Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=O)[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[ClH:17].[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:22])=[C:7]([CH2:23][NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1O
Product: Cl

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-4′-chloro-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 5-(tert-butyl)-4′-chloro-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine. HPLC/MS Rt=7.41 min, m/z 414.1 and 416.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15]C)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].Cl[CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24](C)=[CH:23][C:22]=1[O:29][CH2:30][C:31]1[C:36](C2(OCC3C=CC=CC=3)C=C(C)C=C(C)C2CCl)=[CH:35][CH:34]=[CH:33][CH:32]=1.C[N:56](C=O)C>>[CH2:30]([O:29][C:22]1[C:21]([CH2:20][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([CH3:1])[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:26]([CH3:27])[CH:25]=[C:24]([CH3:23])[N:56]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)C=O
Reactant: CC1=CC(OCc2ccccc2)(c2ccccc2COc2cc(C)cc(C)c2CCl)C(CCl)C(C)=C1
Reactant: COC(=O)c1ccc2c(c1C)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(CN2CCc3ccc(C(=O)O)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of methyl 8-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (76d, 100 mg, 0.46 mmol) in DMF (5 mL) was added NaH (0.032 g, 1.32 mmol, 60% in oil) at 0° C. under N2. After stirring at 0° C. for 30 minutes, 1-(benzyloxy)-2-(chloromethyl)-3,5-dimethylbenzene benzyl 2-(chloromethyl)-3,5-dimethylphenyl ether (Cpd Z, 180 mg, 0.69 mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured into ice-water (20 mL). The reaction mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=1:1) to obtain 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (76e, 120 mg, 61%) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.S(=O)(=O)(O)O.[OH-:16].[Na+].[CH2:18]([OH:20])[CH3:19]>>[Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]([O:20][CH2:18][CH3:19])=[O:16]
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1ccc(C#N)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(C)cc1Cl
Yield: 45 %

Procedure:
A mixture of 2-chloro-4-methylbenzonitrile (5.5 g, 36.28 mmol), conc. sulfuric acid (30 mL) and ethanol (30 mL) was heated under reflux for 22 hr. The reaction mixture was ice-cooled, and neutralized with 8N aqueous sodium hydroxide solution, and ethanol was evaporated. The residue was extracted with ethyl acetate, and the extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was diluted with ethyl acetate-hexane (1:10, 120 mL). The insoluble material was filtered off, and the filtrate was under reduced pressure and concentrated to give the title compound (3.23 g, 45%) as a pale-brown liquid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[OH:23]>C(NCCCC)CCC.C(O)C>[CH3:22][O:21][C:17]1[CH:18]=[C:19]([CH:20]=[C:15]([O:14][CH3:13])[C:16]=1[OH:23])[CH2:11][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[S:1]
Reactant: Sc1nc2ccccc2s1
Reactant: C=O
Reactant: COc1cccc(OC)c1O
Solvent: CCCCNCCCC
Solvent: CCO
Product: COc1cc(Cn2c(=S)sc3ccccc32)cc(OC)c1O
Yield: 82 %

Procedure:
16.7 g of mercaptobenzothiazole, 3.0 g of paraformaldehyde, 15.4 g of 2,6-dimethoxyphenol and 1 g dibutylamine are heated at 110°, with rapid stirring, for 2 hours. 50 ml of ethanol are added and the mixture cooled to 10° thereby obtaining 27.3 g of 3-(3,5-dimethoxy-4-hydroxybenzyl)-benzothiazole-2-thione (compound No. 8) melting at 141°-142°.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:10]3=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CO>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:10]3=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:8]=2)[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: CCCBr
Reactant: Fc1ccc(-c2cc(N3CCNCC3)nc3c2CCCCCC3)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: CCCN1CCN(c2cc(-c3ccc(F)cc3)c3c(n2)CCCCCC3)CC1
Yield: 38.1 %

Procedure:
A mixture of 2-(1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (1.4 g), n-propyl bromide (0.56 g), potassium carbonate (0.68 g), potassium iodide (0.1 g) and methanol (50 ml) is refluxed for 15 hours. The reaction mixture is concentrated under reduced pressure and thereto is added water. The mixture is extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. To the residue is added a solution of maleic acid in ethanol, and the resulting maleate product is recrystallized from ethanol to give the dimaleate of the desired compound (0.6 g), m.p. 149°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][CH:12]([CH3:18])[CH:13](OC)OC)=[S:10])[CH:5]=[CH:6][CH:7]=1>O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([CH3:18])[N:11]=[C:9]2[SH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(C)NC(=S)Nc1cccc(Br)c1
Agent: Cl
Solvent: O
Product: Cc1cn(-c2cccc(Br)c2)c(S)n1
Yield: 68.9 %

Procedure:
Step 1) A mixture of commercially available 3-bromophenylisothiocyanate (10.06 g, 47.0 mmol) and 2-aminopropionaldehyde dimethylacetal (5.96 mL, 47.0 mmol) in EtOH (50 mL) was refluxed for 1 h. Evaporated to dryness to give 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea as an off-white solid (15.69 g, 100%). Step 2) A mixture of the above prepared 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea (15.69 g, 47 mmol) in H2O (85 mL) and 37% HCl (8.5 mL) was refluxed for 4.5 h. Removed from oil bath, added ice and ice water (total volume: 250 mL), the precipitate was filtered off, washed several times with ice water and dried in vacuum at 60° C. to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol as a light orange solid (8.71 g, 69%). Step 3) To a suspension of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol (6.00 g, 22 mmol) in acetic acid (20 mL) and water (5 mL) was added dropwise 35% H2O2 (13.4 mL, 156 mmol) within 15 min keeping the internal temperature below 60° C. Stirred at 23° C. for 30 min, poured onto ice, destroyed excess H2O2 by addition of sat. Na2SO3-sol., adjusted pH with 32% NaOH-sol. until pH 9 is reached, extracted with EtOAc (3×100 mL), the combined organic layers were washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a red oil, which was purified by silica gel column chromatography with EtOAc to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole as a brown oil (3.80 g, 72%). Step 4) A mixture of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole (0.313 g, 1.31 mmol), bis(pinacolato)diboron (0.364 g, 1.438 mmol), potassium acetate (0.389 g, 3.96 mmol) and PdCl2(PPh3)2 (0.023 g, 3 mol %) in DMF at 100° C. for 2 h; then addition of Pd(OAc)2 (0.007 g, 3 mol %) and dppf (0.018 g, 3 mol %) and stirred at 100° C. overnight. This solution obtained was used directly.] according to the general procedure VI. Obtained as an off-white solid (0.140 g, 32%). MS (ISP) 394.0 [(M+H)+]; mp 126-132° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][O:10][CH2:9][CH2:8][NH:7]1)[CH3:2].C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](Cl)=[O:34])=[CH:23][CH:22]=1>ClCCl.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:33]([C:28]1[N:29]=[C:30]([CH3:32])[S:31][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=1)=[O:34])[CH3:2]
Reactant: CCOC(=O)CC1COCCN1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC1COCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Reaction time: 16 h

Procedure:
Morpholin-3-ylacetic acid ethyl ester Chem Pharm Bull 94, 31(1), 1983 (2.10 g) was dissolved in dichloromethane (50 ml) and treated with triethylamine (1.33 g). The mixture was cooled (ice bath) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (1.53 g) in dichloromethane (10 ml) added. The mixture was stirred for 16 h, diluted with water and the organic phase separated. The aqueous phase was extracted with dichloromethane (2×100 ml), the organic phases combined, dried (Na2SO4) and solvent removed at reduced pressure. the residue was column chromatographed (silica gel, 40% ethyl acetate:pentane ˜60% ethyl acetate pentane eluant) to give the title compound (1.46 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:14][C:15]#[N:16])[CH2:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([S:19]P([O-])(OCC)=S)C.C(OCC)(=O)C>O1CCCC1.O>[CH2:1]([O:8][CH2:9][C:10]1([CH2:14][C:15](=[S:19])[NH2:16])[CH2:11][CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP([O-])(=S)SCC
Reactant: N#CCC1(COCc2ccccc2)CCC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=S)CC1(COCc2ccccc2)CCC1
Yield: 71.3 %

Procedure:
To a solution of 9.7 g (45 mmol) of {1-[(benzyloxy)methyl]cyclobutyl}acetonitrile in 100 mL of tetrahydrofuran and 10 mL of water was added 15.13 mL (90.2 mmol) of diethyldithiophosphate and the contents heated at reflux for 16 h. Ethyl acetate and water were added, and the layers separated. The organic phase was dried using magnesium sulfate and concentrated under vacuum to afford the crude product, which was purified by silica gel chromatography using ethyl acetate:hexane (2:8) as the eluent to afford 8.0 g (71%) of 2-{1-[(benzyloxy)methyl]cyclobutyl}ethanethioamide as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.00 (br s, 2H), 7.39-7.30 (m, 5H), 4.59 (s, 2H), 3.58 (s, 2H), 3.09 (s, 2H), 2.14-1.87 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][C:19]([O-:21])=O)=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].CCN=C=NCCCN(C)C.[CH:34]1[CH:35]=C[C:37]2[N:42](O)N=[N:40][C:38]=2[CH:39]=1.CCN(CC)CC.NC1C=NC=CC=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][C:19]([NH:40][C:38]4[CH:37]=[N:42][CH:35]=[CH:34][CH:39]=4)=[O:21])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])Cc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Nc1cccnc1
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1nnc2ccc(Nc3cccc(Cl)c3)nn12)Nc1cccnc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Lithium 2-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)acetate (50 mg, 0.16 mmol) is taken up in DMF (3 ml) and EDCI (45 mg, 0.24 mmol), HOBt (32 mg, 0.24 mmol), Et3N (30 ul, 0.32 mmol), and 3-aminopyridine is added. The reaction mixture is stirred at 60° C. overnight. The reaction mixture is diluted with ethyl acetate, washed with water, and the organic layer concentrated to dryness. Purification by reversed-phase HPLC yields the product, 2-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-N-(pyridin-3-yl)acetamide.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].CCCC.I[Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1>>[Si:24]([O:44][CH2:43][CH2:42][CH2:41][CH2:45][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)I
Reactant: C1CCOC1
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCC
Product: CC(C)(C)[Si](C)(C)OCCCCC1(C#N)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a stirred solution of benzyl 4-cyanopiperidine-1-carboxylate (10 g, 41 mmol) and iodo-tert-butyldimethylsilane butane (12.6 mL, 49 mmol) in THF (80 mL) cooled to −78° C. was added LiHMDS (50 mL, 50 mmol, 1M in THF) dropwise over 30 min. The resulting mixture was stirred while gradually warming to room temperature for 18 h. After quenching with water, the organic phase was diluted with EtOAc and washed with water, brine and dried (Na2SO4). After concentration, the residue was purified by flash chromatography (10% to 20% EtOAc/hexane) to give the title compound as yellow oil (11.88 g, 67% yield). 1H NMR (300 MHz, CDCl3) δ: 7.34-7.28 (5H, m), 5.09 (2H, s), 4.17 (2H, bs), 3.59 (2H, t, J=5.3 Hz), 3.07 (2H, bs), 1.89 (2H, d, J=13.2 Hz), 1.53 (6H, bs), 1.43-1.34 (2H, m), 0.85 (9H, s), 0.01 (6H, s). LCMS (M+H): 431.20.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC(OC)=CC=3)C=2N=1)(C)(C)C.[C:29]([C:33]1[N:34]=[C:35](Cl)[C:36]2[N:41]=[N:40][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[N:38]=1)([CH3:32])([CH3:31])[CH3:30].Cl.[F:53][C:54]1([F:59])[CH2:58][CH2:57][NH:56][CH2:55]1>>[C:29]([C:33]1[N:34]=[C:35]([N:56]2[CH2:57][CH2:58][C:54]([F:59])([F:53])[CH2:55]2)[C:36]2[N:41]=[N:40][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[N:38]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Reactant: FC1(F)CCNC1
Agent: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Agent: Cl
Product: COc1ccc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine and 3,3-difluoropyrrolidine hydrochloride and isolated as white solid (271 mg, 83%). MS(m/e): 403.4 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[N:3]=1.COC1C=CC(OC)=CC=1CO.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(OC)c(COc2cncc(Cl)n2)c1
Agent: COc1ccc(OC)c(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(OC)c(COc2cncc(N3CCNCC3)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(2,5-dimethoxybenzyl)oxy]pyrazine (1.02 g, 3.63 mmol; obtained according to the procedure of example 50, step 1, starting from 2,5-dimethoxybenzyl alcohol), piperazine (0.94 g, 10.9 mmol) and K2CO3 (0.50 g, 3.63 mmol). The yield of the title compound was 0.64 g (53%) which was obtained as a beige solid. Purity 100% (HPLC). MS m/z 331 (M+H)+. HRMS m/z calcd for C17H22N4O3 (M)+ 330.1692, found 330.1692.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37]([C@H:39]2[C:48]3[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][CH:47]=3)[CH2:42][CH2:41][NH:40]2)=[O:38])[CH:29]=[CH:30][C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C:60]([O:64][C:65](=[O:74])[CH2:66][C@@H:67]1[CH2:70][C@H:69]([C:71](O)=[O:72])[CH2:68]1)([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37]([C@H:39]2[C:48]3[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][CH:47]=3)[CH2:42][CH2:41][N:40]2[C:71]([C@@H:69]2[CH2:68][C@H:67]([CH2:66][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:74])[CH2:70]2)=[O:72])=[O:38])[CH:29]=[CH:30][C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HATU (147 mg, 0.39 mmol) was added to a solution of (R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (120 mg, 0.32 mmol), DIEA (0.110 mL, 0.64 mmol) and cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (72.5 mg, 0.34 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over-magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (162.1 mg, 0.285 mmol, 88%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7](Cl)(=[O:9])=[O:8].[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1])(=[O:9])=[O:8])=[O:16]
Reactant: O=S(=O)(Cl)c1sccc1Br
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1sccc1Br

Procedure:
N-[(tert-Butoxy)carbonyl]3-bromothiophene-2-sulfonamido 2,2-dimethylpropanoate (106) is synthesised from 3-bromothiophene-2-sulfonyl chloride (synthesised according to the method detailed in Bioorganic and Medicinal Chemistry Letters 1996, 6, 2651-2656), sodium hydride and [(tert-Butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. δH (500 MHz, DMSO-d6) 8.25 (1H, d, 5.2 Hz), 7.44 (1H, d, 5.2 Hz), 1.39 (9H, s), 1.29 (9H, s).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[C:44]([NH2:51])=[C:43]([Cl:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:53]=[CH:54][CH:55]=[CH:56][C:4]=2[NH:3]1.[N:57]1([CH2:63][CH2:64]O)[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:48])([F:50])[F:49])[C:44]([NH2:51])=[C:43]([Cl:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([O:38][CH2:64][CH2:63][N:57]5[CH2:62][CH2:61][O:60][CH2:59][CH2:58]5)=[O:37])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:53]=[CH:54][CH:55]=[CH:56][C:4]=2[NH:3]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C(=O)CCC(=O)O)CC3)CC2)cc1C(F)(F)F
Reactant: OCCN1CCOCC1
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C(=O)CCC(=O)OCCN4CCOCC4)CC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 9.2 from 100 mg (0.12 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1′-(3-carboxy-propionyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 17 μL (0.14 mmol) 2-morpholin-4-yl-ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:19](=O)([O-])[O-].[K+].[K+].C[CH:26]=[CH:27][CH2:28]Cl>CN(C=O)C>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:27]([CH3:28])=[CH2:26])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1O
Reactant: CC=CCCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(=O)OCc2ccccc2)c(O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a mixture of 17 g of benzyl 2,4-dihydroxybenzoate (0.07 mol) and 10 g of potassium carbonate (0.077 mol) in 60 ml of DMF brought to 70° C. were added 6.81 ml of methyallyl chloride (0.07 mol) dropwise over 1 hour. The mixture was left at 70° C. for 2 hours. It is cooled to about 40° C. and the salts are filtered off. The salts were washed with DMF. The liquids were combined, and the solvent was evaporated off. A brown oil was obtained which was purified on silica (eluent: 70/30 heptane/CH2Cl2). The head fractions were pooled to give 12 g (yield: 57%) of benzyl 2-hydroxy-4-(2-methylallyloxy)benzoate in the form of a colourless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH3:16])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C(OCC)(=O)C.CO>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH3:16])[S:11]([CH3:14])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCN(c1cccc(C(C)=O)c1)S(C)(=O)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Yield: 88.6 %

Procedure:
1.1 g (4.56 mmol) of N-(3-acetyl-phenyl)-N-ethyl-methanesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.2 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-methanesulfonamide as a yellowish-white solid were obtained (yield 88.6%)
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:29][C:25]1[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][N:26]=1)=[O:19]
Reactant: Cc1ccnc(N)c1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: Cc1ccnc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 31 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 4-methyl-2-amino-pyridine with a yield of 31% of theory.