Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][OH:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:17][CH:18]=3)[C:9]([CH:11]=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Yield: 84.8 %

Procedure:
N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (40.0 mg, 0.09 mmol) was dissolved in THF (5.0 mL) and to it was added Dess-Martin Periodinane reagent (44.0 mg, 0.10 mmol). The reaction was stirred at rt until HPLC indicated completion of reaction. Reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3/Na2S2O3 1:1 (3×). The aqueous layer was back extracted with EtOAc (2×). Organic was dried (Na2SO4) and evaporated to give a crude oil that was purified via HPLC (10-90% ACN/H2O) to give a yellow solid (35.0 mg, 88%).1H-NMR (CD3OD) δ 9.76 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H); MS [M+H]+=459; LCMS RT=2.95 min.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([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)([CH3:9])([CH3:8])[CH3:7].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:6]([Si:10]([O:31][C:28]1[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=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)([CH3:9])([CH3:8])[CH3:7]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
11.06 g (162.5 mmol) of imidazole in 30 ml of dimethylformamide are added dropwise at room temperature to 35.24 g (130.0 mmol) of tert.-butylchlorodiphenylsilane and 11.25 g (65.0 mmol) of 4-bromophenol in 150 ml of dimethylformamide. After stirring at room temperature for 1 hour, the reaction mixture is poured onto 1000 ml of 5% sodium bicarbonate solution, the resulting mixture is extracted twice with 400 ml of dichloromethane, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by chromatography (silica gel, 8:2 hexane/ethyl acetate) gives 23.40 g of 4-bromophenyl tert.-butyldiphenylsilyl ether. ##STR43##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:30][C:31](=O)[CH2:32][CH2:33][CH3:34].C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:32]([CH2:33][CH3:34])[CH2:31][CH3:30])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCC(C)=O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC(CC)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 144 h
Yield: 16.9 %

Procedure:
A suspension of 1-(4-nitrophenyl)piperazine (5.00 g, 24.1 mmol, 1.0 eq), sodium triacetoxyborohydride (10.23 g, 48.3 mmol, 2 eq), and pentanone (6.23 g, 72.4 mmol, 3 eq) was stirred at RT in DCM (100 mL). Due to the viscous nature of the reaction mixture a further 50 mL of DCM was added to the reaction mixture (25 mL portion added after ca. 1 h; 25 mL portion added after 4 h). After 6 d, saturated aqueous NaHCO3 solution (25 mL) and 10% aqueous brine solution (25 mL) were added to the reaction mixture. The resulting mixture was stirred for 20 min, the phases separated, and the DCM extract washed with saturated aqueous NaHCO3 solution (25 mL), and 0% aqueous brine solution (25 mL) (50 mL total of aqueous soln in one wash). The phases were separated and the DCM extract dried by passing through a short column of MgSO4. The MgSO4 was rinsed with two portions of DCM (25 mL), and the combined DCM extracts evaporated on a rotary evaporator. To the residue obtained was added hexanes (25 mL) and the slurry stirred at rt for 24 h. The yellow precipitate which formed was collected by filtration and washed with hexanes (2×25 mL). On standing the required product precipitated from the filtrate. The precipitate was collected by filtration and dried under vacuum to provide the title compound as a yellow solid (1.13 g, 16% recovery, 87% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product was used in the next step without further purification. LCMS-ESI (m/z): calcd for C15H23N3O2, 277; [M+H]+ found, 278.
Reaction SMILES: COCCN1CCN(C2C=CC(C=O)=C([N+]([O-])=O)C=2)CC1.[Br-].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:24]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: COCCN1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CO
Product: c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 597.5 %

Procedure:
A solution of 4-[4-(2-methoxyethyl)piperazin-1-yl]-2-nitrobenzaldehyde (0.23 g, 0.68 mmol) obtained in Step 1 was dissolved in methanol (8.0 mL) and the solution was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.32 g, 0.68 mmol) and potassium carbonate (0.19 g, 1.4 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain (E)-3-{2-[4-(2-methoxyethyl)piperazin-1-yl]-2-nitrophenyl}vinyl}-1H-indazole (0.48 g, 100%).
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([Cl:5])=[O:4].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].C(Cl)(=O)C(Cl)=O>CN(C)C=O.C(Cl)Cl>[Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)[C:3]([Cl:5])=[O:4]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a methylene chloride (i000 mL) solution of 2-chloro-2-phenylacetyl chloride (50.0 grams, 0.26 mol) and concentrated sulfuric acid (100 mL) cooled in an ice bath was added dropwise fuming nitric acid (20.0 grams, 0.32 mol). The mixture was allowed to stir for two hours and then poured into ice (500 mL). The organic layer was washed with saturated sodium chloride solution (2×200 mL), dried with magnesium sulfate and filtered through a thin pad of silica gel. To this methylene chloride solution was added oxalyl chloride (13.2 grams, 0.52 mol) and N,N-dimethylformamide (9 drops). The mixture was stirred at room temperature for 1.5 hours, was heated under reflux for 20 minutes, and concentrated in a rotary evaporator to give the desired 2-chloro-2-(3-nitrophenyl)acetyl chloride (50.2 grams, 81% yield whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[BH4-].[Na+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of 2,3-dihydrobenzofuran-5-carbaldehyde (30.0 g, 0.202 mol) in methanol (150 mL) was added sodium borohydride (3.83 g, 0.101 mol) under ice-cooling. The mixture was stirred for 15 minutes at ambient temperature and then diluted with water. The product was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the title compound (yield 27.6 g, 91%) as an oily product.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][CH2:1][C@H:2]2[O:7][CH:6]([O:8][C@:9]3([CH2:18][O:19][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:13][C@H:12]([CH2:14][O:15][C:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:11]([OH:16])[C@@H:10]3[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]2[OH:22])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:27]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: O[C@@H]1[C@H](O)[C@@H](O)C(O[C@]2(COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@@H]2O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.8 %

Procedure:
The procedure of Hough, Mufti, and Khan, Carbohydrate Res., Vol. 21, pp. 144-147 (1972), is modified as shown below. To a solution of 15 g of sucrose (43.82 mmol) in 225 ml of pyridine, a solution of 54.95 g of trityl chloride (197.1 mmol, 4.5 equiv.) in 50 ml of pyridine is added dropwise over a period of 30 minutes. The reaction mixture is then stirred at room temperature for 4 days. After 4 days, the solution is concentrated to a brown syrup, which is dissolved in methylene chloride. This solution is further washed successively with 1M hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous sodium sulfate. The methylene chloride solution is then concentrated in vacuo and the residue applied on a column of silica gel packed in methylene chloride:acetone (4:1) and eluted with that solvent. The 1',6,6'-tri-O-tritylsucrose is obtained (28.59 g) in 58.8% yield as an off-white solid with a melting point of 127° to 130° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:13][C:14](=[O:16])[CH3:15])[C:7](=[N+]=[N-])[C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].CC(C)=[O:19].CC1(C)OO1>CC(C)=O>[C:1]([O:4][CH2:5][CH:6]([O:13][C:14](=[O:16])[CH3:15])[C:7](=[O:19])[C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)OCC(OC(C)=O)C(=[N+]=[N-])C(C)=O
Agent: CC1(C)OO1
Product: CC(=O)OCC(OC(C)=O)C(=O)C(C)=O
Reaction time: 1 h

Procedure:
To a solution of methyl diazo diacetate 7 (20 mg, 0.088 mmol) in acetone (1 mL) was added dimethyldioxirane acetone solution (2.5 mL, ca. 0.07-0.09 M). The resulting mixture was stirred for 1 h and solvent and excess reagents were removed under reduced pressure to obtain 19 as bright yellow oil (yield=19 mg, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(O)(c2ccc(F)cc2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(O)(c4ccc(F)cc4)C3)CC2)cc1
Yield: 78.1 %

Procedure:
The title compound (D162) (76.7 mg) was prepared according to the experimental procedure described in Description 146 (reaction time 1 h) starting from 5-chloro-2-(3-(4-fluorophenyl)-3-hydroxyazetidin-1-yl)nicotinic acid (D112) (64 mg, 0.198 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (45 mg, 0.198 mmol).
Reaction SMILES: C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=C[C:9]3[O:10]CC[O:13][C:8]=3C=2)C)CC1.Cl[C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:40]2[C:48]3[C:43](=[C:44]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)([CH:37]2[CH2:39][CH2:38]2)[CH3:36])=[CH:31][CH:30]=1>>[CH:37]1([C:35]([C:40]2[C:48]3[C:43](=[C:44]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)([C:32]2[CH:33]=[CH:34][C:29]3[O:10][CH2:9][CH2:8][O:13][C:30]=3[CH:31]=2)[CH3:36])[CH2:39][CH2:38]1
Reactant: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCCO4)C3CC3)c[nH]c12
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Product: CC(c1ccc2c(c1)OCCO2)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 94 mg (0.25 mmol) of the compound from Example 188 in analogy to the synthesis of the compound from Example 209. 56 mg (55% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(N([CH2:17][CH3:18])CC)C>CN(C=O)C>[Cl:11][C:4]1[CH:3]=[C:2]([NH:1][C:6]([CH2:5][C:4]2[CH:3]=[CH:2][CH:10]=[CH:9][C:17]=2[CH3:18])=[O:7])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.9 %

Procedure:
19.56 g (116 mmol) of (2-methylphneyl)acetic acid chloride are added, over 1 hour, to a mixture of 20 g (116 mmol) of 4-amino-2-chlorobenzoic acid, 12.9 g (127 mmol) of triethylamine and 150 ml of DMF dried over a molecular sieve. After stirring for 16 h at room temperature, the DMF is removed by evaporation under vacuum. The residue is washed with water and with dichloromethane to give, after drying, 19 g of an off-white powder (Yield=53%).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([P:8](OCC)(=[O:12])[O:9][CH2:10][CH3:11])[CH2:6][CH3:7]>C(S)CC>[CH2:10]([O:9][P:8]([CH2:5][CH2:6][CH3:7])([CH2:3][CH2:2][C:1]#[N:4])=[O:12])[CH3:11]
Reactant: C=CC#N
Reactant: CCCP(=O)(OCC)OCC
Agent: CCCS
Product: CCCP(=O)(CCC#N)OCC
Yield: 94.4 %

Procedure:
53 g of acrylonitrile are added dropwise under nitrogen at a reaction temperature of 70° C. to a mixture of 160 g of diethyl propanephosphonate in 100 g of n-propylmercaptan in the course of 2 hours. After a further 3 hours the solvent (low-boiling solvent such as C3H7SC2H5 and excess C3H7SH) is removed by vacuum distillation; the crude product is obtained in a yield of 173 g with a 95.4% purity, which corresponds to a theoretical yield of 94.4%. The boiling point of the product is 117°-118° C. at 0.027 mbar.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[NH:6][C:5]2[C:15]([CH3:25])=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]3)=[N:18][C:4]1=2)[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:24][CH:21]1[CH2:22][CH2:23][N:19]([C:17]2[CH:16]=[C:15]([CH3:25])[C:5]3[NH:6][C:7](=[O:14])[C:8]4[CH:13]=[CH:12][CH:11]=[N:10][C:9]=4[N:3]([CH2:1][CH3:2])[C:4]=3[N:18]=2)[CH2:20]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC(O)C3)nc21
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC(OC(C)=O)C3)nc21

Procedure:
The title compound, m.p. 188°-189.5° C., was synthesized from 5,11-dihydro-11-ethyl-2-(3- hydroxypyrrolidin-1-yl)-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and acetic anhydride using procedures analogous to those described above. The product was chromatographed over silica gel with ethyl acetate/hexane, and was then crystallized from diisopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:17])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[OH-].[Na+].CI>CO>[CH2:9]([N:14]1[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:10]2)[N:12]=[C:13]1[S:17][CH2:11][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CO
Product: O=C1N(Cc2ccccc2)C(SCc2ccccc2)=NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
To a solution of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (110 mg, 0.28 mmol) in MeOH (5 mL) in a 10 mL CEM microwave test tube was added a 0.6 N NaOH aqueous solution (1.0 mL). After stirring at room temperature for 10 min, MeI (158 mg, 1.08 mmol) was added, and the reaction was stirred at room temperature for 2 hrs. Upon removing the solvent in vacuo, the residue was purified by flash chromatography to give 1′-benzyl-2′-(benzylthio)-6-bromo-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (63.3 mg, 39%). MS m/z 569 (M+H+).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:26][C:25]1=[O:45]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[C:25](=[O:45])[CH2:26]4)=[CH:35][CH:34]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1=O
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)C(=O)C5)cc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-2-one. LCMS calculated for C27H30N5O3 (M+H)+: m/z=472.2. Found 472.1.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Cl)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[Na+].[Na+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(N3CCN(C)CC3)c2c(=O)n1-c1ccccc1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (3) (200 mg, 0.48 mmol) and 1-methylpiperazine (0.267 mL, 2.4 mmol) were dissolved in anhydrous NMP (8 mL) and the resulting solution was degassed and back-filled with argon (two cycles). To this mixture, Na2CO3 (102 mg, 0.96 mmol), Pd(OAc)2 (11 mg, 0.048 mmol) and di-(1-adamantyl)-n-butylphosphine (52 mg, 0.144 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon (two cycles) and then stirred at 160° C. under argon for 16 h. The reaction mixture was allowed to cool to RT and then partitioned between water and ethyl acetate. The organic layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-10% MeOH-DCM with 0.1% TEA) to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-(4-methylpiperazin-1-yl)-2-phenylisoquinolin-1(2H)-one (5) as a yellowish solid. ESI-MS m/z: 481.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([F:14])[C:11]([CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([F:14])[C:11]([CH:15]=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(NCc2ccc(Cl)cc2)nc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To [6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-yl]-methanol (63, 1.0 g, 3.7 mmol) in tetrahydrofuran (50.0 mL) was added Dess-Martin periodinane (1.75 g, 4.12 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (64, 0.67 g, 68.0%).
Reaction SMILES: [Cl:1][C:2]1[C:19]([CH2:20][N:21]2[CH2:40][CH2:39][C:24]3([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]4[N:33]=[C:34]([CH2:37][CH3:38])[S:35][CH:36]=4)=[O:31])[CH2:25]3)[CH2:23][CH2:22]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:19]([CH2:20][N:21]2[CH2:22][CH2:23][C:24]3([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]4[N:33]=[C:34]([CH2:37][CH3:38])[S:35][CH:36]=4)=[O:31])[CH2:25]3)[CH2:39][CH2:40]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1

Procedure:
TFA (10 mL) was added to a solution of tert-butyl 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:4][CH:3]1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O=S(Cl)Cl>>[CH3:1][CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:4][CH:3]1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][C:6]2[CH:5]=[CH:4][C:3]([CH2:11][CH3:12])=[CH:2][CH:7]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: CCCC1CCC(c2ccc(C(=O)O)cc2)C(C)C1
Solvent: O=S(Cl)Cl
Product: CCCC1CCC(c2ccc(C(=O)Oc3ccc(CC)cc3)cc2)C(C)C1
Reaction time: 2 h

Procedure:
20 g of p-(2-methyl-4-n-propylcyclohexyl)-benzoic acid (Examaple 5) is boiled for 1 hour with 24 g of SOCl2, the mixture is evaporated to dryness, the resulting crude acid chloride is dissolved in 150 ml of toluene, to which are added 8 ml of pyridine and 13.2 g of ethylphenol, and the mixture is boiled for 2 hours. Cooling down and customary working up give p-ethylphenyl p-(2-methyl-4-n-propylcyclohexyl)-benzoate.