Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH3:20])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2n1CC
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a mixture of 4,5-dichloro-1H-indole-2-carboxylic acid ethyl ester (207 mg, 0.80 mmol) in DMF (2 mL) was added drop wise a suspension of NaH (41.2 mg, 60% dispersion in mineral oil, 1.03 mmol) in DMF (5 mL). The reaction mixture was stirred for 30 min, then ethyl iodide (156 mg, 1.0 mmol) diluted in 1 mL of DMF was added drop wise at room temperature and the mixture was stirred for an additional 1 hr. The reaction mixture was diluted with 100 mL of EtOAc and washed with saturated ammonium chloride (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified on a flash chromatography column with EtOAc/hexanes to afford 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (160 mg, 70% yield). The 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (160 mg, 0.56 mmol) was diluted in 10 mL of methanol and 4 mL of 1N NaOH and placed in a sealed tube. The reaction mixture was heated under microwave condition at 120° C. for 25 min. The reaction mixture was diluted with 150 mL of EtOAc and washed with 100 mL of 1N HCl, brine (50 L) and dried. The solvent was removed to afford the product 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (120 mg, 84% yield) as a white solid. LCMS for C11H9Cl2NO2 calcd. (m/e) 257, observed 256 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:30])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:29]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(#N)C>[Cl:22][C:21]1[C:16]([N:15]2[C:11]([C:9]([NH:10][C:5]3[C:6]([C:7]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[Cl:30])=[O:8])=[CH:12][C:13]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[N:14]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)Oc1cc(-c2nc3c(Cl)cc(Cl)cc3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(OS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,8-dichloro-2-[1-(3-chloro-2-pyridinyl)-3-[(methylsulfonyl)oxy]-1H-pyrazol-5-yl]-4H-3,1-benzoxazin-4-one (i.e. the product of Example 1, step D) (0.05 g, 0.10 mmol) in acetonitrile (3 mL) was added isopropylamine (0.5 mL, 5.87 mmol) dropwise. The resulting solution was stirred at room temperature overnight. The reaction was concentrated to dryness to yield 0.038 g of the title compound, a compound of present invention, as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][CH:18]([F:27])[O:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.CCN(CC)CC.C(#N)C>CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH:18]([F:27])[F:17])=[CH:21][CH:22]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
A mixture of (3-ethynyl-phenyl)-carbamic acid tert-butyl ester (14.7 g, 67.7 mmol), 1-difluoromethoxy-4-iodo-benzene (18.2 g, 67.7 mmol), NEt3 (47 mL, 338 mmol), acetonitrile (225 mL), CuI (1.29 g, 6.77 mmol), and Pd(PPh3)2Cl2 (2.85 g, 4.05 mmol) was heated to 60° C. for 1 h. The reaction was diluted with EtOAc/Hex (1:10) and then passed through a pad of silica gel and concentrated and purified with chromatography using hexanes/ethyl acetate (10:1) as the eluting solvents gave the title compound (24.3 g, 100%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([CH3:24])=[C:22]([F:25])[CH:21]=[C:20]([C:26]([NH:28][CH:29]4[CH2:31][CH2:30]4)=[O:27])[CH:19]=3)=[CH:14][CH:13]=2)=[N:9][N:8]=1>O.CN(C=O)C.C(O)C>[N:1]([CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([CH3:24])=[C:22]([F:25])[CH:21]=[C:20]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31]4)=[O:27])[CH:19]=3)=[CH:14][CH:13]=2)=[N:9][N:8]=1)=[N+:2]=[N-:3]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A solution of sodium azide (40 mg) in water (3.5 ml) was added to (4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 34) (200 mg) in DMF (1.5 ml) and ethanol (7 ml) and the reaction mixture stirred for 5 hours at 90° C. The reaction was concentrated under vacuum and the residue partitioned between water (15 ml) and chloroform (15 ml) and the aqueous extracted with chloroform (2×15 ml). The combined organic extracts were dried (magnesium sulphate), and the solvent evaporated under vacuum to give 4′-[5-(azidomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C@H:14]([CH3:33])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)=[O:16])[CH2:9][CH2:8][CH2:7]2.Cl>C(#N)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C@H:14]([CH3:33])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:2])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)=[O:16])[CH2:9][CH2:8][CH2:7]2
Reactant: [NH4+]
Reactant: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Cl)cc2)CC1)N1CCCc2cc(F)ccc21
Agent: Cl
Agent: [OH-]
Solvent: CC#N
Product: C[C@H](C(=O)N1CCN(c2ccc(S(N)(=O)=O)cc2)CC1)N1CCCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ammonium hydroxide (28-30% solution, 7.5 mL) was added dropwise to a solution of the (R)-4-(4-(2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene-1-sulfonyl chloride (375 mg, 0.56 mmol) in acetonitrile (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 4 h. The solution was cooled to 0° C. and aqueous 1.0 M HCl was added dropwise. The reaction mixture was extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over MgSO4. After evaporating the solvents under reduced pressure, the residue was purified by silica gel chromatography using 2-10% methanol in CH2Cl2 to give (R)-4-(4-(2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene sulfonamide as colourless oil (94 mg). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=447.1; tR=2.68 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[CH3:12][C:13]([C:15](Cl)=[O:16])=[CH2:14]>C(#N)C.CO>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:15](=[O:16])[C:13]([CH3:14])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(O)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C=C(C)C(=O)NCC(C)O
Temperature: 25 °C

Procedure:
3.75 g of 1-amino-2-propanol (0.05 mol) were placed in a three-necked flask, equipped with dropping funnel and gas inlet and gas outlet pipe, together with 30 ml of acetonitrile (anhydrous) and 13.79 g of K2CO3 (0.1 mol), and cooled to 0° C. in an ice bath. 6.18 g of methacryl chloride (0.06 mol), dissolved in 30 ml of acetonitrile, were added dropwise over 30 minutes with constant stirring and gentle passage of nitrogen. After stirring for a further 60 minutes with ice cooling, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The batch was filtered through a glass frit and the precipitate was discarded. The filtrate was concentrated in a rotary evaporator until a viscous oil was produced. This was dissolved in 30 ml of methanol and separated from any precipitate which appeared. The filtrate was again concentrated in a rotary evaporator and the residual amounts of the solvent were removed in a high vacuum. The yield was 6.66 g.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=O)[CH2:4][CH2:3][C:2]1=[O:9].[CH3:10][N:11]([CH2:13][CH2:14][CH2:15][NH2:16])[CH3:12]>>[CH3:10][N:11]([CH3:12])[CH2:13][CH2:14][CH2:15][NH:16][C:6]([CH:5]1[CH2:4][CH2:3][C:2](=[O:9])[NH:1]1)=[O:8]
Reactant: CN(C)CCCN
Reactant: O=C1CCC(C(=O)O)N1
Product: CN(C)CCCNC(=O)C1CCC(=O)N1
Temperature: 165 °C

Procedure:
129 Grams of 2-pyrrolidone-5-carboxylic acid were slowly added to 133 g of dimethylaminopropylamine with mixing. This mixture was then stirred and heated for 8-10 hours at 165° C. The excess amine was then distilled off leaving the title product in the form of an amber colored watersoluble solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[F:38][C:39]1[C:52]([O:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])=[CH:51][C:50]2[O:49][C:48]3[C:43](=[CH:44][C:45]([F:67])=[C:46]([O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[CH:47]=3)[C:42](=[O:68])[C:41]=2[CH:40]=1>C1COCC1.CC1CCCO1.C1COCC1>[C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([C:42]2([OH:68])[C:43]3[CH:44]=[C:45]([F:67])[C:46]([O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])=[CH:47][C:48]=3[O:49][C:50]3[C:41]2=[CH:40][C:39]([F:38])=[C:52]([O:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])[CH:51]=3)=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccc(Br)cc1OCc1ccccc1
Reactant: COCCOCOc1cc2oc3cc(OCOCCOC)c(F)cc3c(=O)c2cc1F
Agent: [Li]C(C)(C)C
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OCc3ccccc3)c1)c1cc(F)c(OCOCCOC)cc1O2
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
The bromide 13 (807 mg, 1.59 mmol) was dissolved in 20 mL THF/2-methyltetrahydrofuran (1:1) and cooled to −105° C. in a liquid N2/diethyl ether bath. After stirring at −105° C. for 10 min, 4.5 mL of tert-butyllithium (1.1 M in pentanes) was added dropwise. Stirring was continued for another 15 min. 2,7-difluoro-3,6-bis-(2-methoxy-ethoxymethoxy)-xanthen-9-one 9 (912 mg, 2.07 mmol) dissolved in THF (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at −105° C. for 30 min, the cooling bath removed, and the reaction solution was then stirred for an additional 15 min. The resulting mixture was added to 150 mL NH4Cl(sat) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 50% EtOAc in hexane (with 0.1% Et3N) to yield 956 mg (69%) of 14 as a orange-red oil. Rf=0.33 (in 50% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 5H), 6.97 (d, 2H, J=6.98 Hz), 6.86 (m, 3H), 6.72 (m, 2H), 5.30 (s, 4H), 5.05 (s, 2H), 4.02 (s, 4H), 3.85 (m, 4H), 3.56 (m, 4H), 3.36 (s, 6H), 1.38 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.5, 150.8, 149.3, 147.6, 145.6, 145.5, 145.4, 145.2, 140.5, 138.4, 136.9, 128.3, 127.7, 127.5, 119.9, 119.8, 119.3, 118.4, 115.2, 114.9, 113.0, 104.9, 94.5, 81.0, 71.4, 70.6, 69.7, 68.1, 58.9, 54.6, 28.0; 19F NMR (282 MHz, CDCl3) δ −139.0 (dd, 2 F); mass spectrum, calculated for C46H55F2NO13 (MH+) 868.4, Found 867.8.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[F:31][C:32]([F:39])([F:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.[BH4-].[Na+].[CH3:42][OH:43]>C(Cl)Cl.C(O)(=O)C>[F:31][C:32]([F:39])([F:38])[C:42]([OH:4])=[O:43].[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:34]5[CH2:35][CH2:36][CH2:37][C@H:33]5[C:32]([F:39])([F:38])[F:31])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: FC(F)(F)[C@@H]1CCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@H]5C(F)(F)F)c4)cc23)CC1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DCM (3.0 mL) and MeOH (1.5 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (156 mg, 1.12 mmol) and acetic acid (5 drops). After 6 h of stirring at room temperature, sodium borohydride (43 mg, 1.12 mmol) was added and the reaction was stirred overnight at room temperature. The reaction mixture was purified by Gilson Preparatory HPLC to give 5.0 mg of the title compound (8%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C-:22]#[N:23].[K+].O1CCOCCOCCOCCOCCOCC1>C(#N)C>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][C:22]#[N:23])[CH:11]=3)[CH:7]=[CH:8]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CCl)cc32)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CC#N)cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
A solution of 6-chloromethyl-1-(4-methylphenylsulfonyl)indole (21.5 g) in acetonitrile (224 ml) was treated with potassium cyanide (8.8 g) and 1,4,7,10,13,16-hexaoxacyclooctadecane (3.6 g) and stirred at room temperature under a nitrogen atmosphere for 18 hr. The solution was poured onto ice and extracted with methylene chloride. The organic phase was washed with water and brine, dried (MgSO4) and evaporated. The resultant amber oil was purified by flash chromatography, eluting with 1:5 ethyl acetate:hexane, to give 1-(4-methylphenylsulfonyl)indole-6-acetonitrile (14.4 g, 76%) as a white powder; partial NMR (80 MHz, CDCl3): 2.34(s, 3H, ArCH3), 3.84(s, 2H, NCCH2), 6.62(dd, 1H, H3 -indole), 7.94(m, 1H, H7 -indole)
Reaction SMILES: [OH:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[N:12]([CH3:20])[N:11]=2)[CH2:6][CH2:5]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:34]=[C:35]=[O:36])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].O.CCOCC>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:34][C:35]([O:1][CH:2]([CH3:21])[CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[N:12]([CH3:20])[N:11]=3)[CH2:8][CH2:9]2)=[O:36])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: CC(O)CN1CCC(c2nn(C)c3cc(F)ccc23)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1cc(NC(=O)OC(C)CN2CCC(c3nn(C)c4cc(F)ccc34)CC2)cc(OC)c1OC
Temperature: 100 °C
Yield: 29 %

Procedure:
To a solution of 1-(2-hydroxyprop-1-yl)-4-(6-fluoro-1-methyl-1H -indazol-3-yl)piperidine (200 mg; 0.69 mmol) in 5 ml dry DMF was added 3,4,5-trimethoxyphenylisocyanate (200 mg; 0.96 mmol) in 3 ml dry DMF. The reaction mixture was heated to 100° C. for 2 h, followed by cooling to room temperature and addition of a mixture of 25 ml water and 150 ml ether. The reaction mixture was filtered and separated. The ether phase was washed with water, brine, dried with sodium sulphate and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 with ethyl acetate:methanol (9:1, v/v) as eluent. Concentration of the appropriate fractions gave 100 mg (29%) of the title compound. M.p. 74°-77° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12]O)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Se:30]C#N)([O-:23])=[O:22].C1COCC1.C(P(CCCC)CCCC)CCC>CC(OC)(C)C.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][Se:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC(CCO)N1C(=O)OC(C)(C)C
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1CCC(CC[Se]c2ccccc2[N+](=O)[O-])N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
497 mg of alcohol 170 (1.73 mmol) was dissolved and 432 mg of ortho-nitrophenyl selenocyanate (1.90 mmol, 1.1 eq.) suspended in a solvent mixture consisting of 10 ml of anhydrous THF and 3 ml of anhydrous pyridine. This was followed by careful dropwise addition of 0.56 ml of tri-n-butylphosphine (2.25 mmol, 1.3 eq.) at 0° C. to obtain a dark-red solution. After one hour, the batch was diluted with 30 ml of MTBE, filtered over a small amount of silica gel and concentrated. The brown residue was purified using column chromatography over silica gel (EE/CH 1:3), thereby obtaining 685 mg of selenyl ether 171 (1.45 mmol, 84%) as an intensely yellow-colored oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[CH2:10][CH:11]=O.[CH:13](=O)[CH3:14].C(O)(=[O:18])C.O>C(OCCCC)(=O)C>[CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:18])[CH:11]=[CH:13][CH3:14]
Reactant: CC1C=CCC(C)(C)C1CC=O
Reactant: CC(=O)O
Reactant: CC=O
Solvent: O
Solvent: CCCCOC(C)=O
Product: CC=CC(=O)C1C(C)C=CCC1(C)C
Temperature: 100 °C

Procedure:
In a 250 ml flask were added 30 g (0.18 mole) of 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-2-ethanone (94% purity), 12.0 g of butyl acetate, an aliquot according to Table 1 of the catalytic solution as prepared above and a quantity of co-ingredient according to Table 1. The resulting mixture was stirred at 100° C. To said mixture, 4.0 g (0.09 mole) of acetaldehyde, diluted in 10 g of butyl acetate were introduced under the surface of the liquid, over 3 hours. After the completion of the introduction the reaction was cooled to 35° C. To the cooled reaction medium were added 10 g of acetic acid and then 40 ml of water. After stirring a few minutes, the water phase was removed and the organic phase was neutralized by washing it with 25 g of 20% aqueous potassium carbonate.
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC(F)=CC=3N=2)=CC=1.[CH2:77]([O:79][C:80](=[O:90])[CH2:81][CH2:82]C1C=CC(N)=CC=1)[CH3:78].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>>[CH2:77]([O:79][C:80](=[O:90])[CH2:81][CH2:82][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:9][CH:10]=1)[CH3:78]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was synthesized in analogy to example 20, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 20, intermediate c), 3-(4-amino-phenyl)-propionic acid ethyl ester, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N-ethyldiisopropylamine.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[NH:8]1CCCC1.[C:13]([C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:20]([O:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:21])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[N:3]1([NH:8][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][O:22][C:20](=[O:21])[C:19]3[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=3)=[CH:25][CH:26]=2)[CH2:4][CH2:5][CH2:7][CH2:6]1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)OCc2ccc(C(=O)Cl)cc2)cc1C(C)(C)C
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)OCc2ccc(C(=O)NN3CCCC3)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
760 [l (5.5 mmol) of triethylamine, 450 μl (5.5 mmol) of pyrrolidine and 50 ml of THF are introduced into a round-bottomed flask. 1.8 g (5 mmol) of 4-(3-tertbutyl-4-methoxybenzoyloxymethyl)benzoyl chloride, dissolved in 50 ml of THF, are added dropwise and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: OOS([O-])=O.[K+].[C:7]([C:11]1[N:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:7]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]=2)=[CH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)c1ncc(C=O)cn1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ncc(-c2nc3ccccc3[nH]2)cn1
Reaction time: 0.25 h

Procedure:
16.9 g (55 mmol) of oxone [70693-62-8] are added in portions with stirring at 10° C. to a solution of 16.4 g (100 mmol) of 2-tert-butylpyrimidine-5-carboxaldehyde [104461-06-5] and 11.9 g (110 mmol) of 1,2-diaminobenzene in a mixture of 100 ml of DMF and 3 ml of water, and the mixture is subsequently stirred at room temperature until conversion of the aldehyde is complete (about 2 h). The reaction mixture is stirred into a solution of 40 g of potassium carbonate solution in 2000 ml of water, stirred for a further 15 min., the solid formed is filtered off with suction, washed three times with 100 ml of water each time and dried in vacuo. The solid is dissolved in about 50 ml of hot ethyl acetate, and, during cooling, diethyl ether is added until slightly cloudy, the mixture is stirred for a further 12 h, the crystals are filtered off with suction, washed once with 50 ml of diethyl ether and dried in vacuo. Yield: 16.6 g (66 mmol), 66%. Purity: >95% according to 1H-NMR.