Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>>[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH:14][C:20]([C:16]1[S:15][CH:19]=[CH:18][CH:17]=1)=[O:21]
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Reactant: O=C(Cl)c1cccs1
Agent: I
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1cccs1
Yield: 17.8 %

Procedure:
Acylation 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, 100 mg; 0.32 mmol) with 2-thiophenecarbonyl chloride (0.106 mL; 0.96 mmol) in a manner similar to that described in Example 1, Step 3 provided 17 mg of Thiophene-2-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide 6. EI-HRMS m/e calcd for C15H10N2OS2 (M+) 298.0235, found 298.0233.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].Br[CH2:13]C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:13])=[CH:8][C:9]=1[OH:10])=[O:3]
Reactant: CCBr
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)=O)c(O)c1

Procedure:
2,4-Dihydroxyacetophenone was alkylated with bromoethane in acetone in the presence of potassium carbonate to obtain 2-hydroxy-4-methoxyacetophenone. Using this compound and 2-methoxy-benzoic acid as starting materials, the syntheses according to Examples 1a, b, c, and d yielded the compound (m.p.: 153-154.5° C.).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH:11]1([C:14](=O)[CH2:15][CH2:16][C:17](O)=[O:18])[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH:11]1([C@@:14]23[CH2:15][CH2:16][C:17](=[O:18])[N:1]2[C@@H:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][O:4]3)[CH2:13][CH2:12]1
Reactant: O=C(O)CCC(=O)C1CC1
Reactant: N[C@H](CO)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CC[C@@]2(C3CC3)OC[C@H](c3ccccc3)N12
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of (S)-2-amino-2-phenylethanol (2.28 g, 16.6 mmol) and 4-cyclopropyl-4-oxobutanoic acid (1.97 g, 13.8 mmol) in toluene (35 mL) was heated at reflux for about 6 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed with aqueous HCl (1.0 N), saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on a Biotage silica gel column eluting with heptane/EtOAc (3:2) to afford (3S,7aS)-7a-cyclopropyl-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (2.54 g, 10.4 mmol) as a bright yellow needle-like solid. RP-HPLC (Table 1, Method a) Rt 1.77 min; m/z: (M+H)+ 244.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:9])=[CH:4][N:3]=1.FC(F)(F)C(O)=[O:30].OO.C(Cl)(Cl)Cl>ClCCl.CC(OCC)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:9])=[CH:4][N+:3]=1[O-:30]
Reactant: CCCCCCCCC(CCCCCC)COC(=O)c1ccc(Cl)nc1
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(CCCCCC)COC(=O)c1ccc(Cl)[n+]([O-])c1
Reaction time: 5 h

Procedure:
The product from Stage (a) (45.8 g, 0.12 mol) was dissolved in dichloromethane (350 ml) and trifluoroacetic acid (60 ml) was added dropwise during 30 minutes. H2O2 (100 vol, 31 ml, 0.24 mol) was then added during 15 minutes and the solution was boiled under reflux for 4 hours. A further addition of H2O2 (5 ml) was made and boiling was continued for a further 5 hours when it was shown by TLC (SiO2, CHCl3 :CH3CO2C2H5 =1:1) that only a trace of starting material remained. The mixture was poured onto ice and the organic solution was extracted with aqueous sodium carbonate and water, dried (MgSO4) and concentrated at 0.2 mm pressure to 46 g of oil. Microanalysis for C22H36NO3Cl, % theory (found): C: 66.39 (66.2); H: 9.12 (9.5); N: 3.52 (3.2); Cl: 8.91 (8.7). M.S. m/z=397. NMR(CDCl3)=7.65 (m, 2, ArH), 8.90 (2, 1, ArM), otherwise as starting material.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@H:8]([C@@H:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:9][N:10]=[N+]=[N-].CO>C1COCC1>[CH3:7][C@H:8]([C@@H:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])[CH2:9][NH2:10]
Reactant: CC(C)=CCC[C@H](C)[C@@H](C)CN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)=CCC[C@H](C)[C@@H](C)CN
Reaction time: 0.25 h

Procedure:
6.3 mL (6.3 mmol) of 1M lithium aluminum hydride in THF was added dropwise to a solution of 2(R),3(S),7-trimethyl-1-azido-6-octene in 10 mL of THF at 0° C. The reaction mixture was heated to reflux 18 hrs. After cooling in ice bath, ~1 mL of methanol was added dropwise cautiously. After the effervescence stopped, the reaction mixture was concentrated to 30% of the volume and 1N solution of potassium sodium tartrate was added. After stirring 15 mins, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous magnesium sulfate and the solvent was removed to give 399 mg of the desired amine as an oil.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[N:15][O:16][C:17](=O)[C@H:18]([OH:20])[CH3:19])[NH2:14])[CH:10]=[CH:11][CH:12]=1>O.C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:17]([C@H:18]([OH:20])[CH3:19])[O:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: C[C@@H](O)C(=O)ON=C(N)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@@H](O)c1nc(-c2cccc(Cl)c2)no1
Temperature: 90 °C

Procedure:
A solution of 1.53 g (18.6 mmol) sodium acetate in water (12 mL) was added to 3.88 g (16.0 mmol) 3-chloro-N′-{[(2R)-2-hydroxypropanoyl]oxy}benzenecarboximidamide dissolved in ethanol (50 mL). The mixture was heated to 90° C. for 5.5 h and then evaporated to dryness and purified via flash chromatography (Hep/EA=9/1) to give after drying 2.3 g (65%) of the title compound. 1H NMR: 8.09 (t, 1 H), 7.97 (td, 1 H), 7.45-7.51 (m, 1 H), 7.42 (t, 1 H), 5.15 (qd, 1 H), 2.57 (d, 1 H), 1.72 (d, 3 H)
Reaction SMILES: [O:1]=[C:2]1[NH:17][C:6]2[N:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH:15]=O)[N:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1.Cl.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]2[N:9]=[CH:10][C:5]3[CH:4]=[CH:3][C:2](=[O:1])[NH:17][C:6]=3[N:7]=2)[CH2:29][CH2:28]1
Reactant: O=CCCCOc1ncc2ccc(=O)[nH]c2n1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1ccc2cnc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde (235 mg, 1.01 mmol) in dichloroethane (5 mL) was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (270 mg, 1.01 mmol) followed by Et3N (0.28 mL, 2.0 mmol, 2 equiv). After 10 min at RT, NaBH(OAc)3 (297 mg, 1.4 mmol) was added as a powder. The reaction was stirred for 2 h at room temperature and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc (with a little MeOH to help dissolve the solids). The organic layer was washed with brine and concentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) gave the title compound as a white solid (375 mg, 0.836 mmol, 83%). MS: APCI: M+1: 448.1 (Exact Mass: 447.12).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]1=[O:24].BrCC(OC[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O>>[CH2:1]([O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:6]1=[O:24])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O

Procedure:
Prepared by a similar method described for the preparation of 600a/103 (Step D), except benzyl bromoacetate was used instead of methyl bromoacetate to give 600b in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16](C=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34]C[CH2:32][C:31]1=[O:36].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C:61](#[N:63])C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:61][N:63]2[CH2:34][CH2:35][NH:30][C:31](=[O:36])[CH2:32]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC#N
Reactant: O=C1CCCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCNC(=O)C3)ccc21

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (42.6 mg, 0.104 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 2-piperadinone (42 mg, 0.42 mmol), acetic acid (0.120 mL, 2.10 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(3-oxopiperazin-1-ylmethyl)indol-2-yl]isoindolinone (55.6 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CC(O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 140c (270 mg, 0.50 mmol) in THF (5 mL), propan-2-ol (5 mL), and water (2 mL) was added lithium hydroxide (36 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 140 (53 mg, 20%) as a white solid. MS-ESI: [M+H]+ 530.3. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J=5.0 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.89 (s, 1H), 7.78-7.5 (m, 1H), 7.51-7.48 (m, 2H), 7.39 (d, J=2.5 Hz, 1H), 6.07 (d, J=2.0 Hz, 1H), 4.91 (s, 1H), 4.42 (s, 2H), 3.71 (s, 3H), 3.58 (s, 3H), 1.39 (s, 9H)
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:7](=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([O:20][CH2:21][CH3:22])=[O:19])[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc2c(c1)OCO2)C(=O)OCC

Procedure:
Into a one-liter three-necked conical flask are introduced 50 g (333.04 mmol) of piperonal, 53.34 g (333.04 mmol) of diethyl malonate, 2.26 g (26.59 mmol) of piperidine, 110 ml of toluene and 1.6 g (26.66 mmol) of acetic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[N:32][CH:33]=4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl.[NH2:37][OH:38].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:38][NH:37][C:34](=[NH:35])[C:31]1[CH:30]=[CH:29][C:28]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[C:8]3=[N:15][C:14]=2[C:16]#[C:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:33][N:32]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of compound 39a (0.20 g, 0.44 mmol), hydroxylamine hydrochloride (0.20 g, 2.9 mmol) and sodium carbonate (0.20 g, 1.9 mmol,) in ethanol (4 mL) was stirred at 80° C. for 1 h. The reaction mixture was cooled to rt, and the solids formed were collected by filtration and washed with Et2O (2×30 mL) to obtain compound 42a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H22N8O2: 491.2 (M+H). Found: 491.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:7])=[O:6].[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O>[N:29]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:7])=[O:6])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, ethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (23a) (0.31 g, 0.71 mmol) dissolved in 10 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.11 g (1.8 mmol) of sodium azide (NaN3). After work-up, the crude title compound (23b) was used in the next step without further purification. MS (ESI) m/z 466.07 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Br:17])[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>CN(C)C=O.O>[Br:17][C:4]1[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=[C:2]([C:30]2[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[CH:3]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cncc(OC)c3)cc(Br)c2s1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
A stirred mixture of 1-(5,7-dibromo-benzothiazol-2-yl-3-ethyl urea (300 mg, 0.79 mmol), sodium carbonate (167 mg, 1.58 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloro-palladium(II) (45 mg, 0.05 mmol), 3-methoxy-5-pyridineboronic acid pinacol ester (186 mg, 0.79 mmol) in dimethyl formamide (8 ml) and water (2 ml), was purged with nitrogen for 5 min and heated at 100° C. for 1 h. The reaction mixture was concentrated in vacuo then partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 to 5% methanol in ethyl acetate to give 1-[7-Bromo-5-(5-methoxy-pyridin-3-yl)-benzothiazol-2-yl]-3-ethyl-urea 1 as a white solid (49 mg, 15%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:14](=[O:27])[CH2:13]1>CO.[Pd]>[NH2:8][C:6]1[C:5]([CH3:11])=[CH:4][C:3]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:14](=[O:27])[CH2:13]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1ccc(CN2CCC(c3cc(C)c([N+](=O)[O-])cc3C)CC2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CN2CCC(c3cc(C)c(N)cc3C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 4-(2,5-dimethyl-4-nitrophenyl)-1-(4-methoxybenzyl)piperidin-2-one (63 mg, 0.17 mmol) in MeOH (10 mL) was added 10% w/w Pd/C (6 mg), the mixture was degassed and stirred under H2 at room temperature for 14 hr. After removing the catalyst by filtration, the filtrate was concentrated to provide 4-(4-amino-2,5-dimethylphenyl)-1-(4-methoxybenzyl)piperidin-2-one as a pale yellowish oil. ESMS m/z 339.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([OH:48])[CH:39]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:49]([O:53][C:54](=[O:66])[N:55]([CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64]O)[CH3:56])([CH3:52])([CH3:51])[CH3:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:41]=[C:40]([O:48][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][N:55]([C:54]([O:53][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:66])[CH3:56])[CH:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCOCCOCCO)C(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCCOCCOCCN(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
8-[2-(4-tert-Butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (30.0 mg, 43.1 μmol), {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl}-methyl-carbamic acid tert-butyl ester (22.7 mg, 86.2 μmol) and triphenylphosphine (22.6 mg, 86.2 μmol) were dissolved in THF (0.22 mL). TMAD (14.8 mg, 86.2 μmol) was added and the mixture was stirred at 60° C. for 30 minutes in a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-[3-(2-{2-[2-(tert-butoxycarbonyl-methyl-amino)-ethoxy]-ethoxy}-ethoxy)-5-trifluoromethyl-phenyl]-8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (37.4 mg, 86%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH:5]=[CH:6][N+:7]([O-:9])=[O:8].[CH2:12]=[CH:13][CH:14]=[CH2:15]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C1(C)C=CC=CC=1>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][C@H:5]1[C@H:6]([N+:7]([O-:9])=[O:8])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: COC(CC=C[N+](=O)[O-])OC
Reactant: C=CC=C
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1
Product: COC(C[C@@H]1CC=CC[C@H]1[N+](=O)[O-])OC
Reaction time: 30 h
Yield: 125.4 %

Procedure:
214 g (1.0 mole) 75% 4,4-dimethoxy-1-nitro-1-butene and 0.1 g phenothiazine were put in an autoclave at room temperature, together with 850 ml toluene. Then 216 g (4.0 mole) butadiene were added under pressure. Subsequently stirring was conducted under the own pressure (approx. 6 bar) for 30 hours at 100° C. The pressure was released and the temperature reduced. Finally toluene and unreacted butadiene were distilled off. 270 g of an oily residue were obtained, containing about 39% reaction product and about 10% educt, as confirmed by GC. The crude product was employed without any further purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([CH:7]([C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=1)[CH3:8])=[CH2:6])[CH3:2].CCOC(C)=O.[C:30]([OH:33])(=[S:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH2:6][S:32][C:30](=[O:33])[CH3:31])[CH:7]([C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[CH:13][CH:14]=1)[CH3:8])[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(C(=O)OCC)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 45 °C
Yield: 91 %

Procedure:
TEA (0.076 mL, 0.542 mmol) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-ethyl]-acrylic acid ethyl ester (158 mg, 0.493 mmol) in thioacetic acid (2 mL) at 0° C. under argon. The mixture was stirred at 45° C. over night. EtOAc was added and the solution was washed with NaHCO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 5:1→1:1) gave slightly unpure 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-butyric acid ethyl ester (178 mg, 91%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[N:7][N:8]=1.[CH:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:15])=[N:7][N:8]=2)=[O:27])=[CH:29][CH:30]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: CC(C)N(CCSc1nnc(N)s1)C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)Nc2nnc(SCCN(C(C)C)C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole (2.6 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Isopropylbenzoic acid (1.6 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.3 g of the aimed compound.