEDIate AB2) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.81 (s, 3 H) 4.91 (s, 2 H) 6.41 (d, J=8.41 Hz, 1 H) 6.83 (d, J=4.60 Hz, 1 H) 7.26 (d, J=4.60 Hz, 1 H) 7.34 (dd, J=8.36, 2.01 Hz, 1 H) 7.38 (d, J=1.96 Hz, 1 H) 7.51 (d, J=8.12 Hz, 1 H) 7.55-7.65 (m, 2 H) 12.75 (br. s., 1 H). m/z (ESI) 486.0 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([CH3:37])([CH3:36])[C:21]([NH:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=O)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C:20]([C:21]1[S:47][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=2)=[CH:24][N:23]=1)([CH3:37])[CH3:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCC(=O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc([N+](=O)[O-])c2)s1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
To a solution of the product of Step 1 (680 mg, 1.31 mmol) in toluene (6.5 mL) was added Lawesson's reagent (530 mg, 1.31 mmol) and the mixture was heated to 100° C. for 20 hours and then cooled to rt then the mixture was concentrated in vacuo. Purification by chromatography on silica gel (100:0 to 50:50, hexanes:ethyl acetate) provided 461 mg (0.892 mmol, 68%) of 2-(1-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropan-2-yl)-5-(3-nitrophenyl)-1,3-thiazole as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH:6]2[CH3:15].FC(F)(F)[C:18](O)=[O:19].C1N2CN3CN(C2)CN1C3>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:18]=[O:19])[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH:6]2[CH3:15]
Reactant: COc1ccc2c(c1)C(C)CC(=O)N2C
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(cc1C=O)N(C)C(=O)CC2C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 110 mg (0.54 mmol) 6-methoxy-1,4-dimethyl-3,4-dihydro-1H-quinolin-2-one, 3 ml of trifluoroacetic acid and 90 mg (0.64 mmol) of hexamethylene tetraamine. The mixture was stirred under reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was quenched first with water and then with 30 ml of saturated aqueous bicarbonate solution and extracted with chloroform (3×30 ml). The combined organics were then washed with brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue, 72 mg, was purified by silica gel column chromatography eluting with 4/6 ethyl acetate/hexane to afford 50 mg (40%) of a yellow solid which was used directly in the following step. Mass spectrum APCI m/e 234 (p+1). Enantiomeric separation was completed on a Chiralpak AD column eluting with 9/1 hexane/ethanol(EtOH) containing 1% diethylamine. The retention times were 12 minutes and 13.8 minutes respectively.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[CH2:23]=O.Cl>C(O)=O>[CH3:23][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1
Reactant: C=O
Reactant: C1=Cc2ccccc2C(=CC2CNCCO2)c2ccccc21
Agent: Cl
Solvent: O=CO
Product: CN1CCOC(C=C2c3ccccc3C=Cc3ccccc32)C1
Reaction time: 6.5 h

Procedure:
A mixture of 5-(morpholin-2-yl)methylidene-5H-dibenzo[a,d]cycloheptene (0.35 g), 90% formic acid (0.7 g) and 37% formalin (0.65 ml) was stirred at 95°-100° C. for 6.5 hours. After cooling, 4 N hydrochloric acid was added thereto, and the resulting mixture was evaporated to dryness under reduced pressure, neutralized with ammonia water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-methylmorpholin-2-yl)methylidene-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 237°-238° C. (decomp.) (oxalate).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:29](=S)=[S:30].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=4)[CH2:15][NH:16][C:29]3=[S:30])=[CH:9][CH:8]=2)=[CH:27][CH:28]=1
Reactant: S=C=S
Reactant: NCC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(C2CNC(=S)N2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Temperature: 80 °C
Yield: 68.5 %

Procedure:
To a solution of N1-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine (127 mg, 0.312 mmol) in EtOH (2.0 mL) are added CS2 (188 μL, 3.12 mmol) and iPr2NEt (272 μL, 1.56 mmol). The reaction mixture is heated at 80° C. overnight before removal of the solvent. The residue is purified by silica gel chromatography (0˜40% EtOAc/Hexanes) to provide the title compound (95.9 mg, 69% yield) as a white solid product; HPLC-MS calculated for C22H16ClF3N2OS (M+H+) 449.1, found 449.1.
Reaction SMILES: [C:1](NCCCCC1C2C(=C3C(=CC=2)C=CC=N3)N=CC=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:39]1[C:52]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][N:50]=3)[CH:45]=[C:44]([NH2:53])[C:43]=2[CH:42]=[CH:41][CH:40]=1>>[C:1]([NH:53][C:44]1[CH:45]=[C:46]2[C:51]([N:50]=[CH:49][CH:48]=[CH:47]2)=[C:52]2[C:43]=1[CH:42]=[CH:41][CH:40]=[N:39]2)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Nc1cc2cccnc2c2ncccc12
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCCc1ccnc2c1ccc1cccnc12
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cc2cccnc2c2ncccc12

Procedure:
5-(octadecanoylamino)-1,10-phenanthroline was prepared according to the procedure used in Example 5 to prepare 4-(4-(octadecanoylamino)butyl)-1,10-phenanthroline, with the exception that 1,10-phenanthrolin-5-amine was used in place of 4-(aminobutyl)-1,10-phenanthroline.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:6]1[C:2]([CH3:1])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3](=[O:20])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]1=[O:7]
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 3-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 26 mg of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=O.[C:13](/[CH:15]=[C:16](\[O-:18])/[CH3:17])#[N:14].[Na+]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:11]=[C:15](/[C:16](=[O:18])[CH3:17])\[C:13]#[N:14]
Reactant: O=Cc1cc2cn[nH]c2cc1F
Reactant: C/C([O-])=C/C#N
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1cc2cn[nH]c2cc1F

Procedure:
The title compound was prepared from 3.7 g (80% purity, 18.0 mmol) 6-fluoro-1H-indazole-5-carbaldehyde (Example 5A) and 2.08 g (19.84 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate in analogy to the procedure described in Example 2A yielding 2.5 g (61% of th.) of product which was used in subsequent steps without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:22]([OH:24])=[O:23])[NH:4][C:5]([O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:6].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](O)=[O:31].C1C=NC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C>CN1CCCC1=O>[CH:11]1[C:10]2[CH:9]([CH2:8][O:7][C:5]([NH:4][C@H:3]([C:22]([OH:24])=[O:23])[CH2:2][NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[O:31])=[O:6])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(O)c1cccs1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Product: O=C(N[C@@H](CNC(=O)c1cccs1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 3-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine on Wang resin (2 g), thiophene-2-carboxylic acid (1.41 g, 11.0 mmol), HOAT (1.50 g, 11.0 mmol) and diisopropylcarbodiimide (1.68 mL, 10.7 mmol) in N-methylpyrrolidinone (20 mL) was shaken for 3 h and then washed with dichloromethane and methanol to give N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin. The Fmoc group was cleaved by treatment with 25% piperidine in N-methylpyrrolidinone, followed by shaking for 1 h. The resin was washed with dichloromethane and methanol to give 3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[N:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([NH:30][CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1C1=CCCO1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(C(F)(F)F)cc2)nc(N)nc1C1=CCCO1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-(4,5-dihydro-furan-2-yl)-pyrimidin-4-yl ester and 4-trifluoromethylbenzylamine in DME. ES-MS m/e (%): 362 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1>N1C=CC=CC=1>[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:34][CH:33]=1
Reactant: Fc1ccc(I)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A mixture of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (172 mg, 0.5 mmol), prepared according to the method of Example 10, Cu powder (32 mg), anhydrous K2CO3 (207 mg, 1.5 mmol) and 4-fluoroiodobenzene (0.12 mL, 1 mmol) was prepared in 20 mL of pyridine. The solution was stirred at reflux for 14 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 10% citric acid, water, brine and concentrated in vacuo. Separation by column chromatography (silica gel, CH2Cl2-diethyl ether 15:1) provided 190 mg of crude product. Crystallization from CH2Cl2-diethyl ether-hexanes furnished the title compound (yield: 175 mg, 79.9%). mp 168-169° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 6.98 (t, J=9 Hz, 2H), 7.20 (m, 4H), 7.40 (d, J=9 Hz, 2H), 7.69 (m, 2H), 7.92 (d, J=9 Hz, 2H), 7.98 (s, 1H). MS (DCI/NH3) m/z 439 (M+H)+, 456 (M+NH4)+. Anal. calc. for C23H16F2N2O3S.0.25H2O: C, 62.36; H, 3.75; N, 6.32. Found: C, 62.23; H, 3.55; N, 6.26.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[OH:29][CH:26]1[CH2:27][CH2:28][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:24][CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: OC1CCNCC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC(O)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperidin-4-ol (1.2 equiv) to give 166 (16.4 mg, M+1 397.1)
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([NH:12][C:13]([C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)=[O:14])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N(CC)C(C)C)(C)C.[Cl:31][C:32]1[C:33](F)=[N:34][CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>CS(C)=O>[C:1]1([C:7]2[N:11]=[C:10]([NH:12][C:13]([C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:33]3[C:32]([Cl:31])=[CH:37][C:36]([C:38]([F:41])([F:39])[F:40])=[CH:35][N:34]=3)=[O:14])[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(Nc1nc(-c2ccccc2)ns1)[C@@H]1CCCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(-c2ccccc2)ns1)[C@@H]1CCCCN1c1ncc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a stirred solution of (S)-Piperidine-2-carboxylic acid (3-phenyl-1,2,4-thiadiazol-5-yl)-amide; hydrochloride (70 mg; 0.215 mmol) and N,N-diisopropylethylamine (0.037 mL; 0.215 mmol) in DMSO (1 mL) is added 3-chloro-2-fluoro-5-trifluoromethylpyridine (42.9 mg; 0.215 mmol). The reaction mixture is heated at 100° C. for 4 hours. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 468 [M+H+].
Reaction SMILES: OS(O)(=O)=O.[BrH:6].[NH2:7][C:8]1[C:9]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[C:10]([CH2:13][CH2:14][CH2:15]O)[NH:11][N:12]=1.[OH-].[Na+]>>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:9]1[C:10]([CH2:13][CH2:14][CH2:15][Br:6])=[N:11][NH:12][C:8]=1[NH2:7]
Reactant: Br
Reactant: Nc1n[nH]c(CCCO)c1-c1nc2ccccc2s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of concentrated H2SO4 (3 mL) and hydrobromic acid (6 mL of 48%) was added 3-(5-amino-4-benzothiazol-2-yl-2H-pyrazol-3-yl)-propan-1-ol (810 mg, 3.0 mmol). The resulting mixture was refluxed for 2 hrs. The mixture was cooled to room temperature, poured into ice water, and adjusted to pH 3-4 using 5% NaOH solution. The resulting sticky solid was isolated by filtration, washed with water and air-dried to yield 815 mg (80%) of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine as a cream coloured solid. The crude material was used in the subsequent step without further purification. MS (m/z, ES+): 337.1 (Br79M+1, 61%), 339.1 (Br81M+1, 59%), 257.2 (M-HBr, 100%).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C.O>[Cl:20][C:21]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:31][CH:32]=1)=[O:24]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-(2,4-dichlorobenzoyl)benzyl bromide (3.33 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was recrystallized (ethyl acetate) to provide the title compound as white powder (3.38 g, 76%). 1H-NMR (CDCl3) δ: 3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.25-7.84(8H,m).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1([F:22])[CH2:19][C@H:18]2[CH2:20][C@@H:15]1[CH2:16][C@H:17]2O.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:13][C:14]1([F:22])[CH2:19][C@H:18]2[CH2:20][C@@H:15]1[CH2:16][C@@H:17]2[N:27]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:28]
Reactant: O[C@@H]1C[C@H]2C[C@@H]1CC2(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A solution of diethyl azodicarboxylate (0.56 mL, 3.6 mmol) in anhydrous THF (3.0 mL) was added drop-wise to a mixture of (1R,2R,4R)-5,5-difluorobicyclo[2.2.1]heptan-2-ol (0.44 g, 3.0 mmol), phthalimide (0.50 g, 3.4 mmol), and triphenyl phosphine (0.78 mL, 3.4 mmol) in anhydrous tetrahydrofuran (15.0 mL) at r.t. under nitrogen. After stirring at ambient temperature for 66 h, the solvents were removed in vacuo. The residue was partitioned between ethyl acetate and water, and the organic portion was separated, washed with brine, and conc. in vacuo. Flash column chromatography (0 to 35% of ethyl acetate in hexanes) gave the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O>[NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(N)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(C(=O)O)cc1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A mixture of methyl 5-amino-2,4-dimethylbenzoate (1.2 g, 6.70 mmol, 1.00 equiv) and sodium hydroxide (1.5 g, 37.50 mmol, 5.60 equiv) in methanol/H2O (20/20 mL) was stirred overnight at 50° C. After cooling to ambient temperature, the organic phase was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to ˜4-5 with hydrogen chloride (aq., 2 M). The resulting solids were collected by filtration and dried to yield 1.0 g of a yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][C:12]4[C:18]([N+:19]([O-])=O)=[C:17]([O:22][CH3:23])[CH:16]=[CH:15][C:13]=4[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][C:12]4[C:18]([NH2:19])=[C:17]([O:22][CH3:23])[CH:16]=[CH:15][C:13]=4[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1ccc2nc(-c3ccc4c(c3)OCO4)sc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2nc(-c3ccc4c(c3)OCO4)sc2c1N
Yield: 51.7 %

Procedure:
0.96 g (2.9 mmol) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-7-nitro-1,3-benzothiazole is suspended in 100 ml of methanol. 96 mg (10%) of palladium on carbon is added to the reaction mixture which is maintained under stirring under 2.5 bars of hydrogen for 18 hours. The catalyst is filtered out, then the solvents are evaporated off under reduced pressure. 0.45 g (yield=52%) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-1,3-benzothiazol-7-amine is obtained and used in the following stage without other purification.
Reaction SMILES: C(O)(=O)C.CO[C:7](=[O:36])[CH2:8][CH2:9][NH:10][C:11](=[O:35])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:34])[C@H:18]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH:19][C:20](=[O:27])[C@@H:21]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1.[NH3:37]>CO>[NH:22]1[C:23](=[O:26])[CH2:24][CH2:25][C@H:21]1[C:20]([NH:19][C@H:18]([C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:11]([NH:10][CH2:9][CH2:8][C:7]([NH2:37])=[O:36])=[O:35])=[O:34])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:27]
Reactant: COC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Reactant: N
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 72 h

Procedure:
1.0 g of L-pyroglutamyl-L-histidyl-L-prolyl-β-alanine methyl ester acetate was dissolved in 100 ml of methanol. The resulting solution was saturated with ammonia at 0° C, the vessel was made gas-tight and stored at room temperature for 3 days. The solution was then concentrated in vacuo, the residue dissolved in 50 ml of water and lyophilised. Yield: 900 mg. [α]D25 = -94.9° (c = 1 in 1 N acetic acid).