Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][CH:24]([O:36][CH3:37])[CH2:25][C:26]1[N:31]=[C:30]2[CH2:32][O:33][C:34](=O)[C:29]2=[CH:28][CH:27]=1.OS(O)(=O)=O>C1COCC1>[CH3:37][O:36][CH:24]([O:23][CH3:22])[CH2:25][C:26]1[N:31]=[C:30]2[CH2:32][O:33][C:34](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:29]2=[CH:28][CH:27]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COC(Cc1ccc2c(n1)COC2=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (141 mg, 0.93 mmol.) in THF (4 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.9 mL of a 1 M solution in THF, 1.9 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 2-(2,2-dimethoxy-ethyl)-7H-furo[3,4-b]pyridin-5-one (104 mg, 0.47 mmol in THF (1 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 1.5 h and is then poured into cold aqueous 2N H2SO4 solution (10 mL) at 0° C. The resulting mixture is heated at 45° C. for 30 min and then cooled to room temperature and stirred overnight. The reaction mixture is poured into ice water (150 mL) and stirred for 2 h. The solid which formed is collected to give the title compound as a brown solid (76 mg, 46%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:31]3[CH2:32][CH2:33][CH:28]([CH2:27][O:26][CH3:25])[CH2:29][CH2:30]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: COCC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: COCC1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 4-(methoxymethyl)piperidine (117 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (50 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 1.59-1.75 (m, 2 H) 1.98-2.12 (m, 2 H) 3.31 (s, 3 H) 3.41-3.58 (m, 3 H) 3.97-4.15 (m, 2 H) 6.35 (d, J=2.27 Hz, 1 H) 7.40 (s, 1 H) 7.60 (m, J=8.34 Hz, 2 H) 7.99 (m, J=8.59 Hz, 2 H) 8.08 (d, J=2.27 Hz, 1 H) 10.88 (s, 1 H). ESI-MS: m/z 424.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:26][CH3:27])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[O:7][CH2:6][CH2:5]2.N#N.[CH3:30][N:31](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[C:30]([C:2]1[C:3]([O:26][CH3:27])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]1)[O:7][CH2:6][CH2:5]2)#[N:31]
Reactant: COc1c(Br)ccc2c1CCOC2CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [C-]#N
Product: COc1c(C#N)ccc2c1CCOC2CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-[(6-bromo-5-methoxy-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (50 mg, 0.11 mmol), Pd(PPh3)4 (20 mg) and Zn(CN)2 (26 mg, 0.23 mmol) in 5 mL of anhydrous DMF was to 110° C. at N2 atmosphere overnight. The reaction was cooled to room temperature, extracted by EtOAc, washed by water then by brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford tert-butyl 4-[(6-cyano-5-methoxy-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1
Reactant: O=C(O)Cc1cc(Cl)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cc(Cl)ccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A solution of 5 g (26.51 mmol) of 5-chloro-2-fluoro-phenylacetic acid in 60 ml of THF was added dropped to a suspension of 2.012 g (53.02 mmol) of lithium aluminium hydride in 26.5 ml of THF. 30 ml of THF were added, and the mixture was heated under reflux for 3 h. After cooling to 0° C., a solution of 929.7 mg (16.57 mmol) of potassium hydroxide in 4 ml of water was cautiously added and the mixture was stirred overnight at room temperature. The formed precipitate was filtered off with suction and washed with THF. The combined filtrates were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (DCM/methanol 98:2) to give 3.8 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][C@@H:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@@H:18]([OH:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[CH:2]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1.C1(=O)CCCCC1.C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][C@@H:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[CH:2]=1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCOCC
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Temperature: 90 °C
Yield: 85.8 %

Procedure:
From a solution of 17-(3-Pyridyl)-5α-androst-16-en-3α-ol (1.05 g, 3.0 mmol) in dry toluene (60 ml) and cyclohexanone (10 ml) was distilled off part of the solvent (20 ml) to eliminate moisture. After allowing to cool to 90° C., aluminium isopropoxide (1.02 g, 5.0 mmol) was added and the mixture heated under reflux for 90 min. then allowed to cool. The mixture was diluted with diethyl ether (250 ml), washed with aqueous trisodium citrate (15% w/v; 2×30 ml), dried (Na2CO3), and concentrated. Chromatography, on elution with toluene-methanol (40:1), afforded the title compound (0.90 g, 86%) which crystallised from toluene, m.p. 190°-192° C. IR νmax 1713 cm-1 ; 1H-NMR (CDCl3) inter alia δ1.04 (3H,s,19-CH3), 1.07 (3H,s,18-CH3), 5.98 (1H,M,16-H), 7.22 (1H,m,Py 5-H), 7.64 (1H,m,Py 4-H), 8.46 (1H,m,Py 6-H), 8.61 (1H,m,Py 2-H); MS m/z 349 (M+). Anal. Calcd: C,82.47; H,8.94; N,4.01. Found: C,82.00; H,8.94; N,3.84%
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([S:7]([CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:13][CH2:12]1)(=[O:9])=[O:8])[CH3:6])C.[OH-].[Li+].Cl>CO.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([C:14]2([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])[CH2:13][CH2:12][CH:11]([CH2:10][S:7]([CH:5]([CH3:6])[C:4]([OH:35])=[O:3])(=[O:9])=[O:8])[CH2:16][CH2:15]2)(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C)S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
The product from Example 73 (55 mg, 0.1 mmol) was dissolved in methanol (2 mL) and lithium hydroxide (12 mg, 0.5 mmol) added. The reaction was stirred at room temperature overnight, diluted with water, acidified with 2M aqueous hydrochloric acid solution and extracted with ethyl acetate (x3). The organic extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with ethyl acetate to give a white solid (48 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:16]>CN(C)C=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([CH2:14][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2([CH3:12])[CH3:1])=[O:16])=[CH:18][CH:19]=1
Reactant: CC1(C)CCc2ccccc2N1
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CC1(C)CCc2ccccc2N1CC(=O)c1ccc(F)cc1
Yield: 85.2 %

Procedure:
A stirred mixture of 2,2-dimethyl-1,2,3,4-tetrahydroquinoline (4.69 g) and 2-bromo-4'-fluoroacetophenone (3.17 g) in dry N,N-dimethylformamide (6 ml) was heated at 70°-80° C. for 5 hours under nitrogen. The reaction mixture was poured was triturated with diethyl ether to give pale yellow crystals. The crystals were collected and washed with methanol to give N-(4-fluorobenzoylmethyl)-2,2-dimethyl-1,2,3,4-tetrahydroquinoline (3.7 g).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16])(=O)[NH2:2].S(Cl)(Cl)=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16])#[N:2]
Reactant: NC(=O)CN1C(=O)COc2cc(F)ccc21
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCN1C(=O)COc2cc(F)ccc21
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of 4-carbamoylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.24 g), toluene (20 ml), thionyl chloride (2.4 g) and N,N-dimethylformamide (3 drops) was stirred at a temperature of 90° C. to 100° C. for 2 hours. The solvent was distilled off from the mixture, and then methylisobutyl ketone (100 ml) was added thereto and the resulting mixed solution was filtered, the filtrate was washed with water, sodiumbicarbonate solution, and water, in that order, and subsequently dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the desired 4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (1.74 g). mp. 111°-113° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH:25]([CH3:27])[CH3:26])[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][C@H:6]1[C:14]([NH:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24])=[O:15])=[O:4].[CH2:28]([O:35][C:36]([N:38]([CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[C@@H:39]([CH3:43])[C:40](O)=[O:41])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[NH:16][C:14]([C@H:6]1[N:5]([C:3](=[O:4])[C@@H:2]([NH:1][C:40](=[O:41])[C@@H:39]([N:38]([CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:36](=[O:37])[O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:43])[CH:25]([CH3:27])[CH3:26])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:15]
Reactant: C[C@@H](C(=O)O)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(CCS(C)(=O)=O)C(=O)OCc1ccccc1)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carb ox amide (Intermediate 6) (29 mg, 77.5 μmol, Eq: 1.00), (S)-2-((benzyloxycarbonyl)(2-(methylsulfonyl)ethyl)amino)propanoic acid (Intermediate 9) (30.6 mg, 93.0 μmol, Eq: 1.2), HATU (35.3 mg, 93.0 μmol, Eq: 1.2) and diisopropylethylamine (16 μL, 93.0 μmol, Eq: 1.2) were combined with DMF (2 mL) to give a colorless solution. The reaction mixture was stirred at rt overnight and then partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 50% EtOAc in hexanes) to give benzyl (S)-1-((S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(2-(methylsulfonyl)ethyl)carbamate (33 mg).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:7].[ClH:39].[CH3:40][C:41]1([CH3:47])[CH2:46][O:45][CH2:44][CH2:43][NH:42]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:18].[ClH:39].[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:42]2[CH2:43][CH2:44][O:45][CH2:46][C:41]2([CH3:47])[CH3:40])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCCl)C[C@H]1Cc1ccc2ccccc2c1
Reactant: CC1(C)COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)COCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc3ccccc3c2)C1
Yield: 47.1 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(2-naphthylmethyl)piperazine (600 mg), 3,3-dimethylmorpholine hydrochloride (197 mg) and potassium carbonate (420 mg) in N,N-dimethylformamide (10 ml) was stirred at room temperature in the presence of potassium iodide (10 mg) for 2 days. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (100 ml) and the organic layer was separated, washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate-hexane (10:1). The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-2-(2-naphthylmethyl)piperazine dihydrochloride (360 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:3]=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:4]2[CH:3]=[CH:2][N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccncn2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 31.4 %

Procedure:
Palladium hydroxide (20 mg) was added to solution of 6-chloro-4-(4-nitrophenoxy)pyrimidine (300 mg) in an ethyl acetate (10 ml)-methanol (10 ml) mixed solvent, and the mixture was stirred for 13 hours at room temperature under a hydrogen atmosphere at normal pressure. The reaction solution was filtered, the filtrate was concentrated, and the residue was passed through NH silica gel (Fuji Silysia Chemical). Elution was performed with a solvent (ethyl acetate:hexane=1:2) to obtain 70 mg of 4-(4-aminophenoxy)pyrimidine. The title compound (107 mg) was obtained from the obtained 4-(4-aminophenoxy)pyrimidine (70 mg) and 4-methoxyphenyl isocyanate, in the same manner as Example 10.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[CH2:9]([CH2:11][NH2:12])[OH:10].C(O)(=O)C(C)(C)C.CCCCCCC.O1CCCC1.C1(C)C=CC=CC=1>ClCCl.O>[OH:10][CH2:9][CH2:11][N:12]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[CH3:6]
Reactant: CC(=O)CCC(C)=O
Reactant: NCCO
Agent: CC(C)(C)C(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cc1ccc(C)n1CCO
Temperature: 115 °C

Procedure:
A mixture of hexan-2,5-dione (5 g), ethanol amine (26.7 g) and pivalic acid (23.26 g) in a solvent mixture containing n-heptane: tetrahydrofuran: toluene (4:1:1, 50 mL) was refluxed with stirring at 110-120° C. Water formed during the reaction was removed azeotropically during 3 to 4 hrs. The reaction mixture was cooled and the solvent was removed. The residue obtained was dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (30 mL), water (30 mL), and then with brine (30 mL), dried (Na2SO4) and the solvent was evaporated. The crude compound obtained as an oily mass, was purified by column chromatography (silica gel 100-200), using ethyl acetate:hexane (2:8) as an eluent to obtain the title compound.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[C:5]([C:7]1[C:15]2[CH:14]=[CH:13][N:12]([CH3:16])[C:11](=[O:17])[C:10]=2[NH:9][CH:8]=1)=[O:6].C(=O)([O-])O.[Na+].Cl.NO.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:3]=[N:2][O:6][C:5]=1[C:7]1[C:15]2[CH:14]=[CH:13][N:12]([CH3:16])[C:11](=[O:17])[C:10]=2[NH:9][CH:8]=1
Reactant: CN(C)C=C(C(=O)c1c[nH]c2c(=O)n(C)ccc12)c1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ccc2c(-c3oncc3-c3ccccc3F)c[nH]c2c1=O
Yield: 27.3 %

Procedure:
To 3-[3-Dimethylamino-2-(2-fluoro-phenyl)-acryloyl]-6-methyl-1, 6-dihydro-pyrrolo[2,3-c]pyridin-7-one (79 mg, 0.22 mmol) in tetrahydrofuran (20 mL) was added sodium hydrogen carbonate (19 mg, 0.0.27 mmol) and hydroxylamine Hydrochloride (23 mg, 0.27 mmol) and the mixture was heated to 80C. After 5 hr p-toluenesulfonic acid (catalytic amount) was added and the reaction mixture was heated for an additional 1 hr. The solution was cooled, diluted with ethyl acetate, washed with brine, dried (Na2SO4). Concentration gave an amber oil. Preparative reverse phase chromatography afforded 3-[4-(2-Fluoro-phenyl)-isoxazol-5-yl]-6-methyl-1,6-dihydro-pyrrolo[2,3-c]pyridin-7-one (18.6 mg, 25% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34](I)=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34]([C:3]3[S:4][C:5]4=[CH:6][N:7]=[CH:8][CH:9]=[C:10]4[C:2]=3[CH3:1])=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1csc2cnccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cnccc4c3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
149 mg of 3-Methyl-thieno[2,3-c]pyridine (1.0 mmol) is dissolved in 3.0 ml of dry THF and cooled to −78° C. 0.48 ml of n-BuLi 2.5M in hexane (1.2 mmol) is added at −78° C. and stirred at −78° C. for 10 min and room temperature for 10 min. The reaction vessel is cooled to −78° C. again and 2.6 ml of 0.5M ZnCl2 in THF (1.3 mmol) is added at −78° C. and stirred at room temperature for 15 min. 274 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2151431) (0.8 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) are added and the tube is capped. The tube is heated at 80° C. for 3 days. The reaction is quenched by NH4Claq. and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:1) to give 131 mg of the title compound. Yield 45%. mass spectrum (m/e): 365 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[CH2:15][N:14]([CH3:20])[CH2:13][C@H:12]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([CH2:30][O:31][CH2:32][C:33]([OH:35])=O)=[O:29].CCN(C(C)C)C(C)C.C(Cl)CCl>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[CH2:15][N:14]([CH3:20])[CH2:13][C@H:12]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[C:28](=[O:29])[CH2:30][O:31][CH2:32][C:33]1=[O:35]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2NC(=O)COCC(=O)O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)COCC2=O)C1
Reaction time: 8 h

Procedure:
4 {[2-((R)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylcarbamoyl]-methoxy}acetic acid trifluoroacetic acid salt (50 mg) was dissolved in absolute dichloromethane (2 ml) with stirring and admixed with Hünig's base (46 μl). EDC (22 mg) was then added and the mixture was stirred at room temperature for several hours. After standing overnight, further EDC (22 mg) and Hünig's base (46 μl) were added. After 24 h, the solvent was removed and the residue purified by means of preparative HPLC. The product-containing fractions were combined, freed of acetonitrile and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C:11](=[O:14])[C:12]#[CH:13].C(NC(C)C)(C)C>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]#[C:12][C:11](=[O:14])[CH3:10])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: C#CC(C)=O
Reactant: Clc1cc(Cl)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,3-dichloro-5-iodo-benzene (3.44 g, 12.6 mmol) in THF (220 mL) was added PdCl2(PPh3)2 (904 mg, 1.29 mmol), 3-butyn-2-one (2.18 g, 32.0 mmol), copper(I)iodide (380 mg, 2 mmol) and diisopropylamine (44 mL). The reaction mixture was stirred at room temperature for 48 hours, filtered and evaporated. The residue was purified by column chromatography using methylene chloride:hexanes (1:1) as eluent. The desired 4-(3,5-dichloro-phenyl)-3-butyn-2-one product was isolated in 977 mg yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]([N:18]([CH3:20])[CH3:19])[C:14](=[O:17])[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].S(=O)(=O)(O)O.Cl>CC(O)C.O>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH:13]([N:18]([CH3:20])[CH3:19])[CH:14]([OH:17])[CH2:15][CH3:16])[CH2:10][CH2:11][CH2:12]2)=[CH:7][CH:8]=1
Reactant: CCC(=O)C(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: O
Solvent: CC(C)O
Product: CCC(O)C(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminobutan-2-one (3 g prepared as described in Example 48) in industrial methylated spirit (15 ml) was added dropwise to a stirred suspension of sodium borohydride (0.6 g) in industrial methylated spirit (30 ml) and the mixture was stirred at ambient temperature for two hours. The reaction mixture was heated under reflux for two hours, cooled and poured into water. Concentrated sulphuric acid was added and the acidified mixture was cooled in an ice bath and basified. The aqueous mixture was extracted with ether and the extract dried. Removal of the solvent by evaporation gave an oil which was treated with a mixture of excess concentrated hydrochloric acid and propan-2-ol and then the solvents were removed by evaporation. The residue was dried by azeotropic distillation with propan-2-ol to give a solid which was recrystallised from propan-2-ol to give 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminobutan-2-ol hydrochloride (m.p. 224°-227° C.).