Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[Na+].Br[C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:16]2[CH:24]=[CH:23][C:22]3[N:21]([CH3:25])[C:20]4[CH2:26][CH:27]5[NH:31][CH:30]([C:19]=4[C:18]=3[C:17]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1cccc(OC(F)F)c1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(OC(F)F)c4)ccc31)C1CCC(C2)N1
Yield: 43 %

Procedure:
Intermediate 6 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 7:3 hexane/ethyl acetate) to give tert-butyl 2-(3-difluoromethoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (155 mg, 43%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.12-8.22 (m, 1H), 7.76-7.82 (m, 1H), 7.62-7.72 (m, 2H), 7.46 (t, J=8.1 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.21-7.26 (m, 1H), 6.52 (t, J=72.9 Hz, 1H), 5.19-5.38 (m, 1H), 4.55-4.80 (m, 1H), 3.61 (s, 3H), 3.20-3.51 (m, 1H), 2.50 (d, J=8.1 Hz, 1H), 2.12-2.40 (m, 2H), 1.89-1.99 (m, 1H), 1.55-1.67 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[C:24]([O:25][C:26]2[N:31]=[C:30]3[S:32][C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])=[N:34][C:29]3=[CH:28][CH:27]=2)[CH:41]=[CH:42][C:43]=1[F:44])=[O:6]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (0.33 g, 1.5 mmol) produced in Example C61(v) in oxalyl chloride (1.5 mL) was added N,N-dimethylformamide (100 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1.5 mL) and tetrahydrofuran (1.5 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (0.345 g, 1.00 mmol) in N,N-dimethylacetamide (3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (430 mg, 78%) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][C:30]=4[NH:31]3)=[CH:27][CH:26]=2)[C:22]([CH2:39][CH3:40])=[C:21]([O:41]CC2C=CC=CC=2)[C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.C(Cl)Cl.[SiH](C(C)C)(C(C)C)C(C)C>C(O)(C(F)(F)F)=O>[CH2:39]([C:22]1[C:21]([OH:41])=[C:10]([C:11]([OH:13])=[O:12])[C:9](=[O:8])[NH:24][C:23]=1[C:25]1[CH:33]=[C:32]2[C:28]([C:29]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][C:30]=3[NH:31]2)=[CH:27][CH:26]=1)[CH3:40]
Reactant: CCc1c(-c2ccc3c4c([nH]c3c2)CN(C)CC4)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(-c2ccc3c4c([nH]c3c2)CN(C)CC4)[nH]c(=O)c(C(=O)O)c1O
Yield: 100 %

Procedure:
The intermediate from Step 2 (19 mg, 0.030 mmol) was stirred in TFA (0.2 mL), CH2Cl2 (0.2 mL) and TIPSH (0.2 mL) at room temperature for 15 h. The solvents were removed and the residue was dissolved in CH2Cl2 (0.5 mL), then HCl (2.0M in Et2O, 1.0 mL) was added. The precipitate was collected by filtration and washed by ether to afford the title compound as an off-white solid (12 mg, 0.030 mmol, HCl salt) in 100% yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>CN(C=O)C>[CH3:37][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=4[C:4]=3[CH:3]=2)=[CH:29][CH:30]=1)(=[O:35])=[O:36]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(S(C)(=O)=O)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a stirred mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (50 mg, 0.19 mmol) and cesium carbonate (94 mg, 0.29 mmol) in DMF (1.5 mL) was added 1-(bromomethyl)-4-(methylsulfonyl)benzene (72 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 h, the solid was filtered. The filtrate was concentrated, and the residue was purified by preparative TLC to give the title compound (40 mg) as an off-white solid. LCMS m/z=428.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 1.30 (t, J=7.2 Hz, 3H), 2.07-2.15 (m, 1H), 2.50 (dd, J=16.7 and 11.2 Hz, 1H), 2.70-2.86 (m, 4H), 3.05 (s, 3H), 3.52-3.58 (m, 1H), 4.17-4.25 (m, 2H), 5.20 (s, 2H), 6.84 (dd, J=8.8 and 2.4 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.95 (d, J=8.3 Hz, 2H), 8.49 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)C=O.[CH3:13][O:14][CH:15](OC)[O:16][CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:15]([O:16][CH3:17])[O:14][CH3:13])[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Yield: 99.7 %

Procedure:
A mixture of 14.7 parts of 5-chloro-2-nitrobenzaldehyde, 13.3 parts of trimethoxymethane, 0.15 parts of 4-methylbenzenesulfonic acid and 64 parts of methanol was stirred at reflux temperature. After cooling, the reaction mixture was neutralized with sodium carbonate and stirred for 5 min. The whole was filtered and the filtrate was evaporated, yielding 18.3 parts (99.7%) of 4-chloro-2-(dimethoxymethyl)-1-nitrobenzene (interm. 43).
Reaction SMILES: COCCOC[O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1.S(=O)(=O)(O)O.CO>C1COCC1>[OH:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:10][C:11]2[C:12]([CH3:20])([CH3:21])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCOCCOC)C(C)(C)CCC3(C)C)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 108.5 %

Procedure:
A mixture of ethyl 4-(3-methoxyethoxymethoxy5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)benzoate (2.3 g, 4.4 mmol), concentrated sulphuric acid (475 μl), methanol (40 ml) and THF (20 ml)is stirred for 48 h at room temperature. The reaction medium is extracted with ethyl ether. The organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum. The product is purified by crystallization from heptane. 2.06 g (97%) of the expected compound are obtained in the form of an orange-coloured powder. m.p.=113° C.
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH:3]=[CH2:4].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])=[O:16])=[CH:10][N:9]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([N:5]([C:12]1[C:11]([C:15]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])=[O:16])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[NH2:6])[CH2:2][CH:3]=[CH2:4]
Reactant: Cc1cccc(C)c1NC(=O)c1cnc(Cl)nc1Cl
Reactant: C=CCCNN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCN(N)c1nc(Cl)ncc1C(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of 1.3 g (14.9 mmol) of 3-butenylhydrazine in 60 mL of THF was cooled to 0° C. and treated sequentially with 4.0 g (13.5 mmol) of 2,4-dichloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide 30 (Example 1, Step B) and 2.1 mL (14.9 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 23 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (75 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 17:3) to give the title compound. 1H-NMR (DMSO-d6) δ 2.24 (s, 6H), 2.40-2.48 (m, 2H), 3.32 (s, 2H), 3.80 (t, J=7.3 Hz, 2H), 5.03 (dd, J=10.3 Hz, 1.1 Hz, 1H), 5.13 (dd, J=17.2 Hz, 1.5 Hz, 1H), 5.75-5.86 (m, 1H), 7.07 (s, 3H), 8.15 (s, 1H), 9.61 (s, 1H). Mass Spectrum (ESI) m/e=346.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[O:16]1CCOCC1>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:14][CH3:15])[N:3]=[C:2]([CH:1]=[O:16])[CH:11]=[N:10]2
Reactant: COc1cc2ncc(C)nc2cc1OC
Reactant: C1COCCO1
Product: COc1cc2ncc(C=O)nc2cc1OC
Temperature: 100 °C
Yield: 73 %

Procedure:
To a reaction flask under argon is added 1,4-dioxane (20 mL), 2-methyl-6,7-dimethoxyquinoxaline (1.09 g, 5.3 mmol) and SeO2 (1.8 g, 16 mmol). The mixture is heated to 100° C. for 2 hours 45 minutes, cooled, and filtered through Celite. The pad is washed with portions of EtOAc and CH2Cl2. The resulting solution is concentrated, taken up in MeOH/CH2Cl2, loaded onto a silica gel column, and chromatographed (30% EtOAc/CH2Cl2) to provide an off-white solid (73% yield).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](OC(F)(F)F)=[CH:20][CH:19]=3)[N:15]([CH:29]3[CH2:31][CH2:30]3)[C:14]=2[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:36][CH2:35]2)=[O:33])[CH:10]=[N:9]1)C1C=CC=CC=1.C(OC(=O)CN(C1CC1)C(=O)C1C=CC=C([O:58][C:59]([F:62])([F:61])[F:60])C=1)C>[Pd]>[CH:29]1([N:15]2[C:14]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)[CH2:38][CH2:39]3)=[O:33])=[C:13]([C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)[N:17]=[C:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:58][C:59]([F:62])([F:61])[F:60])[CH:19]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)CN(C(=O)c1cccc(OC(F)(F)F)c1)C1CC1
Reactant: O=C(c1c(-c2cnn(Cc3ccccc3)c2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Agent: [Pd]
Product: O=C(c1c(-c2cn[nH]c2)nc(-c2cccc(OC(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described in example 95, the title compound has been obtained from [5-(1-benzyl-1H-pyrazol-4-yl)-3-cyclopropyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared in analogy to the sequence described for the preparation of intermediate 13, but using [cyclopropyl-(3-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester instead of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester in step 13A) by hydrogenation with 10% palladium on charcoal to give the title compound as colorless amorphous solid. MS: 515.2 (MH+).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13]2>C(N(CC)CC)C.C1(C)C=CC=CC=1>[O:21]=[C:11]1[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]([CH2:7][O:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])=[C:17]2[N:12]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][S:18][C:16]=12
Reactant: CCN=C=O
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)OCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Reaction time: 2 h

Procedure:
A few drops of triethylamine and three 0.24 ml portions of ethyl isocyanate were added to a suspension of 1.02 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one in 11.5 ml of toluene, whereby the mixture was stirred at 85° for about 2 hours between each of the additions. After the reaction was finished, the mixture is evaporated in vacuo. By recrystallization of the residue from ethanol, there was obtained pure (4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)methyl-ethylcarbamate of m.p. 136°-137°.
Reaction SMILES: [Br:1][C:2]([F:9])([F:8])[C:3]([F:7])([F:6])[CH:4]=[CH2:5].B.C12BC(CCC1)CCC2.[OH:20]O.[OH-].[Na+]>O1CCCC1.CCCCCC>[Br:1][C:2]([F:9])([F:8])[C:3]([F:7])([F:6])[CH2:4][CH2:5][OH:20]
Reactant: OO
Reactant: C=CC(F)(F)C(F)(F)Br
Agent: B
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCC(F)(F)C(F)(F)Br

Procedure:
Also, the sulfonic acid salt of formula (1) can be synthesized by starting with 4-bromo-3,3,4,4-tetrafluoro-1-butene which is readily available in the industry, effecting hydroboration with a borane such as 9-borabicyclo[3.3.1]-nonane (9-BBN) in a solvent such as n-hexane or tetrahydrofuran by a standard technique, treating the product with an oxidizing agent such as aqueous hydrogen peroxide in the presence of a base such as sodium hydroxide to form 4-bromo-3,3,4,4-tetrafluorobutanol, and esterifying it with carboxylic halide in the presence of a base such as triethylamine.
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C@@H:43]([CH2:62][C:63]1[N:64]=[CH:65][NH:66][CH:67]=1)[C:44]([NH:46][C@@H:47]([CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:53][CH2:52]1)[OH:50])=[O:45].[CH:68]1([CH2:71][O:72][C:73]([C:75]([S:78]([CH2:81][CH:82]([CH2:86][C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[C:83](O)=[O:84])(=[O:80])=[O:79])([CH3:77])[CH3:76])=[O:74])[CH2:70][CH2:69]1>CN(C)C=O>[CH:56]1([CH2:55][C@H:47]([NH:46][C:44]([C@@H:43]([NH:42][C:83]([C@@H:82]([CH2:86][C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=2)[CH2:81][S:78]([C:75]([CH3:76])([CH3:77])[C:73]([O:72][CH2:71][CH:68]2[CH2:70][CH2:69]2)=[O:74])(=[O:80])=[O:79])=[O:84])[CH2:62][C:63]2[N:64]=[CH:65][NH:66][CH:67]=2)=[O:45])[C@@H:48]([OH:54])[C@H:49]([CH:51]2[CH2:52][CH2:53]2)[OH:50])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C(=O)OCC1CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C(=O)OCC1CC1)S(=O)(=O)C[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
77 mg (0.76mmol) of triethylamine, 118 mg (0.76mmol) of HOBT and 289 mg (0.76 mmol) of HBTU were added in sequence at room temperature under nitrogen to a solution of 250 mg (0.69mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4propionamide and 281 mg (0.76 mmol) of rac-α-[[[1-[(cyclopropylmethoxy)carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamic acid in 20 ml of dimethylformamide. The yellow reaction solution was stirred at room temperature overnight. For the working-up, the reaction solution was evaporated in a high vacuum. The residue was taken up in 40 ml of ethyl acetate and extracted twice with in each case 10 ml of saturated sodium hydrogen carbonate solution and 10 ml of saturated sodium chloride solution. The organic extracts were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the residue (560 mg) was chromatographed on 50 g of silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and pyridine as the eluent. After lyophilization from dioxan/water there were obtained 110 mg of the less polar cyclopropylmethyl 2-[[(R)-2-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulfonyl]-2-methylpropionate, MS: 715 (M+H)+, and 142 mg of the more polar epimeric cyclopropylmethyl 2-[[(S)-2-[[(S)-1-[[(1S,2R,3S)-1 -(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulfonyl]-2-methylpropionate, MS: 715 (M+H)+, each as a colourless powder.
Reaction SMILES: CNCCCC1(C2C=CC(F)=CC=2)OCCO1.C(=O)([O-])[O-].[K+].[K+].BrCC([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[CH2:30][CH2:29]1)=O.C(=O)(O)[O-].[Na+].C(O)(=O)C(O)=O.FC1C=CC(C2(CCCN(CC(N3CCC(OC4C=CC=C(Cl)C=4)CC3)=O)C)OCCO2)=CC=1>C(O)C>[Cl:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[O:34][CH:31]1[CH2:30][CH2:29][NH:28][CH2:33][CH2:32]1
Reactant: O=C(CBr)N1CCC(Oc2cccc(Cl)c2)CC1
Agent: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2cccc(Cl)c2)CC1
Agent: CNCCCC1(c2ccc(F)cc2)OCCO1
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: Clc1cccc(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-[3-(methylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane (7.2 g, 30.0 mmol), potassium carbonate (10.6 g, 76.8 mmol) and 120 ml of ethanol at 0° was added dropwise a solution of N-(2-bromoacetyl)-4-(3-chlorophenoxy)piperidine (11.3 g, 34.0 mmol) in 120 ml of ethanol. The solution was stirred 1 hour at room temperature and at reflux for 1 hour. The mixture was poured into saturated sodium bicarbonate, extracted with methylene chloride, washed with water and dried over magnesium sulfate. Filtration followed by evaporation of the solvent provided an oil. Yield: 11.0 g of 1-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-(3-chlorophenoxy)piperidine oxalate. Yield from 4-(3-chlorophenoxy)piperidine: 43%; from N-(2-bromoacetyl)-4-(3-chlorophenoxy)piperidine: 77%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:17])=[C:4]([CH2:10][CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13])[C:5]([I:9])=[CH:6][C:7]=1[I:8].[Cl:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+].Cl>CC(N(C)C)=O.O>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[C:3]([I:17])=[C:4]([CH2:10][CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13])[C:5]([I:9])=[CH:6][C:7]=1[I:8])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CCC(Cc1c(I)cc(I)c(N)c1I)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCl)c1I)C(=O)O
Reaction time: 1 h
Yield: 9.5 %

Procedure:
To a solution of 50 g of 3-amino-α-ethyl-2,4,6-triiodobenzenepropanoic acid (CAS RN, 96-83-3) (0.0875 mol) in 200 ml of DMA at 0° C., 11.87 g of chloroacetyl chloride (0.10 mol) are added. After 60 minutes at room temperature, the solution is dropwise added to 100 ml of H2O to give a precipitate which is filtered. The residue is dissolved in 100 ml of H2O and 43.7 ml of 2N NaOH (0.0875 mol) are added. 42 ml of 2N HCl (0.0084 mol) are added to precipitate a solid which is filtered. 5.4 g of 3-[(2-chloroacetyl)amino]-α-ethyl-2,4,6-triiodobenzenepropanoic acid are obtained (0.083 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:42][C:43]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:44]=1[CH2:45]O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:45][C:44]2[CH:47]=[C:48]([F:51])[CH:49]=[CH:50][C:43]=2[F:42])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: OCc1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(F)c(CSc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 28.5 %

Procedure:
At 0° C., 4-chlorobenzenethiol (5.45 g, 38.2 mmol), triphenylphosphine (11.1 g, 41.6 mmol) and diisopropyl azodicarboxylate (8.16 ml, 41.6 mmol) were sequentially added to a tetrahydrofuran (150 ml) solution of 2,5-difluorobenzyl alcohol (5.00 g, 34.7 mmol). The reaction mixture was stirred at room temperature for 4 days, followed by concentration. The residue thus obtained was purified by silica gel column chromatography (1% ethyl acetate-hexane) to give 2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (2.68 g, 29%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(F)c(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (72 mg, 85%), MS (ISP) m/z=338.4 [(M+H)+], mp 224.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:14]([CH2:16][N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([CH:26]=[CH2:27])=[N:18]3)=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:14]([CH2:16][N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([CH:26]=[CH2:27])=[N:18]3)=[N:15][C:11]=2[CH:10]=1
Reactant: C=Cc1nn(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCO)c2ccccc12
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1nn(Cc2nc3cc(CN)ccc3n2CCCCO)c2ccccc12
Reaction time: 2.5 h

Procedure:
To a suspension of [1-(4-hydroxy-butyl)-2-(3-vinyl-indazol-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (17 mg, 0.036 mmol) in DCM (1 mL) was added TFA (82 μL, 1.1 mmol). The solution was allowed to stir for 2.5 hrs. followed by the removal of the volatiles in vacuo. The resulting trifluoroacetate was dissolved in methanol (3 mL) followed by the addition of acetyl cloride (26 μL, 0.36 mmol) and concentrated after 10 min. This procedure was repeated once allowing the reaction to run for 3 hrs. The solution was concentrated in vacuo and the residue stripped with DCM (thrice). The product was triturated in diethyl ether and the ether decanted to yield 4-[5-aminomethyl-2-(3-vinyl-indazol-1-ylmethyl)-benzoimidazol-1-yl]-butan-1-ol; HCl salt (10 mg, 67%) as an off white solid: