Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH:21]2[CH2:23][CH2:22]2)[C:18]([NH2:20])=[O:19])=[C:5]([F:24])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:24])=[CH:4][C:3]([C:1]([NH2:2])=[O:31])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH:21]1[CH2:22][CH2:23]1
Reactant: Cc1cc(Nc2cc(N[C@@H](C(N)=O)C3CC3)c(F)cc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@@H](C(N)=O)C3CC3)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-2-cyclopropylacetamide (38 mg, 0.110 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (18 mg). MS 364.2 (M+H); UV 219.3, 280.5, 302.6 nm.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH3:14].[C:16]([CH2:24][C:25](=O)[CH3:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>C(O)C.C(O)=O>[C:16]([CH:24]=[C:25]([NH:1][CH2:2][CH:3]([OH:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH3:14])[CH3:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: CCOc1ccccc1OCC(O)CN
Reactant: CC(=O)CC(=O)c1cccnc1
Solvent: CCO
Solvent: O=CO
Product: CCOc1ccccc1OCC(O)CNC(C)=CC(=O)c1cccnc1
Temperature: 25 °C

Procedure:
4.2 g of (-)-1-amino-3-(o-ethoxyphenoxy)-propan-2-ol (laevo-rotatory) ##STR38## are dissolved in 30 ml of ethanol, 3.3 g of the nicotinoyl-acetone ##STR39## are then added and the mixture is heated for 4 hours under reflux, with addition of 1 drop of formic acid as the catalyst. The clear solution is cooled to room temperature and concentrated in a water pump vacuum. An oil is left, which solidifies after a short time. The solid product is recrystallised from toluene. (-)-1-(2-Nicotinoyl-1-methyl-vinylamino)-3-(o-ethoxyphenoxy)-propan-2-ol (laevo-rotatory) is thus obtained ##STR40##
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:8]=[C:9]([CH3:23])[CH:10]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[N:12]=3)[CH:6]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{1-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyrimidine (example E.71) (0.43 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.08 g) which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2]1[NH:3][S:4](=[O:13])(=[O:12])[N:5]=[C:6]([CH2:8][CH2:9][S:10][CH3:11])[N:7]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[NH:3][S:4](=[O:13])(=[O:12])[N:5]=[C:6]([CH2:8][CH2:9][S:10]([CH3:11])=[O:22])[N:7]=1
Reactant: CSCCC1=NS(=O)(=O)NC(N)=N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)CCC1=NS(=O)(=O)NC(N)=N1
Yield: 96.9 %

Procedure:
To a solution of 3-amino-5-[2-(methylthio)ethyl]-1,2,4,6-thiatriazine-1,1-dioxide (1.22 gm, 5.5 mmol) in warm methanol (20 ml) there was added dropwise a solution of 80% pure m-chloroperbenzoic acid (1.2 gm, 5.6 mmol) in chloroform (20 ml). The product crystallized from solution during the addition and was collected by filtration and washed with diethyl ether to give 1.27 gm of pure product, m.p. 180°-182° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11]S(C(C)(C)C)(=O)=O)[CH3:10])=[CH:5][C:4]=1[F:19].N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCOCC1.CO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:26](=[O:28])[CH3:27])[CH3:10])=[CH:5][C:4]=1[F:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(NS(=O)(=O)C(C)(C)C)c1ccc(Br)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)NC(C)c1ccc(Br)c(F)c1
Reaction time: 1 h

Procedure:
20.0 mL 4N HCl in dioxane are added to 17.2 g (53.4 mmol) 2-methyl-propane-2-sulfonic acid [1-(4-bromo-3-fluoro-phenyl)-ethyl]-amide (X.1) in 150 mL MeOH. Stirring is continued for 1 h. After that time, the mixture is concentrated and the residue is triturated from diethylether (150 mL). The precipitate is filtered off, washed with diethylether and suspended in 250 mL DCM. 8.64 mL (107 mmol) pyridine and 5.29 mL (56.1 mmol) acetic anhydride are added and the mixture is stirred for 12 h at rt. After that time, the mixture is transferred to a separation funnel, washed with 1N HCl (200 mL) and sat. aq. NaHCO3-solution (200 mL) and dried over sodium sulphate. The solvent is removed by evaporation to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[Cl:26].C1COCC1.C(N(CC)CC)C>N1C=CC=CC=1>[Cl:26][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[NH:19][C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: Nc1ccncc1Cl
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1c(-c2ccc(C(=O)Nc3ccncc3Cl)s2)noc1C(F)(F)F
Yield: 83 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-amino-3-chloropyridine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and pyridine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCO3 solution followed by water to afford product as a colorless solid (80 mg, 83%). 1H NMR (CDCl3) 2.40 (s, 3 H), 7.59 (d, J=4.0, 1 H), 7.73 (d, J=4.0, 1 H), 8.46 (s, 3 H), 8.59 (s, 1 H). 13C NMR 7.9, 114.5, 114.7, 118.6 (q, J=271), 129.0, 129.7, 135.2, 140.4, 141.0, 149.4, 149.6, 155.6 (q, J=40), 157.6, 159.3. 19F NMR −63.1. LC/MS 6.68 min, [M+1]+ 388.
Reaction SMILES: CO[CH:3](CSC(=O)NCCCCCCCCCCCCCCCCCC)[CH2:4]N.[CH2:29]([S:45][CH2:46][CH:47]([O:50][CH3:51])[CH2:48][NH2:49])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[NH2:49][CH2:48][C:47]1([CH2:46][S:45][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][CH2:3][CH2:51][O:50]1
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CN)OC
Product: CCCCCCCCCCCCCCCCSCC1(CN)CCCO1

Procedure:
2-Hexadecylthiomethyl-2-hydroxymethyltetrahydrofuran IV b1 is allowed to react and worked by the same procedure as described in (3), the summary of the experimental condition and the physical data of the product are listed in the Tables 5 and 6.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].FC(S(O)(=O)=O)(F)F.ClC(Cl)(Cl)C(=N)O[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:19]([CH:2]([OH:3])[C:1]([O:5][CH3:6])=[O:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(O)Cc1ccccc1

Procedure:
To a solution containing methyl glycolate (2.5 mL, 32 mmol) and trifluoromethyl-sulfonic acid (150 mL) in CH2Cl2 (10 mL) was added benzyl 2,2,2-trichloro-acetimidate (7.0 mL, 37 mmol). After stirring for several min, the mixture was poured into aqueous NaHCO3 and extracted with Et2O. The organic extract was washed with saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 9-17% EtOAC/Hex to afford the title compound: 1H NMR CDCl3): d 7.34 (m, 5H); 4.62 (s, 2H); 4.11 (s, 2H); 3.78 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].FC(C(O)=O)(F)F.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:38]1([NH:44][C:45]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CC(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)Nc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of Leu-DTrp-βAla-OEt-TFA (40.6 mg) obtained in Example 51-(1) in chloroform (2 ml) were added TEA (20 μl) and phenyl isocyanate (15 μl) at room temperature under nitrogen. The reaction mixture was stirred for 1 h, and concentrated under reduced pressure. The residue was purified by dry column flash chromatography (Merck, Kieselgel 60) with chloroform/methanol=10/1 for elution to give the product (39.6 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[I-].[Na+].Br[CH2:14][CH2:15][CH2:16][Br:17].[OH2:18]>CN(C=O)C.C(O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:6][CH2:7][CH2:8][O:18][C:5]1[CH:4]=[CH:9][CH:14]=[CH:15][C:16]=1[Br:17]
Reactant: O
Reactant: Oc1ccccc1Br
Reactant: BrCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1ccccc1OCCCOc1ccccc1Br
Reaction time: 0.25 h

Procedure:
2.6 g (110 mmol) of sodium hydride are added in portions with vigorous stirring to a solution of 18.2 g (105 mmol) of 2-bromophenol in 200 ml of DMF. After the mixture has been stirred for a further 15 min., 1.5 g (10 mmol) of sodium iodide are added. A mixture of 4.8 ml (50 mmol) of 1,3-dibromopropane in 50 ml of DMF is added dropwise to this mixture, which is subsequently stirred at room temperature for 60 h. 5 ml of ethanol are added dropwise to the reaction mixture, which is then poured into 1000 ml of water and extracted three times with 200 ml of dichloromethane. The combined organic phases are washed five times with 500 ml of water, dried over MgSO4 and evaporated under reduced pressure. The foam which remains is washed by stirring with 200 ml of n-heptane, filtered off with suction, washed with n-heptane and dried under reduced pressure. Yield: 15.0 g, 77.7% of theory, purity: 98.0% according to 1H-NMR.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F-:15].[K+].CN(C)C=O>O>[F:15][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)c1ccc(Cl)cc1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 25.8 %

Procedure:
A mixture of ethyl α-bromo-4-chlorophenylacetate (37.3 g), anhydrous potassium fluoride (9.7 g) and dry dimethylformamide (75 ml) was heated with stirring at a temperature of 140°-150° C. for a period of 6 hours. The reaction mixture was poured into water and the aqueous mixture extracted with methylene dichloride. The organic extract was washed with aqueous sodium carbonate, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The product was distilled using a spinning band column to give ethyl α-fluoro-4-chlorophenylacetate (7.5 g; 29%) b.p. 67° C. at 0.06 mm Hg.
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(=O)N2CCCc3cc(Cl)cc1c32
Yield: 47.4 %

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (7.49 g, 0.04 mole) and N-chlorosuccinimide (5.34 g, 0.04 mole) in carbon tetrachloride (40 ml) was refluxed for 23 hours. After cooling, the resultant red precipitate was collected by filteration, washed with water and dried. Recrystallization from acetonitrile afforded 4.2 g (47.4%) of red needles, melted at 188°-189° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].O=[C:7]([CH2:13][C:14](=O)[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:14]([CH3:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNCCO
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(CCO)n1
Reaction time: 0.33 h
Yield: 113.5 %

Procedure:
A solution of 2-hydroxyethylhydrazine (15.2 g, 200 mmol) in ethanol (50 mL) was added over a period of 30 minutes to a solution of ethyl 2,4-dioxopentanoate (31.6 g, 200 mmol) in ethanol (200 mL). The reaction mixture was stirred for an additional 20 minutes and then concentrated under reduced pressure to provide 45 g of ethyl 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxylate a light brown oil. A portion (31.1 g) of this material was combined in a Parr vessel with methanol (25 mL) and concentrated ammonium hydroxide (25 mL). The vessel was sealed and the mixture was heated for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a brown resin. The resin was stirred with a mixture of chloroform and methanol until a solid appeared. The solid was isolated by filtration and then recrystallized from isopropanol to provide 7.01 g of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide as a white solid. The rest of the ester was purified by IFC (silica gel eluting with a gradient of 50 to 100% ethyl acetate in hexanes) to provide 6.6 g of a pale yellow oil. This material was dissolved in concentrated ammonium hydroxide (25 mL) and allowed to stand at ambient temperature for 48 hours. A precipitate was isolated by filtration, rinsed with water, and dried to provide 3.74 g of 1-(2-hydroxyethyl)-5-methyl-1H-pyrazole-3-carboxamide as white needles, mp 170-172° C. Anal. Calcd for C7H11N3O2: C, 49.70; H, 6.55; N, 24.84. Found C, 49.59; H, 6.65; N, 24.92.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[C@@H:27]([F:32])[CH2:26]1)[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:31][C@@H:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][C@@H:27]4[F:32])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CCN1CC[C@@H](N)[C@@H](F)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)[C@@H](F)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.35 g, 45.5 mmol), (3S,4R)-1-ethyl-3-fluoro-piperidin-4-ylamine (dihydrochloride salt) (6.30 g, 29.0 mmol), diisopropylethylamine (21.0 ml, 120 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 14 h. The mixture was cooled to 25° C. and was stirred at that temperature for 4 h. The resulting yellow precipitate was collected by vacuum filtration, washed with Et2O (1×30 ml), and air-dried to give (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((3S,4R)-1-ethyl-3-fluoro-piperidin-4-yl)-amine (11.5 g, 90% over 3 steps) as a yellow solid. LCMS (Method G, ESI): RT=0.69 min, m+H=448.3; 1H NMR (400 MHz, CDCl3) δ 9.35 (d, J=8.4 Hz, 1H), 9.12 (s, 1H), 8.29-8.11 (m, 2H), 7.69-7.59 (m, 2H), 7.52 (t, J=7.8 Hz, 2H), 7.26 (s, 1H), 6.65 (d, J=4.2 Hz, 1H), 4.86 (d, J=48.6 Hz, 1H), 4.28-4.05 (m, 1H), 3.27-3.13 (m, 1H), 2.97-2.87 (m, 1H), 2.52 (q, J=7.2 Hz, 2H), 2.49-2.37 (m, 1H), 2.29 (t, J=10.0 Hz, 1H), 2.15-1.98 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]#[N:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C(=O)(O)[O-].[Na+]>CO>[Si:1]([O:18][CH2:19][CH2:20]/[C:21](=[N:24]/[OH:25])/[NH2:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](OCC/C(N)=N/O)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-{[tert-butyl(diphenyl)silyl]oxy}propanenitrile (4.4 g, 14.2 mmol) in methanol (40 ml) was added hydroxylamine hydrochloride (8.9 g, 128 mmol) and sodium bicarbonate (11.9 g, 142 mmol). The mixture was heated at reflux for 48 hours. The mixture was then cooled to room temperature, the solvent was evaporated, ice water was added, and the resulting solution was extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (50-100% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C.ClCCl>C1(C)C(C)=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CCN(c2ccncc2)CC1

Procedure:
4.0 g (26.6 mmol) of 4-chloropyridine hydrochloride, 4.2 g (26.6 mmol) of ethyl piperidine-4-carboxylate and 7.4 ml (53.2 mmol) of triethylamine were stirred in 100 ml of xylene at 130° C. for 24 hours. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH2:44][C:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46])=[CH:36]1>CO>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:53](=[O:54])[CH:48]([NH:47][C:45](=[O:46])[CH2:44][C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[NH:35][CH:36]=2)[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: CC(C)C[C@H](NC(=O)Cc1c[nH]c2ccccc12)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CC(C)CC(NC(=O)Cc1c[nH]c2ccccc12)C(=O)NC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The more polar diastereomer of (4-dimethylamino-4-phenyl-cyclohexyl)amine (143 mg, 0.66 mmole) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (272 mg, 0.98 mmole) were added to a solution of N-(3-indolylacetyl)-L-leucine (189 mg, 0.66 mmole) in MeOH and stirred for 24 h at room temperature. Working up was performed by removing MeOH by distillation. The residue was re-dissolved with water, adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and then evaporated. The product was obtained as a colorless oil in a yield of 320 mg (100%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([N:10]([CH2:32][CH3:33])[CH:11]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[C:22]([CH3:23])=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[CH:31])[CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12]1)[CH3:9]>>[CH2:32]([N:10]([CH2:8][CH3:9])[CH:11]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[C:22]([CH3:23])=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[C:31][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12]1)[CH3:33]
Reactant: Ic1ccccc1
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4ccccc4)c3)c2C)C1
Yield: 70 %

Procedure:
In analogy to the procedure described in Example 31F], iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 70% yield light yellow semisolid. MS: 427.3 (MH+).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31][NH:30]1.O>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]=[CH:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29](=[O:28])[NH:30][CH:31]=2)[CH:11]=1
Reactant: O=Cc1c[nH]c(=O)c2ccccc12
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]cc(C=Cc2cccnc2)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under an N2 atmosphere, 147 g (377 mmol) of triphenyl-(pyridin-3-yl-methyl)-phosphonium chloride in 2.2 l of THF are mixed with 44.1 g (393 mmol) of potassium-tert-butylate and stirred for 30 min. The suspension is heated to 50° C. and a mixture of 50.0 g (289 mmol) of 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde and 2.2 l of THF is added dropwise and finally stirred for 10 h at 60° C. To the cooled reaction mixture is added 700 ml of water and then the THF is evaporated off on a RE. The residue is taken up in 5 l of water and 8 l of EtOAc, the water phase is separated and extracted 3 more times with EtOAc. The organic phases are washed with water and with brine, combined, dried (Na2SO4) and left to stand over night. A solid separates from the mixture and is filtered off and washed with EtOAc[→(E) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one]. The filtrate is extracted twice with 1 N HCl and then discarded. The acidic aqueous phases are immediately rendered basic with sat. Na2CO3 solution and extracted 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, EtOAc/ethanol 19:1→9:1) yields first of all (Z) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one, followed by an (E/Z) mixture of 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one. (E) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-on: m.p. 222-224° C.; 1H NMR (DMSO-d6) δ 11.57 (sb, HN), 8.80 (s, 1H), 8.44 (d, 1H), 8.26 (d, 1H), 8.12 (m, 2H), 7.79 (t, 1H), 7.68 (d, J=16.3 Hz, 1H), 7.56 (m, 2H), 7.39 (dd, 1H), 7.07 (d, J=16.3 Hz, 1H). (Z) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one: 1H NMR (DMSO-d6) δ 11.24 (sb, HN), 8.39 (s, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 7.71 (t, 1H), 7.65 (d, 1H), 7.54 (m, 2H), 7.21 (dd, 1H), 6.90 (s, 1H), 6.81 (s, 2HOlef.).