Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:10]1.[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C>CCOC(C)=O.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>[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:13]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:10]=[C:11]([CH:22]3[CH2:23][C:24]([CH3:31])([CH3:30])[O:25][C:26]([CH3:28])([CH3:29])[CH2:27]3)[CH:12]=2)=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
A flask was charged with trifluoro-methanesulfonic acid 2-(2-methoxy-phenyl)-5-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl ester (354 mg, 0.69 mmol) (Example 1, step E),4-(benzyloxy)phenylboronic acid (238.3 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol), 2M Na2CO3 (2.8 mL) and 2:1 toluene/ethanol (10 mL) and the mixture was heated at 80° C. for 6 hrs. The resulting mixture was diluted with EtOAc and washed with sat. NaCl. EtOAc was removed under vacuum and the residue was purified by silica column chromatography to give 257.8 mg (74.5%) of the title compound.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=[N:9][C:8]=2[NH2:18])[CH3:3].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH:2]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=[N:9][C:8]=2[NH2:18])([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)c1cnc2c(N)nc3ccccc3c2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 2-(prop-1-en-2-yl)benzo[f][1,7]naphthyridin-5-amine (Example 36) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and the crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-isopropylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (CDCl3): δ 8.69 (d, 1H), 8.49 (d, 1H), 8.25 (dd, 1H), 7.65 (dd, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 6.02 (bs, 2H), 3.15 (septet, 1H), 1.37 (d, 6H). LRMS [M+H]=238.2.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]#[N:17].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:16]#[N:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#CC1CCCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(F)cc2)CCCC1

Procedure:
4-Fluoro-aniline (1.11 g, 10.0 mmol), cyano-ketone (Example 32) (1.25 g, 10.2 mmol), calcium chloride (1.5 g, 13.5 mmol) and T.H.F. (20 ml) were heated under reflux for 17 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (135° C., 0.08 mmHg) gave the product as a pale yellow powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][O:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17]([C:29](OCC3C=CC=CC=3)=[O:30])[CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].[OH-].[K+]>CCOCC.O1CCCC1>[C:7]1([CH2:13][O:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17]([CH2:29][OH:30])[CH:16]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 95 mg (25 mmol) of lithium aluminum hydride in 10 ml of ether and 10 ml of tetrahydrofuran was added 1.06 g (25 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, phenylmethyl ester in three portions at 0° C. After stirring for 20 minutes at 0° C., 0.2 ml of saturated sodium bicarbonate solution, 0.2 ml of 10% potassium hydroxide solution and additional saturated sodium bicarbonate solution were added until the inorganic precipitate flocked together. The clear organic phase was decanted and evaporated in vacuo to yield an oil which slowly crystallized. Yield: 0.6 g, melting point 96.6° C.
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: N[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
(1S,2R)-2-amino-1,2-diphenylethanol (3.15 g) was dissolved in dichloromethane (45 ml) and stirred at room temperature. Ethyl bromoacetate (3.0 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (2.31 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure. Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (3.41 g, 77%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:22]([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:22][C:3]1[CH:4]=[C:5]([C@H:8]([CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)C[C@@H](CNC(=O)C(F)(F)F)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C[C@@H](CNC(=O)C(F)(F)F)c1ccc(Cl)c(N)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Methyl (3R)-3-(4-chloro-3-nitrophenyl)-4-(2,2,2-trifluoroacetylamino)butanoate (65a) (3 g, 8.15 mmol) was dissolved in 4 mL of acetic acid and 60 mL of water. At 50° C., iron powder (2.5° C., 2.74 g, 40.75 mmol) was added and the reaction mixture was stirred for 1 h at 50° C. The mixture was cooled to room temperature and then extracted with 100 mL of ethyl acetate. The ethyl acetate solution was washed with 30 mL of water, and the water extraction repeated another ten times to remove the acetic acid. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to provide 2.1 g of methyl (3R)-3-(3-amino-4-chlorophenyl)-4-(2,2,2-trifluoroacetylamino)butanoate (65b).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:26]=[CH:25][CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38]([C:40]1[N:41]([CH3:46])[C:42](Br)=[CH:43][CH:44]=1)=[O:39].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:36][O:37][C:38]([C:40]1[N:41]([CH3:46])[C:42]([C:23]2[CH:24]=[CH:25][CH:26]=[C:16]([N:10]3[N:9]=[CH:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=4)[C:11]3=[O:15])[C:17]=2[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[CH:43][CH:44]=1)=[O:39]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Reactant: COC(=O)c1ccc(Br)n1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2COC(C)=O)n1C
Temperature: 100 °C
Yield: 77 %

Procedure:
Under N2, a mixture of acetic acid 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (described in the preparation of intermediate 4, 300 mg, 0.63 mmol), 5-bromo-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (150 mg, 0.69 mmol), Pd(dppf)Cl2 (150 mg, 0.19 mmol) and K2CO3 (261 mg, 1.9 mmol) in dioxane (15 mL) and water (3 mL) were heated at 100° C. for 3 h. The mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate from the ratio of 8:1 to 5:1) to give 5-[2-acetoxymethyl-3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (237 mg, yield 77%) as a yellow liquid. LC-MS calcd for C28H29N3O5 (m/e) 487.21, obsd 997 [2M+Na]+.
Reaction SMILES: CS[C:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].O.C(OCC)C>C(O)(=O)C.[Zn]>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:3]([CH3:7])[C:4]([OH:6])=[O:5])=[CH:13][CH:12]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CSC(C)(C(=O)O)c1ccc(CC(C)C)cc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 100.8 %

Procedure:
α-Methylthio-α-(p-isobutylphenyl)propionic acid (387 mg) was dissolved in 3 ml of acetic acid, and 200 mg of zinc powder was added. The mixture was heated under reflux for 2 hours. Furthermore, 200 mg of zinc powder was added, and the mixture was heated under reflux for 18 hours. The zinc powder which agglomerated was pulverized, and the mixture was again heated under reflux for 20 hours. Water (30 ml) and 20 ml of diethyl ether were added, and the insoluble matter was separated by filtration. Then, conc. hydrochloric acid was added to adjust the pH of the mixture to 1, and it was extracted four times with 20 ml of diethyl ether. The organic layer was washed with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the diethyl ether and acetic acid. Thus, 319 mg of α-(p-isobutylphenyl)propionic acid was obtained as an oil which crystallized soon. Recrystallization from hexane afforded colorless crystals having a melting point of 74° to 76° C. The IR and NMR spectra of this product were identical with those of the authentic sample.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]1([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CNc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 72 h
Yield: 57 %

Procedure:
Commercial 4-chloro-phenylacetyl chloride (0.95 g) was added dropwise to a stirred solution of commercial ethyl N-phenylglycinate (1 g) and dry pyridine (3 ml) in dichloromethane (20 ml) under nitrogen atmosphere at rt. After stirring for 72 h the mixture was poured into 10% HCl solution and extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 4:1) to give ethyl N-(4-chlorophenylacetyl)-N-phenylglycinate (0.95 g) as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7].[CH3:28][N:29](C=O)C>O.CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7]
Reactant: CN(C)C=O
Reactant: Cc1c(Cl)c(I)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(C#N)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 90 °C
Yield: 72 %

Procedure:
A mixture of 2-(4-chloro-5-methyl-3-iodopyrazol-1-yl)-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (430 mg, 0.86 mmol), Zn(CN)2 (151 mg, 1.3 mmol), dppf (72 mg, 0.14 mmol), and Pd2(dba)3 (79 mg, 0.09 mmol) in DMF (10 mL) and water (0.5 mL) was heated at 90° C. overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc (30 mL) and washed with water (3×5 mL). The EtOAc layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was triturated with 1:1 CH2Cl2/MeOH (3×5 mL) to give the desired product as white powder (250 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.58 (m, 2H), 7.35 (dd, J=8.7, 8.1 Hz, 2H), 5.58 (s, 2H), 3.80 (m, 2H), 2.84 (t, J=5.4 Hz, 2H), 2.25 (s, 3H), 2.00 (m, 2H); MS: (ES) m/z calculated for C19H17ClF4N5O [M+H]+ 399.1, found 399.1.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:14]([C:16]1[O:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=1)[CH3:15]>CN(C=O)C.C(OCC)C>[C:7]([Si:10]([O:23][CH2:22][CH2:21][C:18]1[O:17][C:16]([CH2:14][CH3:15])=[CH:20][CH:19]=1)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:6]
Reactant: CCc1ccc(CCO)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1ccc(CCO[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
Imidazole (255 mg, 3.75 mmol) and TBSCl (414 mg, 2.75 mmol) were added to the solution of 245A (350 mg, 2.5 mmol) in DMF (4 mL). The mixture was stirred at rt for 15 hr and then 100 mg (0.66 mmol) of additional TBSCl was added to drive the reaction to completion. After stirring for an additional hour, the reaction mixture was diluted with diethylether (100 mL) and washed with water (20 mL), 1 N HCl (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 509 mg of compound 434A (80.3%) as a yellow oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]1.[C:43]([C:45]1[CH:46]=[C:47](O)[CH:48]=[CH:49][CH:50]=1)#[CH:44]>C(Cl)Cl>[C:43]([C:45]1[CH:50]=[C:49]([CH:48]=[CH:47][CH:46]=1)[O:42][CH:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)#[CH:44]
Reactant: CN1CCC(O)CC1
Reactant: C#Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#Cc1cccc(OC2CCN(C)CC2)c1
Yield: 39.8 %

Procedure:
Ph3P (1.32 g, 5.04 mmol) in DCM (4 mL), under a nitrogen atmosphere, was cooled with an ice bath and treated with neat DIAD (397 μL, 4.6 mmol). After 25 min the solution was added drop wise to 1-methylpiperidin-4-ol hydrochloride (547 g, 4.6 mmol) and 3-ethynylphenol (277 μL, 4.2 mmol) in DCM (8 mL), cooled with an ice bath, under a nitrogen atmosphere, with stirring. The reaction was then stirred at room temperature 4 h. The volatiles were partially removed by evaporation and the residue was purified by flash chromatography (DCM/MeOH 95/5) affording the title compound as a colorless oil (360 mg, 39%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:15][NH:16][CH2:17][CH2:18][C:19]#[N:20]>>[C:19]([CH2:18][CH2:17][N:16]([CH3:15])[S:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])#[N:20]
Reactant: CNCCC#N
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: CN(CCC#N)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In operating analogously to Preparation V, starting with 2-(trifluoromethyl)benzenesulphonyl chloride and 3-(methylamino)propionitrile, the expected product is obtained as a yellow oil (yield=98%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[C:11]1([CH:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:11]1([CH:17]([NH:19][C:2]2[CH:10]=[CH:9][C:5]3[N:6]=[CH:7][NH:8][C:4]=3[CH:3]=2)[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(N)c1ccccc1
Reactant: Brc1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: CC(Nc1ccc2nc[nH]c2c1)c1ccccc1

Procedure:
The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 1-phenylethylamine (145 mg; 0.154 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.069 mg (29.1%); MS m/z: 238.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.42 (d, 3H, 3J=7.0 Hz); 4.44 (quin, 1H, 3J=6.7 Hz); 5.97 (br s, 1H); 6.34 (br s, 1H); 6.59-6.60 (m, 1H); 7.13-7.16 (m, 1H); 7.24-7.28 (m, 3H); 7.38-7.39 (m, 2H); 7.77 (s, 1H); 11.74 (br s, 1H); HPLC (METHOD [A]): rt 11.42 min (90.3%)
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH3:13][Li].[Cl-].[NH4+]>C(OCC)C>[CH3:13][C:3]1([OH:12])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([CH3:11])[CH:2]1[CH3:1]
Reactant: [Li]C
Reactant: CC1C(=O)c2ccccc2C1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1c2ccccc2C(C)(O)C1C
Temperature: 0 °C
Yield: 91.4 %

Procedure:
In a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus and a reflux condenser 2,3-dimethyl-1-indanone (34) (19.2 g, 0.12 mol) was dissolved in dry diethyl ether (300 ml) under an argon atmosphere. Methyllithium (46.3 ml, 3 M solution in diethoxymethane, 0.14 mol) was added dropwise via a syringe and the mixture was refluxed overnight. The mixture was cooled to 0° C. and a solution of saturated ammonium chloride (100 ml) was added dropwise through the top of the condenser. The mixture was transferred into a separation funnel, the organic layer was washed with water (3×100 ml), dried over magnesium sulfate and filtered. The ether was removed under reduced pressure to afford the raw 1,2,3-trimethyl-1-indanol (19.34 g, 92%) as a yellow liquid which was used for the next step without further purification. Toluene (300 ml) was added to the raw 1,2,3-trimethyl-1-indanol (19.34 g, 0.11 mol) and the solution was transferred into a 500 ml round bottomed flask fitted with a Dean-Stark trap and a magnetic stirring apparatus. p-Toluene sulfonic acid (50 mg, 0.26 mmol) was added and the solution refluxed overnight. After completion of the removal of the water the excess toluene was removed via distillation through the Dean-Stark arm, the residue was cooled to ambient temperature, diluted with diethyl ether (100 ml), washed with a saturated solution of sodium bicarbonate (3×100 ml), dried over magnesium sulfate and filtered. After removal of the solvent in vacuo, the liquid was purified via column-chromatography [(SiO2, 50×9 cm) eluent: cyclohexane:ethylacetate (10:1)] to afford two fractions: 1,2,3-Trimethylindene (37) (8.92 g, 51%) as a pale yellow liquid Rf 0.41; (34) (7.94 g, 45%) (starting material) was obtained as a dark yellow liquid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH:36]1[C:41]([NH2:43])=[O:42]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:39][CH2:40][NH:35][CH:36]([C:41]([NH2:43])=[O:42])[CH2:37]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: NC(=O)C1CNCCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: NC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperazine-2-carboxylic acid amide following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11]N(C)C.[CH2:15]([O:17][C:18](=[O:28])[CH:19]([NH:25][CH:26]=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:11][C:7]1[C:6]2[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][CH:8]=1)([NH:25][CH:26]=[O:27])[C:18]([O:17][CH2:15][CH3:16])=[O:28])[CH3:24]
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Reactant: CN(C)Cc1c[nH]c2c(F)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1c[nH]c2c(F)cccc12)(NC=O)C(=O)OCC
Yield: 101.9 %

Procedure:
A suspension of (7-fluoro-1H-indol-3-ylmethyl)-dimethyl-amine (550 mg, 0.0028 mol.), 2-formylamino-malonic acid diethyl ester (640 mg, 0.0031 mol.), and NaOH (30 mg) in toluene (20 mL) under argon was refluxed for 3 days. The reaction mixture was concentrated and purified by column chromatography on silica gel using 40% ethyl acetate-hexane to give 2-(7-Fluoro-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester (1.0 gm, 99%): mp 164-166° C., 1H NMR (500 MHz, CDCl3): 1.28 (t, J=7.5 Hz, 6H), 3.87 (s, 2H), 4.17-4.31 (m, 4H), 6.80 (s, 1H), 6.86-6.89 (dd, J=8.0 and 8.0 Hz, 1H), 6.97-7.01 (m, 2H), 7.27 (s, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.27 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[C:40]([CH3:45])[N:41]=[C:42]([CH3:44])[CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J36) (239 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (325 mg, 76%).