Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([Br:16])[N:15]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:14]1[N:15]=[C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]([NH2:17])=[N:12][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)nc1C#Cc1ccccc1
Temperature: 120 °C
Yield: 70.6 %

Procedure:
Phenylacetylene (969.2 mg, 1.044 mL, 9.490 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (2 g, 7.908 mmol), triethylamine (8.002 g, 11.02 mL, 79.08 mmol), copper (I) iodide (180.7 mg, 0.9490 mmol) and Pd(PPh3)4 (456.9 mg, 0.3954 mmol) in DMF (24 mL) and the resulting solution heated at 120° C. for 10 minutes. The reaction mixture was cooled to ambient temperature and diluted with EtOAc (20 mL) and 1 MHCl/brine (10 mL/10 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and combined organics washed with brine (2×20 mL), dried over (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 80 g column, eluting with 0 to 50% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-tile compound as an off-white solid (1.53 g, 70%). 1H NMR (400.0 MHz, DMSO) δ 7.04 (br s, 2H), 7.46-7.50 (m, 3H), 7.75-7.77 (m, 2H) and 8.13 (s, 1H) ppm; (ES+) 275.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][N:11]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
3-(3,5-Dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (5.6 g), 4-fluoro-2-trifluoromethylbenzo-nitrile (4.5 g) and potassium carbonate (5.4 g) were added to N,N-dimethylformamide (50 mL), and the mixture was stirred at 110° C. for 4 hours. After cooling the mixture to room temperature, the solution was diluted with ethyl acetate and washed with water three times. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a column chromatography to obtain the title compound (3.8 g).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1.[OH-].[Na+].Cl>CCO>[CH3:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:16])=[O:2])[CH:15]=[CH:14][C:9]=2[N:10]=1
Reactant: COC(=O)CCc1ccc2nc(C)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(CCC(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of 3-(2-methyl-benzothiazol-6-yl)-propionic acid methyl ester (150 mg, 1.67 mmol) in EtOH (5 mL) is added aqueous 1M NaOH (5 mL) and the mixture is stirred at room temperature for 2 hours. The solution is acidified to pH 3 with aqueous 1M HCl and is extracted with ethyl acetate. The organic layer is washed with water, brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1% TFA) to give 3-(2-methyl-benzothiazol-6-yl)-propionic acid.
Reaction SMILES: C(OC(=O)C(=COCC)C#N)C.C(OC(OCC)C(NN)C)C.[CH3:24][CH:25]([N:33]1[C:37]([NH2:38])=[C:36]([C:39]([O:41]CC)=[O:40])[CH:35]=[N:34]1)[CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>C(O)C.[OH-].[Na+]>[CH3:24][CH:25]([N:33]1[C:37]([NH2:38])=[C:36]([C:39]([OH:41])=[O:40])[CH:35]=[N:34]1)[CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)c1cnn(C(C)C(OCC)OCC)c1N
Agent: CCOC(OCC)C(C)NN
Agent: CCOC=C(C#N)C(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)C(C)n1ncc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a solution of 2-(ethoxymethylene)-2-cyanoacetic acid ethyl ester (56.3 g) in ethanol (200 ml) was added dropwise 2-hydrazinopropionaldehyde diethyl acetal (54 g) in ethanol (80 ml) at room temperature. The mixture was refluxed for 4 hours. The reaction mixture was cooled at room temperature and the solvent was distilled off in vacuo to give the crude. 1-(1-methyl-2,2-diethoxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (100 g). The crude product (100 g) was dissolved in aqueous 4N-sodium hydroxide (170 ml) and the mixture was refluxed for 1 hour. The reaction mixture was cooled at room temperature and washed with ethyl acetate (100 ml×2). The aqueous solution was adjusted to pH 3.5 with 6N-hydrochloric acid and stirred for 1 hour. The precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide to give 1-(1-methyl-2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (9.93 g).
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:26])C=1.C(OC(C)C)(C)C>C(Cl)Cl>[Cl:17][C:2]([Cl:1])([Cl:16])[C:3]([NH:5][C:6]1[CH:7]=[N+:8]([O-:26])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:4]
Reactant: O=C(Nc1cnc2c(c1)CCCC2)C(Cl)(Cl)Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: O=C(Nc1cc2c([n+]([O-])c1)CCCC2)C(Cl)(Cl)Cl
Yield: 98.9 %

Procedure:
To a solution of 24.03 g of Compound 2 obtained in the above step (2) in 40 ml of methylene chloride is added 21.2 g of 80% m-chloroperbenzoic acid at room temperature, and the resultant mixture is stirred for 45 minutes. The reaction mixture is mixed with isopropyl ether and the crystals are filtered to give 25.06 g of the titled compound 3 as crystals. Yield: 99% mp.: 244° to 246° C. (dec.)
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][C@H:18]2[C:26]([O:28][CH3:29])=[O:27])[C:13]1=[O:30])=O)C1C=CC=CC=1>C(O)(C)C.[OH-].[Pd+2].[OH-]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:24])[CH3:25])[CH2:19][C@H:18]2[C:26]([O:28][CH3:29])=[O:27])[C:13]1=[O:30]
Reactant: COC(=O)[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)O
Product: COC(=O)[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 20 h
Yield: 93.1 %

Procedure:
20% Palladium hydroxide (0.30 g) was carefully wetted down under nitrogen with isopropanol (10 mL) then (3R,4S)-methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxo-pyrrolidin-1-yl)-1-isopropylpiperidine-3-carboxylate (1.10 g) in isopropanol (10 mL) was added. The mixture was hydrogenated on a Parr shaker for 20 hours. Worked up by filtering off the catalyst under nitrogen through fiberglass filter paper. The filtrate was stripped to give (3R,4S)-methyl 4-((3S)-3-amino-2-oxopyrrolidin-1-yl)-1-isopropylpiperidine-3-carboxylate (695 mg) as an oil. Yield=93%. LCMS detects (M+H)+=284.34.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.O.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>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:8]2[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2](/[CH:37]=[CH:36]/[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:3][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:10][C:9]=2[CH:20]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Yield: 61.1 %

Procedure:
To a solution of 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (79 mg, 0.18 mmol) in DMF (1.7 mL) was added triethylamine (0.125 mL, 0.90 mmol) followed by tert-butyl acrylate (0.184 mL, 1.25 mmol) and Pd(PPh3)2Cl2 (18.9 mg, 0.03 mmol). The mixture was then subjected to microwave irradiation for 1 h at 120° C. after which the reaction was diluted with water (15 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with brine (30 mL), passed through a phase separator to remove water and concentrated in vacuo to give the crude product as an orange oil which was purified by column chromatography (SiO2, 0-50% EtOAc/Heptane) to give (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate as a pale yellow oil (55 mg, 0.11 mmol, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm=1.44 (s, 9H), 3.71 (s, 3 H), 3.78 (s, 3 H), 6.13 (d, J=15.66 Hz, 1 H), 6.76-6.83 (m, 3 H), 6.86 (m, J=8.59 Hz, 2 H), 7.14-7.19 (m, 2 H), 7.31 (m, J=8.59 Hz, 2 H), 7.42 (d, J=16.17 Hz, 1 H), 7.54 (d, J=8.59 Hz, 2 H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21].C(=O)([O-])[O-].[K+].[K+].[C:28](#[N:31])[CH:29]=[CH2:30]>CS(C)=O>[NH2:2][C:3]1([CH2:30][CH2:29][C:28]#[N:31])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21]
Reactant: COc1ccc2c(c1)C(N)C(=O)N2c1ccc(F)cc1
Reactant: C=CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(N)(CCC#N)C(=O)N2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 60 g of 3-amino-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-1H-indol-2-one hydrochloride, 43 g of potassium carbonate, 20 ml of acrylonitrile and 200 ml of dimethyl sulfoxide was stirred at room temperature under argon atmosphere for 2 hours. 2 ml of acrylonitrile was added to the mixture, and stirring was continued overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. Precipitated crystals were collected by filtration to afford 46.8 g of 3-[3-amino-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-2-oxo-1H-indol-3-yl]propanenitrile. Melting point 136° to 138° C. EI-MS (m/z): 325 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH3:12])[CH3:2].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O.Cl[Cu]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:7][C:6]=1[CH3:12])[CH3:2]
Reactant: Ic1ccccn1
Reactant: CCOC(=O)c1ccc(O)cc1C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccccn2)cc1C
Temperature: 120 °C

Procedure:
A mixture of 4-hydroxy-2-methyl-benzoic acid ethyl ester (400 mg), 2-iodo-pyridine (0.29 mL), CuCl (110 mg), 2,2,6,6-tetramethyl-heptane-3,5-dione (TMHD, 0.087 mL), cesium carbonate (940 mg) in NMP (2 mL) was heated at 120° C. for 20 h. Then the reaction was cooled, diluted with EtOAc, solids were filtered off, filtrate was washed with water, diluted NaCl solution, dried over sodium sulfate, filtered off, concentrated, the residue was column purified to give the desired product (531 mg). LC MS ESI+: 258 (M+1)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([S:15][CH3:16])[N:12]([CH3:17])[N:11]=2)=[C:6]([F:18])[CH:5]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:14]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][C:6]=2[F:18])=[N:11][N:12]([CH3:17])[C:13]=1[S:15][CH3:16]
Reactant: BrBr
Reactant: CSc1cc(-c2ccc(Cl)cc2F)nn1C
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1c(Br)c(-c2ccc(Cl)cc2F)nn1C
Reaction time: 72 h

Procedure:
13.7 g (86 mmol) of bromine were added dropwise to a solution of 20 g (78 mmol) of 3-(4-chloro-2-fluorophenyl)-1-methyl-5-methylthio-1H-pyrazole in 400 ml of carbon tetrachloride, and the mixture was then stirred for 3 days. The reaction solution was subsequently washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and finally concentrated. The crude product was purified by silica gel chromatography (mobile phase: hexane/ethyl acetate =9:1). Yield: 22.4 g. 1H-NMR (270 MHz, in CDCl3): δ[ppm]=2.40 (s, 3H), 4.06 (s, 3H), 7.15-7.25 (m, 2H), 7.48 (t, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[NH2:52][CH2:53][CH2:54][C:55]([OH:57])=[O:56]>>[CH:44]1([O:43][N:38]2[C:39]([CH3:42])([CH3:41])[CH2:40][CH:35]([CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:4]3[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]4[CH2:14][C:15]([CH3:29])([CH3:28])[N:16]([O:21][CH:22]5[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[C:17]([CH3:20])([CH3:19])[CH2:18]4)[N:7]=[C:2]([NH:52][CH2:53][CH2:54][C:55]([OH:57])=[O:56])[N:3]=3)[CH2:36][C:37]2([CH3:51])[CH3:50])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: NCCC(=O)O
Product: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(NCCC(=O)O)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and β-alanine according to the procedure of Example 15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:25][C:26]1([CH2:33][CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][CH:29]2[CH2:28][CH2:27][C:26]([CH2:33][CH2:34][C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=4)[N:38]=[CH:37][N:36]=3)([OH:25])[CH2:31][CH2:30]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc2ncnc(CCC3(O)CCC(=O)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC2CCC(O)(CCc3ncnc4ccc(OC)cc34)CC2)cc1
Reaction time: 8 h

Procedure:
4-Methoxybenzylamine (0.026 ml, 0.24 mmol) and then sodium triacetoxyborohydride (0.08 g, 0.377 mmol) were added to a solution of 4-hydroxy-4-[2-(6-methoxyquinazolin-4-yl)-ethyl]cyclohexanone (0.06 g, 0.2 mmol) in dichloromethane (1 ml). The reaction mixture was stirred overnight and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 and then dichloromethane/MeOH 9/1 and 2% triethylamine).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([F:34])[CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([F:34])[CH2:3]1)(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1F
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1C[C@@H](F)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f71) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].I[CH3:19].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([C:7]1[N:8]([CH3:19])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2ccccc2[nH]1
Reactant: CI
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCc1cc2ccccc2n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hexyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, iodomethane was added and stirred for 3 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C@@H:22]([OH:51])[CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:50]=[CH:49][C:30]([NH:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:39])[CH2:34][CH2:33]3)=[CH:29][CH:28]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:41]([NH:40][C:38]([N:35]1[CH2:36][CH2:37][CH:32]([NH:31][C:30]2[CH:49]=[CH:50][C:27]([CH2:26][CH2:25][NH:24][CH2:23][C@H:22]([OH:51])[CH2:21][O:20][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[C:18]4[C:13]=3[CH2:14][CH2:15][C:16](=[O:19])[NH:17]4)=[CH:28][CH:29]=2)[CH2:33][CH2:34]1)=[O:39])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)c4c3CCC(=O)N4)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c4c3CCC(=O)N4)cc2)CC1
Yield: 36 %

Procedure:
4-(4-{2-[((2S)-3-{[8-(Benzyloxy)-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl]oxy}-2-hydroxypropyl)amino]ethyl}anilino)-N-octyl-1-piperidinecarboxamide (0.16 g, 0.228 mmol) was dissolved in ethanol and 10% palladium on carbon (0.07 g) added. The solution was shaken in a Parr apparatus at 50 psi hydrogen atmosphere for 4 hours, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash silica gel chromatography on silica gel Merck-60 to yield the title compound (0.05 g, 0.082 mmol).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:27][O:28][C:29](=[O:47])[CH2:30][N:31]1[C:35](=[O:36])[N:34]([CH2:37][CH:38]=[O:39])[C:33]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[N:32]1.Cl>C1COCC1>[CH3:27][O:28][C:29](=[O:47])[CH2:30][N:31]1[C:35](=[O:36])[N:34]([CH2:37][CH:38]([OH:39])[C:2]([F:4])([F:3])[F:1])[C:33]([C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)=[N:32]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Reaction time: 1 h

Procedure:
6.69 ml of a 0.5 M solution of (trifluoromethyl)trimethylsilane in THF (3.34 mmol) and 39 μl of a 1 M solution of tetra-n-butylammonium fluoride in THF (39 μmol) are successively added at 0° C. to a solution of 948 mg (2.57 mmol) of the compound from Example 225A in 17 ml THF. The temperature is allowed to rise to RT and the mixture stirred for 1 hr more. For the workup, the reaction mixture is treated with 8 ml of 1 N hydrochloric acid. It is stirred for 1 hr at RT, before the THF is removed on the rotary evaporator. The aqueous residue is extracted with ethyl acetate. The organic phase is washed twice with water and once with sat. sodium chloride solution, dried over magnesium sulphate and freed of solvent on the rotary evaporator. The residue is purified by silica gel chromatography (eluent: dichloromethane/methanol 100:1→100:2). 630 mg (65% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)Nc3ccccn3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)Nc3ccccn3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-(2-pyridylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (200 mg), 1 N aqueous sodium hydroxide solution (0.88 ml), ethanol (1 ml), and tetrahydrofuran (1 ml) was stirred at room temperature for one hour. 1 N hydrochloric acid (0.88 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-(2-pyridylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (110 mg, yield: 58%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 187–188° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3cccc([N+](=O)[O-])c3)c2n2ccnc12
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(C=c2c3ccccc3c3[nH]c(=O)c4nccn4c23)c1
Reaction time: 72 h
Yield: 61.1 %

Procedure:
To 0.5 g of 10-(3-nitrobenzylidene)-5H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one suspended in 15 ml of absolute ethanol are added 1.57 g of tin chloride dihydrate. The reaction medium is refluxed for 6 hours and then left at a temperature in the region of 20° C. for 72 hours. The reaction medium is treated with 30 ml of saturated sodium carbonate solution and the insoluble material is filtered off, washed with water, dried and then taken up in 80 ml of dimethylformamide. The new insoluble material is filtered off and discarded. The filtrate is concentrated to dryness under reduced pressure and dried (5 mmHg; 0.65 kPa) at 55° C. 0.28 g of 10-(3-aminobenzylidene)-5H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained in the- form of an orange-coloured powder, the melting point of which is greater than 260° C. (Analysis, C20H14 N4O.0.39 H2O.0.48 DMF; % calculated C: 73.61; H: 4.32; N: 17.17; % found C: 73.6; H: 3.9; N: 16.9).