Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[C:11]([NH:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:19]3[CH:20]=[C:15]([NH:14][C:11](=[O:13])[CH3:12])[CH:16]=[CH:17][CH:18]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.127 g, 0.4 mmol, 1 eq), 3-acetamidobenzeneboronic acid (0.091 g, 1.3 equiv, 1.3 eq), dichlorobis(triphenylphosphine)palladium(II) (0.055 g, 02 eq) and 2M aq Na2CO3 (1.1 ml) in dioxane (5 mL) was heated at 110° C. for 3 h. The solvent was removed under reduced pressure, redissolved in ethylacetate and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue (0.167 g) was used in the next step of the synthesis without further purification. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.03 min, [M+H]+ m/z 385.1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15](=[O:25])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:9]1)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>ClCCl>[NH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:25])[CH2:9]1.[F:30][C:29]([F:32])([F:31])[C:27]([O-:33])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)NCc2ccc(Cl)cc2)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCN(CC(=O)NCc2ccc(Cl)cc2)C1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 60 mg (S)-{1-[(4-Chloro-benzylcarbamoyl)-methyl]-piperidin-3-yl}-carbamic acid tert-butyl ester (intermediate 7.7A) in 5 ml dichloromethane is treated with 50 μl TFA and stirred overnight at room temperature. The mixture is evaporated to yield the title compound as a trifluoroacetate.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.Cl.C(O[CH:25](OCC)[CH2:26][NH:27][C:28]#[N:29])C>COCCOC.O>[NH:29]1[CH:25]=[CH:26][N:27]=[C:28]1[NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12
Reactant: CCOC(CNC#N)OCC
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3c[nH]nn3)CS[C@H]12
Agent: Cl
Solvent: COCCOC
Solvent: O
Product: O=C(O)C1=C(CSc2c[nH]nn2)CS[C@@H]2C(Nc3ncc[nH]3)C(=O)N12
Temperature: 51 °C
Yield: 10 %

Procedure:
To a suspension of 7-amino-3 (1H-1,2,3-triazol-4-yl)thiomethylceph-3-em-4-carboxylic acid (31.3 g., 0.1 moles) in a mixture of 1,2-dimethyoxyethane (250 ml.) and concentrated HCl (12 ml., 0.138 moles) in water (50 ml.) was added 2,2-diethoxyethylcyanamide (52.05 g., 0.3 moles). The mixture was stirred and heated at 51° C. for 4 hours and the resulting solution was evaporated under reduced pressure to remove the 1,2-dimethoxyethane. The residual oil was diluted with water (250 ml.), the pH of the resulting suspension was adjusted to 4.8 using sodium bicarbonate and then filtered. The filtrate was applied to a column of "Amberlite" XAD-2 (500 ml.) ("Amberlite" is a Trade Mark). The resin was first washed with water (2000 ml.) and then eluted with 40% v/v aqueous methanol. The required fractions were combined and evaporated to dryness to give 7-(imidazol-2-yl)amino-3-(1H-1,2,3-triazol-4-yl)thiomethylceph-3-em-4-carboxylic acid (3.79 g., 10%) having an n.m.r. spectrum identical to the product of Example 5.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37]([CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:39])=[O:38]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:46]3[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:38])=[O:39])[CH2:44][CH2:45]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 699.3 [(M+H)+]
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:5][O:4]1.C(=O)(O)[O-].[Na+].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:5][CH:3]([OH:4])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Product: OC1CN(Cc2ccccc2)C1

Procedure:
reacting (±)-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine to provide 1-benzyl-3-azetidinol, reacting the 1-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 35° C. to about 45° C., and isolating 1-benzyl-3-azetidinol (2E/Z)-2-butenedioate;
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCCCC1>C(O)C>[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]2=[O:1])=[CH:20]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccn2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccn2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 2.5 %

Procedure:
To a solution of ethyl 4-oxo-2-(2-pyridinylamino)-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.32 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.047 g, 0.32 mmol) in ethanol (2.0 mL), piperidine (0.038 mL, 0.39 mmol) was added at ambient temperature. The mixture was refluxed for 10 h. Cooled to ambient temperature, the precipitate was removed by filtration and the filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0030 g, y. 2.5%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][CH:7]=[CH:6][CH:5]=1.[N+:9]([C:12]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])([O-:11])=[O:10]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)[C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:20]=[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:22]=[CH:23][C:12]=1[N+:9]([O-:11])=[O:10])[CH3:19]
Reactant: CNCc1ccco1
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)N(C)Cc1ccco1
Temperature: -15 °C

Procedure:
N-Methyl-N-furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-methyl-N-furfuryl-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=2)=[C:4]([F:22])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O1CCOCC1.CO>Cl>[Cl:1][C:2]1[C:3]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=2)=[C:4]([F:22])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2c(Cl)cnc(N3CCC(NC(=O)OC(C)(C)C)CC3)c2F)c(C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cnc(-c2c(Cl)cnc(N3CCC(N)CC3)c2F)c(C)c1
Yield: 121.7 %

Procedure:
A solution of tert-butyl (1-(5′-chloro-3′-fluoro-3,5-dimethyl-[2,4′-bipyridin]-2′-yl)piperidin-4-yl)carbamate (160 mg, 0.368 mmol) in 4 M HCl in dioxane (3.0 mL, 12.0 mmol) and MeOH (1.0 mL) was stirred at rt for 2 h. After concentration, the residue was further dried under vacuum to give 150 mg (100%) of pale yellow solid as a di-HCl salt: LRMS (M+H)+: 335.0; 1H NMR (400 MHz, DMSO-d6) δ 1.50-1.72 (m, 2 H), 1.94-2.03 (m, 2 H), 2.10 (s, 3 H), 2.37 (s, 3 H), 2.89-3.12 (m, 2 H), 3.20-3.33 (m, 1 H), 3.92-4.08 (m, 2 H), 6.62 (br. s., 1 H), 7.77 (s, 1 H), 8.12-8.31 (m, 4 H), 8.44 (s, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][C:24]#[C:25][Si](C)(C)C)[CH:22]=2)[O:19][C:18]([CH3:31])([CH3:30])[CH2:17][C:16]3([CH3:33])[CH3:32])=[CH:7][CH:6]=1.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH3:30][C:18]1([CH3:31])[CH2:17][C:16]([CH3:32])([CH3:33])[C:15]2[C:20](=[C:21]([CH2:23][C:24]#[CH:25])[CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[CH:10][CH:9]=3)[CH:14]=2)[O:19]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(CC#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#CCc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure K and using {4-[2,2,4,4-tetramethyl-8-(3-trimethylsilanyl-prop-2-ynyl)-chroman-6-ylethynyl]-phenyl}-acetic acid methyl ester (Compound 48, 0.105 g, 0.21 mmol), methanol (3 mL), tetrahydrofuran (3 mL), water (1.5 mL) and lithium hydroxide monohydrate (0.128 g, 3.07 mmol), the title compound was obtained as a pale yellow solid (0.077 g, 95%). 1H NMR (300 MHz, CDCl3): δ7.51 (d, 1H, J=2.2 Hz), 7.49 (d, 2H, J=8.2 Hz), 7.39 (d, 1H, J=2.2 Hz), 7.25 (d, 2H, J=8.2 Hz), 3.66 (s, 2H), 3.52 (d, 2H, J=2.6 Hz), 2.61 (t, 1H, J=2.6 Hz), 1.83 (s, 2H), 1.36 (s, 6H), 1.35 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH:33]=[CH2:34])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:10]1[OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[CH2:1]([O:8][C@:9]1([CH:33]=[CH2:34])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:10]1[O:32][S:36]([CH3:35])(=[O:38])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Nucleoside 24 (2.57 g, 5.53 mmol) was dissolved in anhydrous pyridine (18 cm3) and cooled to 0° C. Methanesulfonyl chloride (1.28 cm3, 16.6 mmol) was added dropwise and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5 cm3) and the resulting mixture was extracted with dichtoromethane (3×80 cm3). The combined extract was washed with saturated aqueous sodium hydrogencarbonate (3×120 cm3) and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 25 as a yellow foam (2.53 g, 84%). δH (CDCl3) 8.92 (1H, br s, NH), 7.71 (1H, d, J 1.4, 6-H), 7.41-7.28 (10H, m, Bn), 6.57 (1H, d, J 7.8, 1′-H), 5.99-5.61 (4H, m, 2′-H, 1″-H and 2″-Ha, 2″-Hb), 4.86-4.50 (4H, m, Bn), 4.37 (1H, dd, J 1.5, 2.4, 4′-H), 8.82 (1H, dd, J 2.6, 11.0, 5′-Ha), 3.55 (1H, dd, J 1.2, 11.0, 5′-Hb), 3.02 (3H, s, CH3), 1.47 (3H, d, J 1.1, CH3). δC (CDCl3) 163.7 (C-4), 151.5 (C-2), 138.7, 136.7 (Bn), 135.7 (C-6), 130.9 (C-1″), 128.8, 128.5, 128.4, 127.6, 127.0 (Bn), 121.8 (C-2″), 111.9 (C-5), 85.1 (C-1′), 84.5 (C-3′), 84.0 (C-4′), 80.7 (C-2′), 73.7 (C-5′), 69.2, 67.7 (Bn), 38.9 (CH3), 11.8 (CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[OH:12].CO.C[O-].[Na+].[CH2:18]([OH:21])[CH:19]=[CH2:20].C1(C)C=CC=CC=1>>[C:8]([C:4]1[CH:5]=[C:6]([CH2:20][CH2:19][CH2:18][OH:21])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:12])([CH3:9])([CH3:11])[CH3:10]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: C=CCO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(CCCO)cc(C(C)(C)C)c1O
Temperature: 210 °C
Reaction time: 7 h
Yield: 52 %

Procedure:
A pressure container was charged with 62.7 g (0.38 mol) of 2-methyl-6-t-butylphenol and 7.3 g (0.038 mol) of a methanol solution containing 28% of sodium methoxide. Then the mixture was heated under reduced pressure to distill 6.5 g (0.2 mol) of methanol. Thereafter, 22.2 g (0.92 mol) of allyl alcohol and 18.7 g (0.19 mol) of toluene were added to the reaction system, the atmosphere in the reaction system was replaced by nitrogen and then, the reaction system was tightly closed. Then, the reaction system was raised up to 210° C. and kept at that temperature for 7 hours. Then, the reaction mixture was cooled to room temperature. A sample of the reaction solution was analyzed by gas-chromatography. The desired product, 3-(3-t-butyl-4-hydroxy-5-methylphenyl)propanol was obtained in a yield of 52%.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2[OH:13])=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl.COC(C)(C)C>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2CCCCC2O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: COC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.00 g (15.8 mmol) rac-2-p-tolyl-cyclohexanol in 60 ml dichloromethane were added drop-wise 51.84 g (18.3 mmol) of a 15% solution of Dess-Martin periodinane [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] in dichloromethane, and then drop-wise a solution of 300 μl water in 300 ml dichloromethane within 30 min. The resulting solution was stirred for further 30 min. at ambient temperature. Then the reaction mixture was diluted with 350 ml tert.-butyl methyl ether and evaporated to a quarter of the initial volume. The residue was diluted with 800 ml tert.-butyl methyl ether, washed with a total of 600 ml of a 1:1 mixture of saturated NaHCO3 solution and a 10% Na2S2O3 solution and with brine. The combined aqueous extracts were re-extracted with tert.-butyl methyl ether. The combined organic extracts were washed with brine, died over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography on silica gel with dichloromethane as eluent: 2.39 g rac-2-p-tolyl-cydohexanone as colorless powder: MS (ISP): 189.3 MH+.
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(N)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([NH2:43])=O)=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]#[N:43])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:44])=[CH:27][CH:26]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(N)=O
Agent: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(N)=O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C#N
Yield: 68 %

Procedure:
Following the procedure as describe in Preparation 20, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxamide with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a pale yellow solid in 68% yield: mp 136-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.31 (m, 2H), 7.18-7.13 (m, 2H), 4.41 (s, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.46 (t, J=6.0 Hz, 2H) 2.37 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.1 (d), 161.4, 161.1, 155.3, 150.3, 132.8 (d), 130.5 (d), 115.9 (d), 114.4, 92.4, 46.6, 42.7, 42.3, 17.3; MS (ES+) m/z 317.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[O:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20].C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:45]2[CH:53]=[CH:52][CH:51]=[C:50]3[C:46]=2[CH:47]=[N:48][NH:49]3)O1>C(#N)C.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>[NH:49]1[C:50]2[C:46](=[C:45]([C:2]3[N:3]=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:5]4[O:10][C:9]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:27]=5)=[CH:8][C:6]=4[N:7]=3)[CH:53]=[CH:52][CH:51]=2)[CH:47]=[N:48]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2oc(I)cc2n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3o2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (40 mg, 1.0 eq) was dissolved in acetonitrile (0.4 ml) and treated with 3-(methylsulfonyl)phenylboronic acid (23 mg, 1.05 eq), PdCl2(PPh3)2 (7.7 mg, 0.10 eq) and 1M Na2CO3 (0.33 ml). The vial was sealed and heated with stirring in the microwave to 100° C. for 30 minutes. Reaction mixture was quenched with saturated aq. NaHCO3 and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The residue was dissolved in acetonitrile (0.4 ml) and treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (53 mg, 2.0 eq), PdCl2(PPh3)2 (7.7 mg, 0.10 eq) and 1M Na2CO3 (0.33 ml). The vial was sealed and heated with stirring in the microwave to 150° C. for 15 minutes. The crude reaction mixture was concentrated and purified by reverse phase HPLC to afford 2-(1H-indazol-4-yl)-6-(3-(methylsulfonyl)phenyl)-4-morpholinofuro[3,2-d]pyrimidine 111 MS (Q1) 476 (M)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=O.O.[NH2:12][NH2:13]>CCO>[N:6]1[CH:7]=[CH:8][N:9]=[CH:10][C:5]=1[C:3]([NH:12][NH2:13])=[O:2]
Reactant: COC(=O)c1cnccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cnccn1
Yield: 100.5 %

Procedure:
To a stirred solution of pyrazine-2-carboxylic acid methyl ester (11.1 g, 80 mmol) in 140 mL of EtOH was added hydrazine hydrate (15.6 mL, 320 mmol). The resultant solution was heated to reflux for 2 h. The solvent was removed under reduced pressure and dried under high vacuum to yield the title amide (11.1 g, 100%) as a white solid. The product was used in subsequent steps without purification. 1H NMR (d6-DMSO δ 10.1, br s, 1H; δ 9.12, d, 1H; δ 8.83, d, 1H; δ 8.70, dd, 1H; δ 4.64, br s, 2H), LC/MS (APCI, ES, M+H=139).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH2:13][CH:14]2[C:19](=[O:20])[NH:18][CH:17]=[CH:16][N:15]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.C(Cl)CCl.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[O:20]=[C:19]1[NH:18][CH:17]=[CH:16][N:15]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:14]1[CH2:13][C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:6][CH:7]=1)=[O:31]
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)Nc2ccc(CCC=O)cc2)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)Nc2ccc(CCCN3CCCCC3)cc2)cc1

Procedure:
To a 20 mL flask equipped with stirring was added N-[4-(3-oxo-propyl)-phenyl]-2-[3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetamide (45 mg, 0.102 mmol), ClCH2CH2Cl (2 mL), piperidine (Aldrich, 0.02 mL, 0.204 mmol) and one drop of HOAc. NaBH(OAc)3 was added after 5 min. The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 (40 mL). The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative TLC (10% MeOH—CH2Cl2) afforded the title compound. MS (ESI): 511 (M+H)+.
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.[CH:23](N(CC)C(C)C)(C)C.ClCCl>O.C(COC)OC.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]>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:23][C:12]1[CH:11]=[C:6]([CH:5]=[CH:4][CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(Cc2cccc(F)c2)c1
Yield: 84.8 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (1.00 g; 4.36 mmol), 3-fluorophenylboronic acid (0.371 g; 4.80 mmol), N,N-diisopropylethylamine (1.5 mL; 8.73 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.356 g; 0.436 mmol) in water (2 mL) and dimethoxyethane (6 mL) was irradiated in a microwave oven at 130° C. for 15 minutes. The resulting mixture was partitioned between water and ethyl acetate and the phases were separated. The organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to yield 0.903 g (85%) of methyl 3-(3-fluorobenzyl)benzoate.