Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=O)[CH3:2].N.CO.C([BH3-])#[N:34].[Na+]>C(O)(=O)C.C(#N)C.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.C1COCC1>[NH2:34][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Reactant: [BH3-]C#N
Agent: [Ti+4]
Agent: CC[O-]
Agent: N
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CC(N)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Temperature: 60 °C

Procedure:
A 4 mL vial was charged with 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide (synthesized according to general procedures F and G, 100 mg, 0.23 mmol), 7 M NH3 in MeOH (100 μL, 0.70 mmol), and 2 mL THF. The resulting slurry was stirred well, then titanium ethoxide (98 μL, 47 mmol) was added and the mixture heated to 60° C. for three hours. Sodium cyanoborohydride (22 mg, 0.35 mmol) and acetic acid (5 drops) were then added and the mixture was maintained at 60° C. overnight. The reaction mixture was diluted with ˜2 mL of acetonitrile/H2O and purified by reversed phase HPLC to afford 4-(1-amino-ethyl)-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide: MS (ES) M+H expected 428.0, found 428.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([F:40])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([F:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3F)ccc2NC(=O)OC(C)(C)C)c1
Yield: 14.2 %

Procedure:
To a solution of tert-butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.27 g, 0.63 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.105 g, 0.63 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (0.446 g, 3.23 mmol). The resultant mixture was stirred overnight at rt. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product (50 mg, 14%). LCMS for C27H33ClFN6O4 (M+H)+: m/z=559.2.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]2=[N:21][CH:22]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[C:19]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]5=[N:21][CH:22]=4)[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2cc(N3CCN(c4ccc5ncsc5c4)C3=O)cnc21
Yield: 52.5 %

Procedure:
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 0.2 g, 0.9 mmol) was reacted with 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (I-187a: 0.32 g, 1.0 mmol), 1,4-dioxane (15 mL), copper iodide (0.052 g, 0.2 mmol), trans N,N′-dimethyl-cyclohexane-1,2-diamine (0.038 g, 0.27 mmol) and potassium phosphate (0.65 g, 2.2 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 0.22 g of the product (52.3% yield).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][C:35]([NH2:39])=[CH:34][C:33]=2[CH3:40])=[O:30])[CH2:5]1)=[O:3].C(O)(=O)C.[N-:45]=[C:46]=[O:47].[K+]>O>[NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:33]([CH3:40])=[CH:34][C:35]([NH:39][C:46]([NH2:45])=[O:47])=[CH:36][C:37]=2[CH3:38])=[O:30])[CH2:5]1)=[O:3]
Reactant: [N-]=C=O
Reactant: Cc1cc(N)cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(NC(N)=O)cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5.5 parts of 3-(aminocarbonyl)-N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazineacetamide in 70 parts of acetic acid was added dropwise a solution of 1.62 parts of potassium isocyanate in 20 parts of water. Upon completion, stirring at room temperature was continued for 30 minutes. Upon standing overnight at room temperature, the reaction mixture was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.55 parts of 3-(aminocarbonyl)-N-[4-[(aminocarbonyl)amino]-2,6-dimethylphenyl]-4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazineacetamide; mp. 142.5° C. (compound 168).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C@H:13]([N:18]([CH2:26][C@H:27]2[C@@H:31]([F:32])[CH2:30][N:29](C(OCC3C=CC=CC=3)=O)[CH2:28]2)[C:19]([C@@H:21]2[CH2:25][CH2:24][CH2:23][O:22]2)=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=2[F:50])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[C:12]([C@H:13]([N:18]([CH2:26][C@H:27]2[C@@H:31]([F:32])[CH2:30][NH:29][CH2:28]2)[C:19]([C@@H:21]2[CH2:25][CH2:24][CH2:23][O:22]2)=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=2[F:50])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)C(=O)[C@@H]1CCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)N(C[C@@H]1CNC[C@@H]1F)C(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (583 mg, 0.845 mmol) in degassed EtOAc (8 mL, 0.1 M solution) was added Pd/C (899 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for overnight. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude product, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)tetrahydrofuran-2-carboxamide was obtained in 27.9% yield (131 mg) as a free amine 1H NMR (CD3Cl, 400 MHz): δ 7.82 (1H, m), 7.53 (2H, m), 7.35-7.27 (3H, m), 7.14 (1H, m), 7.06 (1H, m), 6.14 (1H, s), 5.45 (2H, m), 4.85 (2H, m), 4.72 (1H, m), 4.21 (1H, m), 3.97 (1H, m), 3.83 (1H, m), 3.02 (1H, m), 2.80 (1H, m), 2.33-1.80 (6H, m), 1.25 (1H, s), 1.01 (1H, m), 0.99 (9H, s). LC/MS (uplc): MH+556.4, 0.99 min.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27](Br)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.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]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3)c2s1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.14 ml of 2M aqueous sodium carbonate solution and 5.7 mg (0.007 mmol) of PdCl2(dppf) are added to a mixture of 56mg (0.14 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 18.7 mg (0.15 mmol) of phenylboronic acid in 1 ml of DMF. The reaction mixture is heated to 80° C. After 3 h at this temperature, a further 5.7 mg (0.007 mmol) of PdCl2(dppf) are added, and the mixture is stirred at 80° C. for a further 12 h. The reaction mixture is filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of 1N hydrochloric acid and drying under high vacuum result in 10.6 mg (18% of theory) of the title compound.
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21].C([Li])CCC.[CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[O:30]>O1CCCC1>[CH3:19][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:29]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[OH:30])=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)[C:17]([CH3:18])=[CH:16][CH:15]=1
Reactant: O=Cc1ccncc1
Reactant: Cc1ccc(C)n1-c1ccc(Br)c(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C)n1-c1ccc(C(O)c2ccncc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 12 mL of an anhydrous ether solution of 1.08 g (3.4 mmol) of 1-(4-bromo-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-pyrrole, 1.4 mL of n-butyllithium (a tetrahydrofuran solution, 2.44 M) was added at one time at −60° C. and the mixture solution was stirred for one hour. Then, 5 mL of a tetrahydrofuran solution of 350 mg (3.27 mmol) of 4-formylpyridine was added thereto at −60° C. and the mixture solution was stirred while raising the temperature to room temperature over one hour. The reaction solution was partitioned between a saturated ammonium chloride aqueous solution and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The obtained residue was purified by a silica gel column (n-hexane:ethyl acetate=1:1) to obtain 754 mg (66%) of a target product as a pale yellow oil.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)CC.N>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH3:12]
Reactant: CCC(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCC(=O)CC(=O)OC
Yield: 89.9 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 106.5 g (1.15 mol) of propionyl chloride. The pH in the subsequent reaction with ammonia was adjusted to 9.1. This gave 117 g (GC purity 79.0%) of methyl propionylacetate (yield 71.0%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=O)[CH2:8][CH2:7]2.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: O=C1CCc2cccc(O)c21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Oc1cccc2c1CCC2
Yield: 91.3 %

Procedure:
To a solution of 7-hydroxyindan-1-one (6.0 g, 40 mmole) in trifluoroacetic acid (30 ml), triethylsilane (10.23 g, 87.9 mmole) was added. The mixture was refluxed for 5 hours, poured into water (200 ml) and extracted with diethyl ether (2×200 ml). The extract was washed with water. The ethereal solution was extracted with 4NNaOH (3×50 ml). The alkaline extract was washed with diethyl ether then acidified to pH1 with hydrochloric acid. The aqueous mixture was extracted with diethyl ether and the ethereal extract was washed with water and aqueous saturated sodium chloride, was dried, and the solvents evaporated to give 4-hydroxyindane as a colourless oil (4.9 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([CH2:14][O:15]C(=O)C)=[O:13])[NH:7][C:6](=[O:19])[CH2:5]2.O.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[CH2:14][OH:15])[NH:7][C:6](=[O:19])[CH2:5]2
Reactant: CC(=O)OCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 9e (58 mg, 0.22 mmol) was dissolved in 1 mL of methanol under stirring at room temperature, and 1 mL of water and sodium hydroxide (15 mg, 0.375 mmol) were then added to the solution. Upon completion of the addition, the reaction mixture was stirred for another 1 hour. The reaction was completed until TLC showed the disappearance of starting materials. The above mixture was filtered, the filter cake was washed with water thrice and dried to give the title compound N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 9f (46 mg, yield 93.8%) as a gray solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccnc2)C(=O)C1

Procedure:
A mixture of 3-Oxo-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 9.99 mmol) and 3-Picolyl chloride hydrochloride (1.63 g, 9.99 mmol) in DMF (20 mL) is treated by 60% NaH in mineral oil (0.80 g, 19.98 mmol) at 0° C. After completion, the reaction mixture is quenched by H2O, EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless oil; ES-MS: M+H=292.2et=4.15.
Reaction SMILES: [O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:8][C:9]([CH3:13])([CH3:12])[CH:10]=O.[NH2:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:8][C:9]([CH3:13])([CH3:12])[CH:10]=[N:14][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C=NC(c1ccccc1)c1ccccc1

Procedure:
A 100-mL round-bottomed flask containing a stir bar was charged with Na2SO4 (8.0 g) and CH2Cl2 (40 mL). Trimethylacetaldehyde (8) (7.65 mL, 52 mmol, 1.3 equiv) and aminodiphenylmethane (9) (6.89 mL, 40 mmol, 1.0 equiv) were added sequentially via syringe while stirring. The flask was capped with a plastic stopper, and the mixture was stirred at room temperature. The mixture became cloudy after 5 min. After stirring for 1 h, the mixture was decanted into a 200 mL round-bottomed flask, rinsing with CH2Cl2 (4×5 mL), and concentrated to 8-10 mL using a rotary evaporator. The flask was then maintained at 1 torr for 10 min. The resulting pale yellow solid was taken up in CH2Cl2 (50 mL), transferred to a 250-mL separatory funnel, and washed with NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered through a medium porosity fitted disk funnel into a 200-mL round-bottomed flask, and concentrated in vacuo (30 torr→1 torr) to provide a pale yellow oil that solidified to a white solid within 5 min at 1 torr. The solid was broken up into approximately 1-cm diameter pieces using a spatula, and was maintained at 1 torr for another 15 min to provide N-(2,2 dimethylpropylidene) diphenylmethanamine (2a) as a white solid in approximately 98% 1H-NMR purity. The product was used in the next step without further purification. Yield: 9.79 g (38.9 mmol, 97%).
Reaction SMILES: [Br:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]([O:6][C:7](=[O:20])[C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[CH3:24]>ClCCl.FC(F)(F)C(O)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[C:22]([CH3:23])=[C:21]2[C:5](=[CH:4][C:3]=1[CH3:24])[O:6][C:7](=[O:20])[CH:8]=[C:9]2[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cccc(C#CC(=O)Oc2cc(C)c(Br)c(C)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(-c2cc(=O)oc3cc(C)c(Br)c(C)c23)c1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a stirring solution of methyl 3-(3-(4-bromo-3,5-dimethylphenoxy)-3-oxoprop-1-yn-1-yl)benzoate (9-3) (95 mg, 0.25 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (2 mL) was added palladium acetate (5 mg, 0.02 mmol) under ice-cooling. After stirred for 3 h under ice-cooling, the mixture was diluted with 1,2-dichloromethane and evaporated to dryness. Chromatography of the residue on a silica gel (chloroform:hexanes=1:1-1:0) gave title compound 9-4 (69 mg, 73% yield) as a light brown gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]1(=[O:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C(OCC)(=O)C>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[CH2:12]1
Reactant: Fc1cccc2cc[nH]c12
Reactant: O=C1C=Cc2ccccc21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CC(c2c[nH]c3c(F)cccc23)c2ccccc21
Temperature: 25 °C
Yield: 82 %

Procedure:
Triethylamine (4.5 mL; 32 mmol; 1.2 equiv.) was added to 3-bromo-indan-1-one (5.6 g; 27 mmol) in 100 mL THF at 0° C. and stirred 1 h at r.t. The reaction mixture was filtered to remove triethylammonium bromide and concentrated in vacuo to give inden-1-one. 7-Fluoroindole (3.3 g, 22 mmol ) and Sc(OTf)3 (550mg, 5 mol %) were added to inden-1-one in 100 mL CH2Cl2 at 0° C. The reaction mixture was allowed to warm to room temperature over night. 100 mL ethyl acetate was added and the mixture was filtered through a silica gel plug and concentrated in vacuo. After flash chromatography (heptane/ethyl acetate, silica gel) 5.9 g 3-(7-fluoro-1H-indol-3-yl)-indan-1-one (82%) was isolated.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([OH:15])[N:9]=2)[CH2:7][CH2:6]1>C(O)(=O)C>[CH:5]1([C:8]2[N:13]=[C:12]([OH:14])[C:11]([N+:1]([O-:4])=[O:2])=[C:10]([OH:15])[N:9]=2)[CH2:7][CH2:6]1
Reactant: Oc1cc(O)nc(C2CC2)n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)nc(C2CC2)nc1O
Temperature: 15 °C

Procedure:
To 128.8 ml acetic acid are added 50.57 ml fuming nitric acid without exceeding 20° C. 57 g (0.375 mole) 2-cyclopropyl-4,6-dihydroxy-pyrimidine are added in portions without exceeding a temperature of 15° C. Then the reaction mixture is stirred for half an hour at 15° C., mixed with ice, and the deposit is washed with lots of water and dried. 69.8 of 2-cyclopropyl-4,6-dihydroxy-5-nitro-pyrimidine is obtained. Melting point 230°-235° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)O)cc2C1
Reactant: C1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)N3CCCCC3)cc2C1

Procedure:
8.1 g (0.025 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxycarbonylmethoxy-tetralin, 2.5 ml (0.025 mole) of piperidine, 11 g (0.025 mole) of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and 5.3 ml of triethylamine in 250 ml of dimethylformamide were mixed at ambient temperature for 6 hours. The solvent was evaporated off, the residue was taken up in water, it was extracted with ethyl acetate, the organic phase was washed with a saturated NaHCO3 solution, filtered over celite and washed with a dilute solution of acetic acid and with water. It was dried and the solvent was evaporated off under reduced pressure. The product was purified by crystallization from a 1:1 ethyl/hexane mixture. The product of the heading was obtained.