Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5](=[O:8])[CH2:6]Br.C(=O)(O)[O-].[Na+].[SH:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21]>C1COCC1.O.C(OCC)C.Cl>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:8])[CH2:6][S:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CC(C)(S)C(=O)O
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(SCC(=O)c1cc(F)cc(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-difluorophenacyl bromide (845 mg, 3.60 mmol) in THF (12 mL) and water (12 mL) was added sodium bicarbonate (317 mg, 3.78 mmol) and 2-mercaptoisobutyric acid (432 mg, 3.60 mmol). The reaction mixture was allowed to stir at ambient temperature for 1.0 h under a stream of nitrogen. The reaction mixture was diluted with diethyl ether (50 mL) and 1 M HCl (15 mL). The organic layer was then washed with 20 mL saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z=229 (M−CO2H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:30]#[N:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Intermediate 1) and 3-cyanophenylboronic acid. The title compound was obtained in 46% yield as yellow foam. MS (m/e): 507.3 (MH+, 100%).
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)=[CH:34][CH:33]=4)[N:21]=3)[CH:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1cccc(Nc2cccn3nc(Cl)nc23)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5cccc(S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
N(8)-(3-Methanesulfonyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-phenyl)-amine (75.0 mg, 0.232 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (50.0 mg, 0.261 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.009 g, 8%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=6.2 Hz, 1H), 7.81 (s, 1H), 7.59-7.43 (m, 5H), 7.20 (d, J=8.0 Hz, 1H), 6.97 (d, J=7.5 Hz, 2H), 6.85 (s, 1H), 6.79 (t, J=7.4 Hz, 1H), 6.59 (s, 1H), 3.19-3.14 (m, 4H), 3.07 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:29])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CC(c1ccc(Br)cc1)c1ccc(Cl)cc1F)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=450.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27]3)[N:23]=1>>[ClH:1].[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([C:27]3[C:26]4[C:30](=[CH:31][CH:32]=[C:24]([C:22]5[N:23]=[C:19]([CH3:18])[S:20][CH:21]=5)[CH:25]=4)[NH:29][C:28]=3[OH:33])=[N:7][CH:6]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: Cc1nc(-c2ccc3c(c2)CC(=O)N3)cs1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Product: Cc1nc(-c2ccc3[nH]c(O)c(-c4ccc(S(=O)(=O)N5CCN(C)CC5)cn4)c3c2)cs1
Product: Cl
Yield: 35 %

Procedure:
The title compound was prepared as described for Example 101 using 1-[(6-chloropyridin-3-yl)sulfonyl]4-methylpiperazine (described in: Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203) and 5-(2-methyl-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one. The crude product was purified on a silica gel column using chloroform/methanol/conc NH3(aq), (50:3:0.3), as the eluent. The base was dissolved in chloroform/methanol and converted to the hydrochloride salt using HCl in diethyl ether (1 M). Yield: 35% of the title compound: MS (ES) m/z 470 (M++1).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](O)=[O:13])=[CH:8][CH:7]=1>C1C=CC=CC=1>[Cl:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([Cl:3])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: O=C(Cl)COc1ccc(Cl)cc1

Procedure:
Thionyl chloride (0.431 mole, 51.26 grams) was slowly added to p-chlorophenoxyacetic acid (0.287 mole, 53.5 grams) in 160 ml of benzene at room temperature. The reaction mixture was refluxed for 18 hours. The excess thionyl chloride and benzene were stripped from reaction mixture under vacuum (aspirator) and the residue p-chlorophenoxyacetyl chloride was distilled at 70°C./0.05 mm Hg.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([OH:5])=[O:4].[CH3:34][Si](C=[N+]=[N-])(C)C.CC(O)=O>ClCCl.CO>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:31](=[CH:32][CH:33]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[C:20]([C:21]([F:22])([F:23])[F:24])=[C:19]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:18][N:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([O:5][CH3:34])=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Yield: 97.8 %

Procedure:
To a stirred solution of 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Preparation 131B isomer 1, 230 mg, 0.50 mmol) in dichloromethane (5 mL) and MeOH (5 mL) was added (trimethylsilyl)diazomethane (0.42 mL, 0.84 mmol) dropwise at 0° C. The excess reagent was quenched by the slow addition of glacial AcOH (0.02 mL, 0.34 mmol) at 0° C. and the solution was concentrated. The resulting residue was mixed with ethyl acetate (30 mL). The ethyl acetate solution was washed with sat. aq. sodium bicarbonate (10 mL) and brine (10 mL), dried (sodium sulfate), filtered through a pad of silica gel, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate:hexane 45%) to yield methyl 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetate (230 mg, 0.489 mmol, 97% yield) as an oil: LC/MS M+1=471.09; 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, d, J=8.58 Hz), 7.76 (2H, d, J=7.26 Hz), 7.50-7.67 (3H, m), 7.41-7.49 (2H, m), 5.23 (1H, d, J=5.28 Hz), 3.82 (3H, s), 3.03-3.15 (4H, m).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.CON(C)[C:22](=[O:24])[CH3:23].Cl>>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:22](=[O:24])[CH3:23])[CH:16]=[CH:15]2
Reactant: CON(C)C(C)=O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc2cc(C(C)=O)ccc2c1
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
n-BuLi (1.6M in hexane, 73 ml) was added dropwise to a solution of 2-bromo-6-methoxynaphthalene (25.29 g) at −78° C. and the mixture was stirred for 15 minutes. A solution of N-methoxy-N-methylacetamide (11.03 g) was added to the mixture and stirred for 1 hour at −78° C. 1N-HCl was added, and the whole was extracted with ethyl acetate. The extract was concentrated and crystallized from cyclohexane to give the titled compound (17.50 g) as a colorless powder.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10]>O>[O-:11][C:9]([C:8]([F:13])([F:12])[F:7])=[O:10].[NH2:1][N:2]1[CH:6]=[NH+:5][N:4]=[CH:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: Nn1cnnc1
Solvent: O
Product: Nn1cn[nH+]c1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-1,2,4-triazole (1.27 g, 15.14 mmol) was dissolved in 5 ml of distilled water. Trifluoroacetic acid (1.12 ml, 15.14 mmol) was added via syringe at room temperature and the reaction was stirred at room temperature for 1 hour. The water was removed in vacuo with heating to approximately 90° C. for 4 hours.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9](O)=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.Cl.[CH3:16][NH:17][O:18][CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O>[CH3:19][O:18][N:17]([CH3:16])[C:9]([C:6]1[S:7][CH:8]=[C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:13][CH2:12][C:5]=12)=[O:10]
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CON(C)C(=O)c1scc2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (20 g, 95 mmol) in DMSO (150 mL) is added N,O-dimethylhydroxylamine hydrochloride (12.06 g, 124 mmol) and DIPEA (65 mL, 380 mmol), followed by TBTU (33.59 g, 105 mmol, dissolved in DMF (70 mL)). The reaction mixture is stirred at rt for 2 h before it is poured into water/ice and extracted twice with diethyl ether (2×100 mL). The organic extracts are washed with sat. aq. NaHCO3 solution, 10% aq. citric acid solution and brine, dried over Na2SO4, filtered, evaporated and dried to give 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (23 g) as a brown oil; LC-MS: tR=1.01 min, [M+1]=254.14.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[C:34]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:45]2[CH2:46][CH2:47][CH:42]([C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:43][CH2:44]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC(C(=O)c3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in acetonitrile (5 ml) was added diisopropylethylamine (0.45 mmol, 74 μL) and 4-benzoylpiperidine hydrogen chloride (0.15 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (59 mg) which was characterized by its mass spectrum: MS m/z (%): 462 ([M+H]+, 100).
Reaction SMILES: [C:1]([O:9][CH:10]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(#N)C>ClCCl>[Br-:17].[O:20]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][N+:16]1[CH:15]=[CH:14][S:13][C:12]=1[CH:10]([O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(OC(=O)c1ccccc1)c1nccs1
Solvent: CC#N
Solvent: ClCCl
Product: CC(OC(=O)c1ccccc1)c1scc[n+]1CC(=O)c1ccccc1
Product: [Br-]
Reaction time: 3 h
Yield: 33.2 %

Procedure:
1-(2-Thiazolyl)ethyl benzoate (2.0 g, 8.5 mmole), 2-bromo-1-phenyl-1-ethanone (1.7 g, 8.5 mmole), and acetonitrile (0.4 mL) were combined and heated at 115 C with stirring for 3 hr. After cooling, the reaction was diluted with 50 mL dichloromethane and extracted with 5×30 mL water. The combined, filtered water layers were evaporated to yield 2.2 g crude product, which crystallized from acetonitrile/ether after several days to afford 1.22 g of the title compound, mp 130–131.5 C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][Br:20])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.[C:21]([NH:28][C@H:29]([C:38]([OH:40])=O)[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:24]([O:23][C:21]([NH:28][C@H:29]([C:38]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][Br:20])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:40])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound (U) (3.51 g, 10 mmol) was dissolved in a solution of 25% TFA in DCM (10 ml) and stirred at room temperature for 30 mins. The solution was evaporated to dryness in vacuo and the residue evaporated from DCM three more times to remove residual traces of TFA. This residue was coupled to Boc-tyrosine (2.8 g, 10 mmol) using the procedure described for the synthesis of compound (U). The resultant product was purified by column chromatography (silica; 50% ethyl acetate in hexane (Rf =0.19)) as a colourless powder (4.9 g, 96%), mp 96-100° C. 1H NMR (CDCl3): δ 6.7-7.1 (m, 6H, ArH, Ile-NH, NH), 5.15 (d, J=8.2 Hz, 1H, Tyr-NH), 4.30 (m, 1H, αCH), 4.2 (m, 1H, αCH), 3.35-3.50 (m, 1H, NCH), 3.40 (t, J=6.0 Hz, 2H, CH2Br), 3.25 (m, 1H, NCH), 3.01 (dd, J=6.1, 13.6 Hz, 1H, Tyr-βCH), 2.93 (dd, J=6.1, 13.6 Hz, 1H, Tyr-βCH), 2.05 (m, 2H, CH2), 1.9 (m, 1H, Ile-βCH), 1.4 (m, 10H, Ile-γCH, (CH3)3), 1.05 (m, 1H, Ile-γCH), 0.89 (d, J=6.32 Hz, 3H, Ile-γCH3), 0.83 (t, J=7.37 Hz, 3H, Ile-δCH3). ISMS 514/516 (M+H). HRMS calcd for C23H35N3O5 (M-HBr), 433.2577; found 433.2573.
Reaction SMILES: [CH2:1]1[C:5]2(CCCC[C:6]2=[O:11])[CH2:4]CC1.C1(=O)CCCCC1.C[Mg]Cl.[Cl-].[NH4+].[CH3:24][C:25]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][C:26]21[CH2:30][CH2:29][CH2:28][CH2:27]2>O1CCCC1>[C:6]([O:35][C:25]1([CH3:24])[CH2:34][CH2:33][CH2:32][CH2:31][C:26]21[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:11])[C:5]([CH3:1])=[CH2:4]
Reactant: O=C1CCCCC12CCCC2
Reactant: CC1(O)CCCCC12CCCC2
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C1CCCCC1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(C)CCCCC12CCCC2
Temperature: 25 °C
Yield: 87 %

Procedure:
With stirring under nitrogen atmosphere at room temperature, a mixture of 100 g of spiro[4.5]decan-6-one (which had been synthesized from cyclohexanone by a method as described in A. P. Krapcho, Synthesis, 1974, p 383 and references cited therein) and 200 ml of tetrahydrofuran was added dropwise to a tetrahydrofuran solution of 1.28 mol methylmagnesium chloride (which had been prepared from 31.1 g of metallic magnesium, 400 ml of tetrahydrofuran and chloromethane), during which time the temperature was kept below 60° C. The reaction mixture was refluxed for 30 minutes, after which a saturated ammonium chloride aqueous solution was added to stop the reaction. Through ordinary work-up of extraction, washing and drying, and subsequent vacuum distillation, there was obtained 93.3 g (yield 87%) of the target compound, 6-methylspiro[4.5]decan-6-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]([CH2:39][OH:40])[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:40][CH2:39][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[CH:21]=2)=[O:27])[CH2:31]1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: OCC1CNc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC(CO)c5ccccc54)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
100 mg (0.25 mmol) of 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 50 mg (0.32 mmol) (2,3-dihydro-1H-indol-3-yl)-methanol in 50 μL (0.27 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU and the mixture was stirred for 5 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and evaporated down by roughly half. The precipitated solid was suction filtered and dried.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[ClH:1].[ClH:1].[NH2:23]/[C:22](=[N:25]\[OH:26])/[C:20]1[CH:19]=[CH:18][C:16]2[CH:17]=[C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])[S:14][C:15]=2[CH:21]=1
Reactant: NO
Reactant: N#Cc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 80 °C

Procedure:
800 mg (2.0 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzo-thiopene-2-carboxamide hydrochloride, 278.1 mg (4.0 mmol) of hydroxylamine hydrochloride and 829.5 mg (6.0 mmol) of potassium carbonate in 8 ml of an 8:1 mixture of water and ethanol are heated at 80° C. for 3 h. The mixture is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol/25% ammonia 100:20:4). The product fractions are combined and concentrated, methanol and 4M HCl in dioxane are added and the mixture is then again concentrated and dried under high vacuum. 447.3 mg (53.6% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)CCN
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7, 4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acetic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](=[O:17])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH2:11].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O-])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[Na+].Cl[Si](C)(C)C>C(#N)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([NH:11][C:10](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(NC(=O)OC(C)(C)C)c2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
15.0 g (121 mmol) of 4-fluorobenzaldehyde were added to a solution of 21.3 g (184 mmol) of tert-butyl carbamate and 32.3 g (181 mmol) of sodium p-toluenesulfonate in 430 ml of acetonitrile under argon. While cooling to 0-10° C., 26.3 g (242 mmol) of chlorotrimethylsilane were added dropwise, and the mixture was left to stir at room temperature overnight. After addition of 400 ml of water, the precipitated product was filtered off with suction and dried in vacuo at 50° C. 36.3 g of tert-butyl [(4-fluorophenyl)(toluene-4-sulfonyl)methyl]carbamate were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH:9]C(=O)OC(C)(C)C)[C:3]1=[O:17].[ClH:18].O1CCOCC1>ClCCl>[ClH:18].[NH2:9][C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[C:3]1=[O:17]
Reactant: CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCCC[C@H](N)C1=O
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of (S)-tert-butyl 1-methyl-2-oxoazepan-3-ylcarbamate (prepared according to Example 14; 0.152 g, 0.627 mmol) in dichloromethane (2 mL) was added 4M hydrogen chloride in dioxane (2 mL, 8 mmol), and the reaction mixture was allowed to stir overnight. The reaction mixture was concentrated to yield (S)-3-amino-1-methylazepan-2-one hydrochloride (0.112 g, 99.9% yield) which was taken on to the next step.