Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O>CO.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]
Reactant: Cn1ccnc1COc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cn1ccnc1COc1ccccc1N
Yield: 86.9 %

Procedure:
A solution of 1.13 g of 1-methyl-2-[(2-nitrophenoxy)methyl]-1H-imidazole in 70 ml of methanol with 0.14 g of palladium on charcoal 10% was hydrogenated at 50 psi for 6 hours at room temperature. The catalyst was then separated by filtration and the solvent evaporated. The residue was finally purified by chromatography on a silica gel column (eluent: chloroform-methanol 48/2) giving rise 0.856 g of the title compound as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl[C:14]1C=CC(F)=C(F)C=1>>[CH3:14][C:4]([C:3]1[C:2]([Cl:1])=[CH:10][C:9]([F:11])=[C:8]([F:12])[CH:7]=1)=[O:6]
Reactant: Fc1ccc(Cl)cc1F
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Product: CC(=O)c1cc(F)c(F)cc1Cl
Yield: 82 %

Procedure:
According to the process disclosed in EP-A2-303,291, 2-chloro-4,5-difluorobenzoic acid is prepared by acylating 1-chloro-3,4-difluorobenzene to give 2-chloro-4,5-difluoroacetophenone with a yield of 82% of theory and then oxidizing with sodium hypochlorite to 2-chloro-4,5-difluorobenzoic acid in a yield of 85.1% of theory. The total yield of this process thus only amounts to about 70% of theory, relative to the 1-chloro-3,4-difluorobenzene as the starting material. It is further a disadvantage of this process that, according to the illustrative example, the acylation must be carried out at a temperature of 120° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:17]3[N:18]=[C:19]4[C:11]([C:9]([NH:8][CH:6]([C@@H:4]5[CH2:3][C@H:2]([O:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:5]5)[CH3:7])=[O:10])=[CH:12][N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:14]4=[N:15][CH:16]=3)=[N:21][N:22]2[CH3:30])=[CH:27][CH:26]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a partial suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (100 mg, 0.19 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylamine (39 μL, 0.28 mmol) followed by methanesulfonyl chloride (16 μL, 0.21 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to give methanesulfonic acid cis-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester as an off-white foam which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1.Cl>O1CCOCC1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=3)[N:13]=2)=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)cc3)cc(OCC(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)cc3)cc(OCC(F)(F)F)n2)cc1
Yield: 100 %

Procedure:
Tert-butyl 4-((4-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoate (34 mg, 0.06 mmol) and 4 N HCl in dioxane (1 mL) were stirred for 8 hs then concentrated under vacuum to give 4-((4-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)amino)benzoic acid (31 mg, 0.06 mmol) which was carried to the next step without purification.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[C:2]([CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:7]([O:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: COc1ncnc(OC)c1Br
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ncnc1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of 5-bromo-4,6-dimethoxypyrimidine (473 mg; 2.15 mmol) in anh. THF (5 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.50 ml; 2.40 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (503 mg; 2.15 mmol) in anh. THF (2 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 60 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (15 ml), Et2O (30 ml) and water (15 ml). The separated organic layer was then washed with brine (15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 5-(4,6-dimethoxypyrimidin-5-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow solid. LC-MS (conditions A): tR=0.66 min.; [M+H]+: 374.06 g/mol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[NH2:12][C:13]1[C:14]([Cl:23])=[C:15]([CH2:20][C:21]#[N:22])[C:16]([Cl:19])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:12][C:13]1[C:14]([Cl:23])=[C:15]([C:20]2[C:21]([NH2:22])=[N:1][C:2]3[N:3]=[C:4]([S:10][CH3:11])[N:5]=[CH:6][C:7]=3[CH:8]=2)[C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: N#CCc1c(Cl)ccc(N)c1Cl
Reactant: CSc1ncc(C=O)c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3c(Cl)ccc(N)c3Cl)c(N)nc2n1
Temperature: 110 °C
Yield: 79.5 %

Procedure:
A mixture of 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (2.0 g, 11.82 mmol), (3-amino-2,6-dichloro-phenyl)-acetonitrile (2.85 g, 14.18 mmol) and K2CO3 (4.9 g, 35.49 mmol) in DMF (20 mL) is heated to 110° C. for 30 hours. The solution is cooled to room temperature and the solid is removed by filter paper and concentrated to give crude product. Flash silica gel column purification, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3) (100/7%), gives the title intermediate as a solid (3.31 g, 80.0%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]=[O:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Mg]Br)[CH:19]=[CH2:20]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([OH:15])[CH2:20][CH:19]=[CH2:18])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 2 h

Procedure:
(S)-2,2-Dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid t-butyl ester (2.29 g, 9.44 mmol) was dissolved in dry tetrahydrofuran (25 mL). Then at −78° C., allyl magnesium bromide (1.0M in diethyl ether, 9.9 mL) was added. The mixture was warmed to −15° C. and stirred for 2 h. The mixture was extracted with diethyl ether and aqueous citric acid solution. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and solvents were evaporated to afford (S)-4-(2-hydroxy-pent-4-enyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.54 g) as an oil.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].F[C:7]1[C:8]([CH:14]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH3:15])=[N:9][CH:10]=[CH:11][C:12]=1[I:13]>C(O)C.O>[I:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH:14]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH3:15])[C:7]=1[O:1][CH2:2][CH3:3]
Reactant: Cc1ccc(C)n1C(C)c1nccc(I)c1F
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOc1c(I)ccnc1C(C)n1c(C)ccc1C
Yield: 8.5 %

Procedure:
A solution of sodium ethoxide was initially prepared by dissolving 2.0 g (87 mmole) of sodium metal in 300 ml of anhydrous absolute ethanol. To the stirring solution thus prepared was added 3.5 g (10.2 mmole) of N-[(3-Fluoro-4-iodopyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole and the mixture was refluxed under nitrogen for 4 days. The solution was cooled, diluted to 1 liter with water, and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated to a resin. Chromatography over flash silica gel (30% ethyl acetate in hexanes) gave initially 320 mg (8.5%) of N-[(4-Iodo-3-ethoxypyrid-2-yl)-eth-2-yl]-2,5-dimethylpyrrole: 1H NMR (300 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.62 (d, 1H), 5.80 (s, 2H), 4.10 (t, 2H), 4.00 (q, 2H), 3.15 (t, 2H), 2.20 (s, 6H), 1.45 (t, 3H); MS (FD) m/e 370 (Mt). Further elution provided the titled compound, 1.7 g (64%): IR (KBr, cm-1) 2991, 1608, 1495, 1309, 1075; 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, 1H), 7.15 (t, 1H), 5.60 (s, 2H), 4.20 (q, 2H), 4.10 (t, 2H), 2.98 (dt, 2H), 2.10 (s, 6H), 1.38 (t, 3H): MS (FD) m/e 262 (Mt). Anal. Calc'd. for C15H19FN2O 0.25 H2 O: C, 67.55; H, 7.31; N, 10.50. Found: C, 67.56; H, 7.35; N, 10.46.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[C:3]([C:11]([O:13][CH3:14])=[O:12])[CH:2]=1>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:2]1
Reactant: COC(=O)c1ccncc1C(=O)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)C1CCNCC1C(=O)OC
Temperature: 80 °C
Yield: 58.5 %

Procedure:
A mixture of dimethyl pyridine-3,4-dicarboxylate (1.00 g, 5.10 mmol, 1 eq) and Pd(OH)2 (20 mg, 0.2 eq) in 20 mL of acetic acid was heated at 80° C. overnight under H2, and then cooled to room temperature. The resulted mixture was filtered and concentrated in vacuo. To the mixture was added 100 mL of water. The pH was adjusted to 7-8 by adding NH3H2O. The mixture was extracted with CH2Cl2 (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as pale yellow oil (600 mg, 57.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 201.15 (M+1).
Reaction SMILES: [N:1]1[NH:2][C:3](=[S:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>>[CH2:16]([S:15][C:3]1[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1][N:2]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: S=c1[nH]nc2n1C=Cc1ccccc1C2
Agent: C[O-]
Agent: [Na+]
Product: C1=Cn2c(nnc2SCc2ccccc2)Cc2ccccc21

Procedure:
The reaction of 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepine-3-thione with benzyl bromide in the presence of sodium methoxide gave 3-benzylthio-11H-s-triazolo[3,4-b][3]benzazepine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Solvent: CCO
Product: COc1ccc(N)cc1Br
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Stannous chloride (96.839 g, 5.0 eq.) was added to a solution of 2-bromo-4-nitroanisole (23.7 g, 1.0 eq.) in ethanol (250 mL) and the mixture was stirred at 70° C. for 2 h, partitioned between ethyl acetate and sodium bicarbonate solution 10%. The pH was adjusted to 9 with 1N sodium hydroxide solution and the aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with hexane/ethyl acetate 1:1, to yield 13.82 g (67%) from the desired product as light brown solid. MS (m/e): 204.1 (MH+, 100%).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:26]=[CH:25][C:20]3[N:21]=[N:22][N:23]([CH3:24])[C:19]=3[CH:18]=2)[C:8]=1[CH3:27]>C1COCC1.O.C(Cl)Cl>[CH3:27][C:8]1[N:9]([CH2:16][C:17]2[CH:26]=[CH:25][C:20]3[N:21]=[N:22][N:23]([CH3:24])[C:19]=3[CH:18]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]=1[CH2:6][C:5]([OH:28])=[O:4]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc3nnn(C)c3c2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc2nnn(C)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 M Lithium hydroxide (116 μl) is added to a cooled (0° C.) solution of [2-methyl-1-(3-methyl-3H-benzotriazol-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.041 g, 0.116 mmol) in THF/water (4 ml of a 1:1 mixture). After stirring at room temperature for 4 hours, the reaction mixture is diluted with DCM (3 ml) and stirred vigorously for 10 minutes. The resulting mixture is passed through a phase separation cartridge and the aqueous portion is acidified to pH 1-3 with 1M HCl. This portion is extracted with DCM (2×3 ml) and the organic extracts are combined and concentrated in vacuo to yield the titled compound as a white solid. (MH+336)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([OH:9])=[O:8])[CH2:4][CH2:5][SH:6].[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[C:10]([S:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[NH2:2])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N[C@@H](CCS)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H](CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of anhydrous homocysteine hydrochloride (0.1 mole) in 60 ml of dimethylformamide is added 42 g (0.15 mole) of tritylchloride. The reaction mixture is stirred at room temperature for 2 days. Upon addition of 10% sodium acetate solution (500 ml) S-trityl-homocysteine precipitates together with triphenylcarbinol. Recrystallization in acetone affords pure S-tritylhomocysteine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1)=[O:6].[Cl:26][C:27]1[N:32]=[C:31](Cl)[C:30]([Cl:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[N:32]=[C:31]([NH:1][C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[C:5]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[O:6])[C:30]([Cl:34])=[CH:29][N:28]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of tert-butyl (3-{[(3-aminobenzoyl)amino]methyl}phenyl)carbamate (0.60 g, 1.8 mmol) and 2,4,5-trichloropyrimidine (0.183 mL, 1.6 mmol) in DMF (4.3 mL) was added potassium carbonate (0.331 g, 2.4 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give the crude, which was purified by silica gel column chromatography to give the desired product (138 mg, 18%). LCMS for C23H23Cl2N5O3 (M-tBu+H)+: m/z=432.0, 434.0, 436.0. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 8.04 (t, J=2.0 Hz, 1H), 7.96 (s, 1H), 7.83 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.67 (ddd, J=7.6, 2.4, 1.2 Hz, 1H), 7.48 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 4.54 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:11]12[CH3:12])[C@@H:24]1[C:19]([CH:20]=[C:21]([O:28][CH2:29][O:30][CH3:31])[CH:22]=[CH:23]1)=[CH:18][CH2:17]3)=[O:8])=[O:4].[OH-].[K+]>CO>[C:3]([CH2:5][NH:6][C:7]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:11]12[CH3:12])[C@@H:24]1[C:19]([CH:20]=[C:21]([O:28][CH2:29][O:30][CH3:31])[CH:22]=[CH:23]1)=[CH:18][CH2:17]3)=[O:8])([OH:4])=[O:2]
Reactant: COCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(=O)NCC(=O)OC)CC[C@@H]34)[C@H]2C=C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(=O)NCC(=O)O)CC[C@@H]34)[C@H]2C=C1
Yield: 87.3 %

Procedure:
To a solution of 17β-methoxycarbonylmethylaminocarbonyloxy-3-methoxymethyloxy-1,3,5-estratriene (0.77 g) in methanol (40 ml) was added 2 N aqueous potassium hydroxide (6 ml), and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with ion exchange resin (DOWEX, 5W-X8), neutralized, and filtered to remove the ion exchange resin. The filtrate was concentrated in vacuo to give 17β-carboxymethylaminocarbonyloxy-3-methoxymethyloxy-1,3,5-estratriene (0.65 g, Yield: 88%) as an amorphous solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A mixture of 4-fluorobenzaldehyde (4.96 g, 40 mmol), imidazole (2.86 g, 42 mmol), and potassium carbonate (6.08 g, 44 mmol) in DMSO (40 ml) was stirred at 110° C. overnight. The reaction mixture was allowed to return to room temperature, and poured into ice water (100 ml). The resulting precipitates were collected by filtration and washed with water and then with ethyl acetate to afford 4-(imidazol-1-yl)benzaldehyde (2.33 g, yield 34%) as a pale yellow crystalline powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:8][CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].[Cl-].[OH:22][NH3+:23]>C(O)C.O>[OH:22][N:23]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)COc1ccc(C(C)=O)cn1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)COc1ccc(C(C)=NO)cn1
Yield: 43.8 %

Procedure:
To a solution of methyl 2-((5-acetylpyridin-2-yl)oxy)acetate (1.23 gm, 0.059 mole) in ethanol (10 mL), a solution of sodium acetate (0.942 gm, 0.0117 mole) and hydroxylammonium chloride (1.2 gm, 0.0117 mole) in water (5 ml) was added and the reaction mixture was refluxed for 1 h. The reaction mixture was coiled to room temperature and solvent was evapourated in vacuum. The residue was diluted with ice cold water and solid seperated was filtered, washed with water and dried over P2O5 under vacuum to yield 1.15 gm (88%) of title product as off white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21]N1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCCC1CC[CH2:70][N:69]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:68]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:24][CH:23]1[CH2:22][CH2:21][CH2:68][N:69]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:70]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCCBr)C1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 3-(5-bromopentyl)-1-piperidinecarboxylate. LCMS (System B): tRET=3.28 min; MH+ 525
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.[C:36](O)([C:38]([F:41])([F:40])[F:39])=[O:37]>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([O:28][C:36](=[O:37])[C:38]([F:41])([F:40])[F:39])[CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(C(C)(C)C)nc32)cc1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Product: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Temperature: 70 °C

Procedure:
A mixture of (S)-1-[5-tert-Butyl-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 106) and triethylsilane in TFA was heated to 70° C. for 22 h and evaporated to dryness. The residue was used without further purification in the consecutive step.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][C:2]1[C:1](=[O:10])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(Br)=Cc2ccccc21

Procedure:
The indanone compound of formula 6 prepared in Step 3, NBS (2 to 3 eq), and AIBN (1 to 0.2 eq) are dissolved in CCl4. Then, the mixture is allowed to reflux for 30 min to 1 h with stirring and then is further irradiated by a tungsten lamp (375 W) for 1 to 2 h with stirring, to obtain the 2-bromo-1H-indenone of formula 7. In other way, the mixture may be allowed to reflux for 2 to 9 h with stirring while being irradiated by a tungsten lamp (375 W), to obtain the 2-bromo-1H-indenone of formula 7.