Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]Br.[Br:4][C:5]1[C:6]([SH:12])=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[Br:4][C:5]1[C:6]2[S:12][CH2:2][O:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Oc1cccc(Br)c1S
Reactant: BrCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc2c1SCO2
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a solution of 17 g dibromomethane and Aliquat 336® in 200 ml toluene is added dropwise a solution of 21 g 3-bromo-2-mercapto phenol [prepared according to the procedure of S. Cabiddu et al., Synthesis, loc. cit.] and A. Bashall and J. Collins, Tetrahed. Lett., loc. cit.] 24 g of 50% sodium hydroxide and 50 ml H2O. The reaction mixture is then heated at reflux for 16 hours and cooled to ambient temperature. The organic phase is separated, washed with 1N sodium hydroxide and water, dried and concentrated under reduced pressure to give an oil. The oil is purified via distillation to give 14 g 4-bromo-1,3-benzoxathiole. The oil is dissolved in 60 ml of tetrahydrofuran under a nitrogen atmosphere, cooled to -70° C. and treated sequentially with 45 ml n-butyllithium (1.6N in hexanes) for 1 hour and excess sulfur dioxide until no further exotherm is noted. The reaction mixture is contacted with 2 ml isopropyl alcohol, concentrated in vacuo and crystallized from ether/tetrahydrofuran to give a solid. The solid is added to 150 ml acetic acid and cooled to 20° C. A slurry of 8.0 g N-chlorosuccinimide in 30 ml acetic acid is added portionwise with cooling to maintain a reaction temperature of 20°-25° C. The reaction mixture is stirred for three hours at room temperature and the solvent is removed under reduced pressure to give an oil which is dissolved in methylene chloride and washed with water. The organic phase is dried, and the solvent removed under reduced pressure to give an oil which is dissolved in 250 ml ether and cooled to 10° C. Excess ammonia (anhy.) is bubbled through the reaction mixture with external cooling. The reaction mixture is washed with water, dried, and concentrated under reduced pressure to give a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[CH3:19][N:20]1[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:24]2[N:20]([CH3:19])[C:21]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:23]=2[CH3:25])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 17.5 g. (0.1 mole) p-chlorobenzoyl chloride and 13.3 g. (0.1 mole) aluminum chloride in 150 ml. of dichloroethane is added rapidly to a solution of 25.3 g. (0.1 mole) of ethyl 1,4-dimethyl-3ethoxycarbonylpyrrole-2-acetate in 100 ml. of refluxing 1,2 -dichloroethane. The solution is refluxed for 3.5 hours and poured into ice-hydrochloric acid. The organic layer is separated, and the aqueous layer washed with 1,2-dichloroethane. The combined organics are washed successively with water, N,N-dimethylaminopropylamine, dilute HCl and brine. The solution is then dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue product is crystallized from cyclohexane and recrystallized from methanol to give ethyl 5-(p-chlorobenzoyl)-1,4 dimethyl-3 -ethoxycarbonylpyrrole-2-acetate as a white solid, m.p. 91-93° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][C@@H:18]([NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:19]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:15]3[CH2:16][CH2:17][C@@H:18]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:19][C:20]=3[CH:21]=[CH:22][CH:23]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N[C@@H]1CCc2c(cccc2NS(=O)(=O)c2ccc(C(C)C)cc2)C1
Agent: Cl
Solvent: C1CCOC1
Product: CCCN[C@@H]1CCc2c(cccc2NS(=O)(=O)c2ccc(C(C)C)cc2)C1
Yield: 28 %

Procedure:
(R)—N-[5-(4-Isopropyl-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propionamide (0.48 g, 1.20 mmol) was dissolved in 10 mL of THF and 5 mL (8.36 mmol) of a borane-THF complex was introduced dropwise over 20 min. The resulting mixture was stirred at reflux for 3 h. The solution was cooled, 5 mL of 2 N HCl was added slowly, and the mixture was stirred at 40° C. for 1 h. The cooled solution was quenched with water, then NaOH (2N) and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and the filtrate was evaporated in vacuo to give the product as a colorless oil (130 mg, 28%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.CCN(CC)CC.Cl.[CH:21]12[O:28][CH:25]([O:26][CH2:27]1)[CH2:24][NH:23][CH2:22]2>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]2=[C:2]([N:23]2[CH2:24][CH:25]3[O:28][CH:21]([CH2:27][O:26]3)[CH2:22]2)[N:7]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: C1NCC2OCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc2c(N3CC4COC(C3)O4)nc(Cl)nc21
Yield: 46.2 %

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.5 g, 2.46 mmol), Et3N (1.05 mL, 7.5 mmol) and 6,8-dioxa-3-azabicyclo[3.2.1]octane hydrochloride (373 mg) in CH2Cl2 (5 mL) is stirred for 18 h. Concentration in vacuo followed by silica gel chromatography (hexane/ethyl acetate) gives 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6,8-dioxa-3-azabicyclo[3.2.1]octane as a white powder (320 mg). This material (0.16 g, 0.57 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.186 g, 0.85 mmol), aq. Na2CO3 (0.425 mL, 2M), and tetrakis triphenylphosphine palladium (20 mg) in 1:1 toluene:ethanol. The reaction mixture was heated in a microwave at 120 C for 20 min to give 4-(4-(6,8-dioxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. To this material (190 mg, 0.56 mmol) in CH2Cl2 is added Et3N (0.42 mL) and a solution of triphosgene (83 mg, 0.28 mmol) in CH2Cl2. After 30 min half of the solution is added to 3-aminopyridine (105 mg, 1.12 mmol). After 2 h aq. workup and silica gel chromatography (EtOAc/MeOH) gives the title compound as an off-white solid (104 mg). HRMS m/z=459.1894 (M+H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].O.[CH3:30][N:31]([CH3:41])[C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[ClH:42]>C(O)C.C1(C)C=CC=CC=1.CO.CCOCC.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>[ClH:42].[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:35]3[CH:36]=[N:37][C:32]([N:31]([CH3:41])[CH3:30])=[CH:33][CH:34]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(N(C)C)nc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
In a carousel tube, 1-methylethyl[(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 61) (80 mg, 0.217 mmol), potassium carbonate (59.9 mg, 0.433 mmol), tetrakis(triphenylphosphine)palladium(0) (12.52 mg, 10.83 μmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid hydrate (47.8 mg, 0.26 mmol, available from Apollo) were dissolved in Ethanol (0.5 mL) and Toluene (0.5 mL). The tube was placed in a carousel and heated under nitrogen for 18 hr at 90° C. The reaction mixture was filtered and the solvent evaporated before being taken up in DCM and purified by SP4 on a 12+M silica cartridge using a gradient of 20-100% EtOAc in cyclohexane. Appropriate fractions were collected and concentrated. The sample was dissolved in 1:1 MeOH:DMSO 1 mL and purified by MDAP. The solvent was evaporated in vacuo. To form a salt, the product was dissolved in MeOH and HCl (0.217 mL, 0.217 mmol) 1M in ether was added. Solvent was evaporated to yield the product as a pale yellow solid (76 mg). LCMS (Method C): Rt=0.66, MH+=411
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]=[CH2:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[S:19]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]O)=[CH:20]1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]=[CH2:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C=CCOc1ccc2[nH]c(C(=O)OCC)cc2c1
Reactant: OCCc1ccsc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(c1)cc(C(=O)OCC)n2CCc1ccsc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
To solution of 5-allyloxyindole-2-carboxylic acid ethyl ester (1.0 g, 4.08 mmol) in THF (10 mL) was added azodicarboxylic acid bis[dimethylamide] (TMAD; 1.4 g, 8.15 mmol). After stirring at room temperature for 20 min, 2-(3-thienyl)ethanol (0.78 g, 6.12 mmol) was added followed by the addition of tributyl phosphine (1.65 g, 8.15 mmol). After stirring at room temperature for 18 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na2SO4. Purification by flash colunmn chromatography (silica gel, EtOAc/hexanes) yielded the desired product as an oil (1.36 g, 94%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].C1(C)C=CC=CC=1.[CH3:17][C:18]1[CH:31]=[C:30]2[C:21]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([C:33](Cl)=[O:34])[C:28]=3[C:29]2=[O:32])=[CH:20][CH:19]=1>O>[CH2:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:33]([C:27]1[C:28]2[C:29](=[O:32])[C:30]3[C:21](=[CH:20][CH:19]=[C:18]([CH3:17])[CH:31]=3)[S:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)=[O:34])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCC(C)C
Reactant: Cc1ccc2sc3cccc(C(=O)Cl)c3c(=O)c2c1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2sc3cccc(C(=O)N(CC(C)C)CC(C)C)c3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.9 %

Procedure:
1.0 g (7.75 mmoles) of diisobutyl amine is dropped into a toluene solution of 7-methyl-9-oxo-9H-thioxanthene-1-carbonyl chloride (0.22 g, 0.78 mmoles). After 2 hours at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed with water. A crude oil is obtained after evaporation of the solvent. 11.5 mg of a yellow solid are isolated by flash chromatography of the crude oil (SiO2— eluent: CH2Cl2:MeOH 96:4).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CN(C)CCN(C)C.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH:30]=[O:31])=[CH:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccs2)OCCO1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2ccc(C=O)s2)OCCO1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of commercially available 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (5.00 g, 28.49 mmol) in THF (145.0 mL) at −78° C. was added dropwise N,N,N′,N′-tetramethyl-ethylendiamine (4.41 mL, 29.06 mmol) followed by n-BuLi (18.14 mL of a 1.6 M solution in hexanes, 29.06 mmol), maintaining the temperature at −78° C. The reaction mixture was then stirred for 2 h at −78° C. before DMF (6.74 mL, 87.22 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 16 h. The reaction mixture was poured in sat. aq. NaH4CI (200 mL) and extracted with EA (2×200 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-2-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.87 min; [M+AcCN+H]+=240.32. The crude material was dissolved, under inert atmosphere (N2) in MeOH (51.2 mL) and treated at 0° C., portionwise, over 20 min, with NaBH4 (1.35 g, 34.19 mmol in five equal portions). The reaction mixture was stirred at rt for 45 min. The reaction mixture was poured in water (90 mL) and the aq. layer was extracted with EA (2×225 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC:rf (50:50 hept-EA)=0.40. LC-MS-conditions 02: tR=0.72 min; [M+H]+=201.46.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17]OS(C)(=O)=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[I-:23].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][I:23])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CS(=O)(=O)OCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CI)CC3
Temperature: 60 °C
Yield: 78.4 %

Procedure:
A mixture of 9-bromo-5-methylsulfonyloxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (2.3 g, 5.91 mmol) and sodium iodide (7.9 g, 52.7 mmol) in DMF (30 mL) was heated at 60° C. for 22 h and poured into water (400 mL). The precipitates formed was collected by filtration, washed with water, and dried in vacuo to give 1.95 g of the title compound (78%): mp 260°~270.5° C.; 1H NMR (270 MHz, CD3OD) δ7.22 (s, 1H), 7.19 (s, 1H), 4.95~5.07 (m, 1H), 3.50 (dd, 1H, J=10.2, 4 Hz), 3.24 (d, 1H, J=10.2 Hz), 2.97 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz), 2.70 (dm, 1H, J=13.5 Hz), 1.90~2.07 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[OH:27])(O)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[OH:27])[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1C(=O)C(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Temperature: 90 °C
Yield: 43.4 %

Procedure:
A mixture of ethyl [4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate (0.90 g, 2.00 mmol), triethylsilane (2.00 mL, 12.2 mmol) and trifluoroacetic acid (0.94 mL, 12.2 mmol) was heated at 90° C. for two days. After cooling down to ambient temperature, the mixture was diluted with ethyl acetate (200 mL), washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexanes, 1/3) to give the title compound (0.37 g, 43%): 1H NMR (300 MHz, CDCl3) δ 7.35-7.22 (m, 3H), 6.82-6.71 (m, 2H), 6.52 (t, 1H), 5.10 (s, 1H), 4.45 (s, 2H), 4.21 (q, 2H), 1.23 (t, 3H); MS (ES+) m/z 426.4 (M+1), 428.4 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[NH:7][C:8](=[O:27])[C:9]([I:26])=[C:10]([O:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CS(C)=O>[N:1]([C:6]1[NH:7][C:8](=[O:27])[C:9]([I:26])=[C:10]([O:17][C:18]2[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:2]=[N-:3]
Reactant: CCOC(=O)c1c(Cl)[nH]c(=O)c(I)c1Oc1cc(C)cc(C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(N=[N+]=[N-])[nH]c(=O)c(I)c1Oc1cc(C)cc(C)c1
Temperature: 50 °C
Yield: 69.2 %

Procedure:
Sodium azide (0.20 g, 3.12 mmol) was added to a solution of intermediate 3 (0.50 g, 1.56 mmol) in DMSO (5 ml), and the mixture was heated at 50° C. for 5 hours Reaction mixture was partitioned between water (30 ml) and ethyl acetate (40 ml). The organic layer was dried over magnesium sulfate and concentred. Flash chromatography (SiO2, CH2Cl2/ethanol 95:5) gave the desired product (0.49 g, 70%) as a white solid, m.p.=216–218° C.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1.C[Si]([N:33]=[C:34]=[O:35])(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:34](=[O:35])[NH2:33])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH2:27][CH3:28])[CH:3]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCNCC2)CCO1
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C(N)=O)CC2)CCO1
Reaction time: 2.5 h
Yield: 90.5 %

Procedure:
To a solution of 4-amino-5-chloro-2-ethoxy-N-[{4-(4-piperidinylmethyl)-2-morpholinyl}-methyl]benzamide (Example 22) (1.0 g) in methylene chloride (15 ml) was added trimethylsilyl isocyanate (0.34 g) at room temperature, and the mixture was stirred for 2.5 hours. The solvent was removed in vacuo, and then to the residue was added water. The precipitated solid was filtered in vacuo, washed with aqueous ethanol and dried to give the titled compound (1.0 g) as a white solid. Melting point 201-207° C. (recrystallized from E/H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(F)c(F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Benzyloxyphenyl)-3-hydroxy-2-(3,4-difluoro-phenoxy)-2-methylpropionic acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stared vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 3-(4-benzyloxyphenyl)-2-(3,4-difluorophenoxy)-2-methylpropionic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25](Cl)=[O:26]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:28]=[C:29]([Cl:31])[CH:30]=[C:22]([O:21][C:20]([F:33])([F:19])[F:32])[CH:23]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cc(Cl)cc(OC(F)(F)F)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cc(Cl)cc(OC(F)(F)F)c1
Yield: 38.9 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]-pyridin-2(3H)-one and 3-trifluoromethoxy-5-chlorobenzoyl chloride to afford the title compound (38 mg, 38.9%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.93-6.96 (m, 1H, Harom), 7.44 (t, 1H, Harom-5, J=8.0 Hz), 7.58 (s, 1H, Harom-2), 7.63-7.65 (m, 1H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 7.82 (m, 1H, Harom′), 7.86 (m, 1H, Harom′), 8.08 (t, 1H, Harom′, J=1.6 Hz), 10.53 (s, 1H, NHamide), 11.20 (s, 1H, NHPy7), 11.40 (s, 1H, NHPy9). LC-MS, tR=5.13 minutes, m/z: 467.05 (M+H)+, calculated for C20H13N4O4F3Cl. HRMS (EI): m/z [M+H] calculated for C20H13N4O4F3Cl: 465.0585; found: 465.0583.
Reaction SMILES: Br[C:2]1[C:3]([F:33])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]([OH:31])[C:20]4[N:24]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:23]=[CH:22][CH:21]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:32]=1.[CH3:34][C:35]([OH:39])([CH3:38])[C:36]#[CH:37].C(NC(C)C)(C)C>CN(C=O)C>[F:33][C:3]1[C:2]([C:37]#[C:36][C:35]([OH:39])([CH3:38])[CH3:34])=[CH:32][C:6]2[C:7]3[N:8]([C:13]([CH:19]([OH:31])[C:20]4[N:24]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:23]=[CH:22][CH:21]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C(O)c1ccnn1C1CCCCO1

Procedure:
9-Fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford the title compound which was carried forward to the next step without further purification.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[CH3:17][C:18]1([CH3:25])[CH2:21][CH:20]([C:22](Cl)=[O:23])[CH2:19]1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:22]([CH:20]2[CH2:21][C:18]([CH3:25])([CH3:17])[CH2:19]2)=[O:23])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CC1(C)CC(C(=O)Cl)C1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)C2CC(C)(C)C2)c(O)c1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 3,3-dimethylcyclobutanecarbonyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.