Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][C@H:12]([CH3:15])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][O:14][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CO)COCOCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)COCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a mixture of diol 3 (29.2 mmol, 6.13 g), DMAP (0.82 mmol, 100 mg) and triethylamine (116.7 mmol, 16.2 mL, 11.8 g) in anhydrous CH2Cl2 (60 mL) was added tosyl chloride (37.9 mmol, 7.23 g) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The mixture was then diluted with CH2Cl2 (100 mL) and was then washed with a saturated aqueous solution of NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The residue was chromatographed on a silica gel using hexane/EtOAc (7:3) as an eluent to give the oily tosylate 4 (10.2 g, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=3[O:21][CH3:22])[NH:9][C:5]=2[CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:26]>>[NH2:2][C:1]([C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=3[O:21][CH3:22])[NH:9][C:5]=2[CH:4]=1)=[O:26]
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C#N)cc2[nH]1
Reactant: O=S(=O)(O)O
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C(N)=O)cc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
One gram (2.91 mmol) of 5-cyano-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole was added batchwise to 15 ml of concentrated sulfuric acid, and the resulting mixture was stirred for 24 hours at ambient temperature. The solution was then poured onto 300 ml of ice water, and the product precipitated was subjeted to suction filtration and recrystallized from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[F:10][C:11]([F:19])([CH2:16][O:17][CH3:18])[C:12](OC)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:12](=[O:13])[C:11]([F:19])([F:10])[CH2:16][O:17][CH3:18])=[N:6][CH:7]=1
Reactant: COCC(F)(F)C(=O)OC
Reactant: NNc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: COCC(F)(F)C(=O)NNc1ccc(Br)cn1

Procedure:
(5-bromo-2-hydrazinylpyridine (1.83 g, 9.73 mmol) and methyl 2,2-difluoro-3-methoxypropanoate (1.00 g, 6.49 mmol) were refluxed in toluene (35 mL) overnight. The reaction mixture was concentrated and purified by chromatography (EtOAc: hexanes=1:4) to give N′-(5-bromopyridin-2-yl)-2,2-difluoro-3-methoxypropanehydrazide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:19]Br>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
A solution of 4-Oxo-piperidin-1-carboxylic acid tert-butyl ester (10 grams, 50 mmol) and aluminium chloride (0.67 grams, 5 mmol) in tetrahydrofuran (30 mL) and diethyl ether (30 mL) was cooled to 0° C., and then treated with bromine (2.6 mL, 50 mmol) over a period of 30 minutes. Stirred the reaction mass for 24 hours at 0-5° C. After completion of reaction, the obtain solids were filtered and the mother liquor was concentrated under vacuum. The obtain crude was triturated with diethyl ether and solids were filtered and dried under vacuum to obtain the title compound (10 grams).
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)[S:3]1.C(=O)([O-])[OH:25].[Na+]>Cl>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:25])[NH:6][C:5]3=[O:7])=[CH:10][CH:11]=2)[CH2:19][CH2:20]1
Reactant: N=C1NC(=O)C(Cc2ccc(OCCN3CCOCC3)cc2)S1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=C1NC(=O)C(Cc2ccc(OCCN3CCOCC3)cc2)S1
Yield: 92.7 %

Procedure:
In 50 ml of 2 N-HCl is dissolved 4.1 g of the above 2-imino-5-[4-(2-morpholinoethyloxy)benzyl]thiazolidin-4-one and the solution is heated under reflux for 16 hours. After cooling, the reaction mixture is neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and distilled to remove the ethyl acetate, whereupon 3.8 g (92.7%) of 5-[4-(2-morpholinoethyloxy)benzyl]thiazolidine-2,4-dione is obtained as crystals. These crystals are recrystallized from dimethylformamide-water. Colorless prisms, m.p. 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=O)=[CH:4][CH:3]=1.[NH2:16][OH:17]>CO>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=[N:16][OH:17])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)c1c(Cl)ccc(C=O)c1F
Solvent: CO
Product: CCOC(=O)c1c(Cl)ccc(C=NO)c1F
Temperature: 60 °C

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-formylbenzoate (1.1 g, 4.0 mmol) in MeOH (5 mL) was added (aq. solution) hydroxylamine (4 mL) and the reaction mixture was heated at 60° C. for 2-3 h. The reaction mass was concentrated and extracted with EtOAC. The organic layer was washed with brine and concentrated to afford 0.900 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.31 (t, J=6.9 Hz, 3H), 4.40 (q, J=6.6 Hz, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 8.20 (s, 1H), 11.89 (br s, 1H).
Reaction SMILES: C[O-].[Na+].Br[CH2:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[O:19]1CCOC[CH2:20]1.Cl>CO>[CH3:20][O:19][CH2:5][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: C1COCCO1
Reactant: COC(=O)c1cccc(CBr)c1[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(C(=O)OC)c1[N+](=O)[O-]

Procedure:
Methanol solution (4.7 mL) of sodium methoxide (197 mg) was added dropwise into the mixture of methyl 3-bromomethyl-2-nitrobenzoate (1 g) and methanol (7 mL) under heating and refluxing. Two minutes later, the mixture was cooled down with ice and 1.82 mL of 4M hydrogen chloride dioxane solution was added dropwise thereto. After removing the solvent, diethylether and water were added and the organic layer thereof was dried over sodium sulfate. After removing the solvent, the obtained residue was purified with silica gel column chromatography to obtain 621 mg of methyl 3-methoxymethyl-2-nitrobenzoate.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.O>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Reactant: [H][H]
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Reaction time: 16 h

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, 5.63 g (0.048 mol), in 100 mL of methanol saturated with gaseous ammonia is treated with 0.5 g of Raney nickel #30 and hydrogen gas in a shaker at 50 psi and 40° C. After 16 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluent to give 4.93 g of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil with acceptable IR, NMR, C-NMR and MS spectra.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[C@@H:4]([CH3:15])[CH2:3]1.[C:17](Cl)(=[O:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[C:17]([C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:14])([CH3:13])[C@@H:4]([CH3:15])[CH2:3][C:2]2([CH3:16])[CH3:1])=[CH:7][C:8]=1[CH3:12])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)[C@@H](C)CC2(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)[C@@H](C)CC2(C)C
Yield: 90.1 %

Procedure:
To a solution of (S)-1,1,3,4,4,6-hexamethyl1,2,3,4-tetrahydronaphthalene ([α]546 -49.1° (C=1 in n-hexane)) (100.0 g; 0.463 mol) in 1,2-dichloroethane (300 g), acetyl chloride (38.0 g; 0.484 mol) and anhydrous aluminum chloride (71.0 g; 0.533 mol) were added, and the resultant mixture was stirred at 20° C. for 1 hour. The reaction mixture was treated with 10% hydrochloric acid (300 ml) and then separated into a water layer and an organic layer. The organic layer was washed with dilute hydrochloric acid and saturated sodium carbonate solution, dried and concentrated to give (S)-7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (107.5 g; 0.417 mol; 90%). B.P., 109° C./0.2 mmHg. [α]546 -36.9° (C=1 in ethanol).
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:29]=[CH:30][C:23]=12>C1COCC1.C(OCC)(=O)C>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:28]1[C:24]2=[N:25][CH:26]=[N:27][C:22]([O:20][C@@H:9]([CH2:8][O:7][CH:3]3[CH2:6][CH2:5][CH2:4]3)[C:10]([NH:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)=[O:11])=[C:23]2[CH:30]=[N:29]1
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
Sodium hydride (44.4 mg, 1.11 mmol) was added to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (186 mg, 0.74 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (255 mg, 0.96 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (262 mg, 73.8%). 1H NMR (400 MHz, DMSO) δ 1.39-1.52 (m, 1H), 1.56-1.67 (m, 1H), 1.77-1.91 (m, 2H), 2.13-2.24 (m, 2H), 2.44 (s, 3H), 3.88-4.02 (m, 2H), 4.06-4.15 (m, 1H), 5.89-5.94 (m, 1H), 7.56-7.70 (m, 3H), 7.73-7.78 (m, 1H), 8.31-8.33 (m, 1H), 8.54 (s, 1H), 8.63 (s, 1H), 9.10 (s, 1H), 11.17 (s, 1H). m/z (ESI+) (M+H)+=480.33; HPLC tR=2.45 min.
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[CH:13]=[CH:12][C:11]([N:14]([C:19]2[C:38]([CH:39]3[CH2:41][CH2:40]3)=[CH:37][C:22]3[C:23]([C:33](=[O:36])[NH:34][CH3:35])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[O:25][C:21]=3[CH:20]=2)[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:5]=1[C:6](OC)=[O:7]>C1COCC1.CO>[Br:3][C:4]1[CH:13]=[CH:12][C:11]([N:14]([C:19]2[C:38]([CH:39]3[CH2:41][CH2:40]3)=[CH:37][C:22]3[C:23]([C:33]([NH:34][CH3:35])=[O:36])=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[O:25][C:21]=3[CH:20]=2)[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:5]=1[CH2:6][OH:7]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 3 h
Yield: 99 %

Procedure:
LiBH4 (1.593 mL, 3.19 mmol) solution (2M in THF) was added dropwise to a solution of methyl 2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (0.76 g, 1.062 mmol) in tetrahydrofuran (6.0 mL) and methanol (0.600 mL) at 0° C. under N2. The mixture was stirred for 3 hours at the same temperature. It was quenched with 1M NaOH and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The organic phase was washed with brine, dried over Na2SO4. It was concentrated to dryness to give the crude product (>99%) as tan foam which was used for the next step without further purification. LCMS (m/z, ES+)=587 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[F:13].[C:14]([Cu])#[N:15]>CN(C=O)C>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[F:13])#[N:15]
Reactant: N#C[Cu]
Reactant: CC(=O)Nc1ccc(Br)c(F)c1C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#N)c(F)c1C
Temperature: 150 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
To a solution of N-(4-bromo-3-fluoro-2-methylphenyl)acetamide (72B) (2.18 g, 8.86 mmol) in DMF (20 mL) was added CuCN (2.61 g, 29.1 mmol). The mixture was stirred at 150° C. for 12 h and was then poured into ice (50 g). After warming to rt, the product was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried and concentrated. The residue was purified via flash chromatography eluting with a solution of 5% methanol in 95% of EtOAc/hexane (1:1) to provide the title compound (1.51 g) as a white solid. LCMS: m/z 193 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:8]([CH2:12][C:13](O)=O)[C:9](O)=O)[CH:7]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[CH2:18]([N:25]1[CH2:13][CH2:12][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(Cl)cc1C(CC(=O)O)C(=O)O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(Cl)cc1C1CCN(Cc2ccccc2)C1

Procedure:
1.0 g of 2-(5-chloro-2-methoxyphenyl)succinic acid is suspended in 50 ml of xylene, 0.47 ml of benzylamine is added and the mixture refluxed for 8 hours with separation of water. The solvent is evaporated and the residue taken up in ethylacetate and extracted with 2N HCl, followed by 2N NaOH and aqueous NaCl. The organic layer is dried, filtered and the solvent evaporated. The dried residue is purified by flash chromatography using t-butylmethylether/hexane 1/1 providing the amorphous product: MS (EI): M+=329; NMR (DMSO): 2.65 (1H, dd), 3.1 (1H, dd), 3.45 (3H, s), 4.2 (1H, dd), 4.6 (2H, s), 7.0 (1H, d), 7.25-7.4 (7H, m).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]3[O:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:19]([NH:26][CH:27](C)[CH2:28][O:29][C:30]1[CH:38]=[C:34]([C:35]([NH2:37])=[O:36])[C:33]([OH:39])=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(C)C>[C:35]([C:34]1[CH:38]=[C:30]([CH:31]=[CH:32][C:33]=1[OH:39])[O:29][CH2:28][CH2:27][N:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH:16]([OH:18])[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:13][CH:12]=1)(=[O:36])[NH2:37]
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O

Procedure:
A solution of 14.3 g of 1-[2-(cyclopropyl-methoxy)ethyl]-4-(2,3-epoxypropoxy)-benzene (German Offenlegungsschrift No. 2,649,605) and 16.3 g of 5-[2-(benzylamino)propoxy]-salicylamide in 200 ml of isopropanol is refluxed for 18 hours. The reaction mixture is concentrated by evaporation to leave crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-3-[4-[2-(cyclopropylmethoxy)ethyl]-phenoxy]-2-propanol in the form of brown oil, which can be further processed without additional purification.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:22]([O-:24])=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:19][O:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].C(=O)([O-])O.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:22]([O:24][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:19][O:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: COCc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.6 ml of DMF was added 4.2 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. Pivaloyloxymethyl iodide (34 mg) was added, and the mixture was stirred for 1 hour, diluted with 30 ml of ethyl acetate, and washed with 20 ml of saturated aqueous saline and 20 ml of semi-saturated squeous saline. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a volume of about 1 ml. The concentrate was purified by column chromatography on silica gel (chloroform:methanol=95:5) to give the title compound was obtained in a yield of 18.4 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15](N)=[N:14][NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.[ClH:17]>>[Cl:17][C:15]1[C:8]2[C:9](=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[NH:13][N:14]=1
Reactant: COc1ccc2cc3c(N)n[nH]c3nc2c1
Reactant: Cl
Product: COc1ccc2cc3c(Cl)n[nH]c3nc2c1
Yield: 25 %

Procedure:
3-Chloro-7-methoxy-1H-pyrazolo[3,4-b]quinoline was prepared from 7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 3d) by diazotization in hydrochloric acid. The product was recrystallized from ethanol and then from acetic acid and obtained in about 25% yield as a brown solid, m.p. 296°-297° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:18](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH3:18])[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1cccc(CNC)c1

Procedure:
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into the corresponding tert-butoxycarbonylamino derivative by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at N and deprotected again to yield the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3](=[O:38])[NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27](C(OC(C)(C)C)=O)[N:26]=[CH:25]4)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:3](=[O:38])[N:2]([CH3:1])[CH3:39])[CH:10]=[CH:9][CH:8]=4)[N:20]=3)=[CH:30][CH:29]=2)[CH:25]=[N:26]1
Reactant: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (50 mg, 0.10 mmol) was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether and the yellow solid was purified by prep HPLC (method 25-50_70 mins) to afford 3-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1,1-dimethylurea. (36 mg, 86%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][NH:36][CH3:35])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-formylphenyl)benzamide (150 mg), methylamine (38% in methanol, 0.5 ml) and 3 Å molecular sieves (500 mg) in methanol (10 ml) was stirred at ambient temperature overnight. Sodium borohydride (39 mg) was added to the solution and the mixture was stirred at ambient temperature for 4 hours. The mixture was diluted with chloroform and the solution was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) and the product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-methylaminomethylphenyl)benzamide (160 mg) as a white powder.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])[CH:9]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Fc1ccnc(CCl)c1
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2cc(F)ccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-4-fluoropyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: mp 228-231° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) 8.52 (dd, J=8.38, 5.56 Hz, 1H), 7.24-7.14 (m, 2H), 7.06-6.90 (m, 3H), 6.85 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.30 (s, 1H), 5.15 (d, J=16.0 Hz, 1H), 5.02-4.91 (m, 2H), 4.67 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 171.0, 167.6, 158.9 (2), 155.3, 152.0 (2), 144.7, 141.9, 138.4, 132.2, 128.9, 124.0, 123.7, 120.9, 111.7, 111.0, 110.8, 109.7, 109.5, 109.3, 99.4, 80.1, 64.5, 63.9, 58.1, 45.8, 11.9; MS (ES+) m/z 404.9 (M+1).