Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2cccs2)n1
Product: Cc1cc(Cl)nc(/C=C/c2cccs2)n1
Yield: 57.3 %

Procedure:
In analogy to example 12c), by heating (E)-6-methyl-2-(2-thiophen-2-yl-vinyl)-pyrimidin-4-ol (0.38 g, 1.74 mmol) in POCl3 (3.19 ml, 34.8 mmol) at 130° C. for 4.5 h was obtained (E)-4-chloro-6-methyl-2-(2-thiophen-2-yl-vinyl)-pyrimidine (0.236 g, 57%) as a light yellow solid. EI mass spectrum, m/e: 236 (M calculated for C11H9ClN2S: 236).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[C:14]([F:21])[CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].O>O1CCCC1>[F:21][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)[CH:20]=[CH:19][C:15]=1[CH2:16][OH:17]
Reactant: CC(=O)Nc1nc(CCc2ccc(C(=O)O)c(F)c2)cs1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CO)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.7 %

Procedure:
To a suspension of 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzoic acid (555.0 mg, 1.800 mmol) in anhydrous tetrahydrofuran (4 ml) was added 1,1′-carbonyldiimidazole (364.8 mg, 2.250 mmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was added dropwise to a mixture of sodium borohydride (1.362 g, 36.0 mmol), tetrahydrofuran (36 ml) and water (9 ml), which had been cooled to −25° C. After stirring at not more than 0° C. for 1 hr, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and a mixture of methanol (0.5 ml) and diisopropyl ether (15 ml) was added to the residue. The precipitate was collected by filtration and dried under reduced pressure to give N-(4-{2-[3-fluoro-4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (342.8 mg, 1.165 mmol, yield 64.7%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:24]([C:26]1([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28][CH2:27]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[F:23][C:20]([F:21])([F:22])[CH2:19][O:18][C:14]1[C:13]2[C:9]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][N:1]([CH2:24][C:26]4([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28][CH2:27]4)[CH2:2][CH2:3]3)=[N:10][O:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1(C=O)CCC1
Reactant: FC(F)(F)COc1cccc2onc(OCC3CCNCC3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole (0.33 g, 1.0 mmol, EXAMPLE 2, Step 2) and methyl 1-formylcyclobutanecarboxylate (0.17 g, 1.2 mmol, J. Org. Chem. 1993, 58, 6843-6850) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.42 g, 2.0 mmol) at room temperature. After being stirred at room temperature for 16 h, sat. aq. sodium hydrogencarbonate (20 mL) was added to the mixture. The mixture was extracted with dichloromethane (30 mL×2). The combined extract was dried over magnesium sulfate and concentrated in vacuo to give 0.46 g (quant.) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].[Cl:13][CH2:14]OS(Cl)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[C:1]([O:7][CH2:14][Cl:13])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=S(=O)(Cl)OCCl
Reactant: CC(C)CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(=O)OCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
1.532 g of isovaleric acid (1), 5.04 g of NaHCO3 and 0.518 g of tetrabutylammonium hydrogen sulfate were dissolved in a mixture solution of 50 ml of water and 50 ml of dichloromethane, and this mixture was ice-cooled. Then, to this mixture was added 3.025 g of chloromethyl-chlorosulfonate, and the reaction mixture was stirred for 0.5 hour at the same temperature and for 3 hours at room temperature. After the reaction, the organic layer was separated, washed with saturated saline solution and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane: chloroform=3:1) to give 1.38 g (60%) of isovaleryloxy-methylchloride [Compound (2)].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([C:12]3[C:20]4[O:19][CH2:18][O:17][C:16]=4[CH:15]=[CH:14][C:13]=3[NH2:21])=O)[C:4]=2[O:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:29])[C:25](=O)[CH2:26][CH3:27].S(=O)(=O)(O)O>C(O)(=O)C>[O:3]1[C:6]2[CH:7]=[CH:8][C:9]([C:10]3[C:12]4[C:13](=[CH:14][CH:15]=[C:16]5[O:17][CH2:18][O:19][C:20]5=4)[N:21]=[C:25]([C:24]([O:23][CH3:22])=[O:29])[C:26]=3[CH3:27])=[CH:4][C:5]=2[O:1][CH2:2]1
Reactant: Nc1ccc2c(c1C(=O)c1cccc3c1OCO3)OCO2
Reactant: CCC(=O)C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1nc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C)OCO3
Yield: 75.2 %

Procedure:
5-Amino-1,3-benzodioxole-4-yl 1,3-benzodioxole-4-yl ketone (2.7 g) and 2-ketobutyric acid methyl ester (1.9 g) were dissolved in acetic acid (30 ml), followed by addition of sulfuric acid (0.3 ml). The mixture was refluxed for 1.5 hours and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and water successively, dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as yellow crystals (2.6 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[NH:9][C@@:3]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][C@H:5]2S(C1C=CC=CC=1)(=O)=O.P([O-])([O-])(O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CO.[Na].[Hg]>[NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[NH:9][C@@:3]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][CH2:5]2
Reactant: N[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: [Hg]
Solvent: CO
Product: N[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Reaction time: 0.67 h
Yield: 55.2 %

Procedure:
(1R*,2R*,5S*,6R*)-2-amino-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Description 5; 1.0 g, 2.9 mmol) in methanol (20 mL) was treated with disodium hydrogen phosphate (1.65 g, 11.6 mmol) and 10% sodium amalgam (2.67 g), and the mixture stirred for 40 minutes. Saturated sodium bicarbonate solution (100 mL) was then added and the suspension extracted with dichloromethane (2×100 mL). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the title compound as a gum (315 mg, 1.6 mmol).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[NH:14][CH:13]=[C:12]2[CH:30]=[O:31])(=[O:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:30]=[O:31])(=[O:3])[CH3:2]
Reactant: COc1cccc(CC2NC=C(C=O)c3cc(OCCCOC(C)=O)c(OC)cc32)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cccc(Cc2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (150 mg, 0.30 mmol) in methanol (6 mL) was added powdered potassium hydroxide (169 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 hrs. The solvent was evaporated and the residue was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (78 mg, 67% yield) as a yellow oil. The crude product was used without further purification. To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (78 mg, 0.20 mmol) in chloroform (3 mL) was added manganese (IV) oxide (208 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 15 hrs, filtered through a Celite® pad, and washed with chloroform. The filtrate was concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (20 mg, 23% yield). The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH2:34][O:35][C:36]([F:39])([F:38])[F:37])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][O:35][C:36]([F:39])([F:38])[F:37])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CCOC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
500 mg (1.29 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 495 mg (1.89 mmol) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate and 1.39 ml (1.39 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF were reacted according to General Method 7B. Purification by column chromatography (24 g silica cartridge, flow rate: 35 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 386 mg (62% of theory)
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:29][CH3:30]>CN(C=O)C>[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[CH:24]=[CH:25][N:26]([CH2:29][CH3:30])[N:27]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2ccccc2)n1
Reaction time: 0.17 h

Procedure:
Sodium hydride (3.3 mg, 0.082 mmol, 60% in mineral oil) was added to a solution of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (5.4 mg, 0.016 mmol, from Example 62) in DMF (0.20 mL). After 10 minutes, iodoethane (3.9 μL, 0.049 mmol, Aldrich) was introduced. After 15 minutes reaction time, the reaction was quenched with water. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.1 mg, 53%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(=O)O[CH2:27][CH2:26][O:25]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:27][CH2:26][OH:25])=[C:10]([Cl:16])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1OCCO1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(OCCO)c(Cl)c1

Procedure:
To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.0 g) and potassium carbonate (0.55 g) in toluene (20 mL) is added ethylene carbonate (1.6 g) and the mixture is heated to reflux for 3 hours. To the cooled reaction mixture is added 2.5 M aqueous sodium hydroxide (50 mL), and the separated organic layer is then washed successively with water, then saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is then removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white foam.
Reaction SMILES: I(Cl)(=O)=O.[I:5](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:28]=1[NH2:29].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.ClCCl.O>[CH3:26][C:27]1[CH:33]=[C:32]([I:5])[C:31]([CH3:34])=[CH:30][C:28]=1[NH2:29]
Reactant: O=I(=O)Cl
Reactant: Cc1ccc(C)c(N)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(I)c(C)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.0 g (71.8 mmol) of benzyltrimethylammonium dichloriodate and 12.8 g (92.5 mmol) of potassium carbonate are added to a solution of 8.8 ml of (70.8 mmol) of 2,5-dimethylaniline in 250 ml of methanol and 600 ml of dichloromethane and stirred for 1 hour at ambient temperature. Then the inorganic salts are suction filtered and the solvent is distilled off. The residue is combined with a solution of 13.5 g (70.8 mmol) of sodium pyrosulphite in 640 ml of water and extracted with ether. The combined organic extracts are dried over sodium sulphate and evaporated down. The crude product is triturated with petroleum ether, suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([CH:10]([CH3:12])[CH3:11])=[O:21])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Sc1cnc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CC(C)S(=O)c1cnc(Cl)c(Cl)c1
Yield: 16 %

Procedure:
10 g (0.045 mol) of 2,3-dichloro-5-isopropylthiopyridine (as crude product) were reacted with 7.8 g (0.045 mol) of m-chloroperbenzoic acid in 60 ml of methylene chloride by a method similar to Example 1, Precursor β. After the crude product had been purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1), 1.7 g of product of value were obtained. Yield: 16%; m.p.: 62-64° C.; 1H-NMR (in d6 dimethyl sulfoxide): δ [ppm]=1.0 and 1.25 (2×d, 2×CH3); 3.2 (m, CH); 8.3 and 8.5 (2×d, pyr H).
Reaction SMILES: [S:1](=[O:34])(=[O:33])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([N:15]([C:17]2[CH:22]=[C:21]([NH:23][C@@H:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[N:20]=[CH:19][N:18]=2)[CH3:16])[CH2:6]1)[NH2:2].Cl>CO>[S:1](=[O:34])(=[O:33])([O:3][CH2:4][C@H:5]1[CH2:6][C@@H:7]([N:15]([C:17]2[CH:22]=[C:21]([NH:23][C@@H:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[N:20]=[CH:19][N:18]=2)[CH3:16])[C@H:8]([OH:9])[C@@H:12]1[OH:11])[NH2:2]
Reactant: CN(c1cc(N[C@H]2CCc3ccccc32)ncn1)[C@@H]1C[C@H](COS(N)(=O)=O)[C@H]2OC(C)(C)O[C@H]21
Agent: Cl
Solvent: CO
Product: CN(c1cc(N[C@H]2CCc3ccccc32)ncn1)[C@@H]1C[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]1O
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of {(3aR,4R,6R,6aS)-6-[{6-[(1S)-2,3-dihydro-1H-inden-1-yl-amino]pyrimidin-4-yl}(methyl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methyl sulfamate (12.0 mg, 0.02 mmol) in methanol (3.00 mL) was added 1.00 M hydrochloric acid (0.10 mL), and the mixture was stirred for 8 h. After quenching by addition of saturated NaHCO3 solution, the resulting mixture was evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 5 to 10% methanol in DCM to afford the title compound (7.80 mg, 71%). 1H NMR (400 MHz, CD3OD) δ: 8.01 (s, 1H), 7.27-7.13 (m, 4H), 5.67 (s, 1H), 5.42-5.34 (m, 1H), 4.88-4.75 (m, 1H), 4.17 (d, 2H, J=5.6 Hz), 4.04 (dd, 1H, J=8.8, 6.1 Hz), 3.88 (dd, 1H, J=5.8, 4.1 Hz), 3.05-2.96 (m, 1H), 2.89 (s, 3H), 2.93-2.83 (m, 1H), 2.62-2.52 (m, 1H), 2.34-2.24 (m, 2.01 (dt, 1M, d=13.0, 8.3 Hz), 1.94-1.83 (m, 1H), 1.44 (ddd, 1H, J=13.0, 10.8, 9.1). LC/MS: Rt=5.79 min, ES+ 450.2 (AA Waters).
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.O>[C:10]1([C:9](=[N:2][CH:3]2[CH2:7][CH2:6][O:5][C:4]2=[O:8])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC1CCOC1=O
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Br
Solvent: O
Solvent: ClCCl
Product: O=C1OCCC1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-aminodihydrofuran-2(3H)-one hydrobromide (5 g, 27.5 mmol) in DCM (50 mL) was added benzophenone imine (5 g, 27.5 mmol) and the reaction mixture was stirred at RT for 3 days. The reaction mixture was diluted with water and DCM, the organic layer was extracted, washed with aquous sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo to give 3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one as a thick colorless gel which crystallized to a white solid.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:12](=O)[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1>CO>[O:17]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:12]=[N:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=Cc1ccco1
Reactant: NNC(=O)c1ccccc1O
Solvent: CO
Product: O=C(NN=Cc1ccco1)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 76.1 g (0.5 mol) of salicylohydrazide and 1 liter of methanol, and 57.6 g (0.6 mol) of furfural was dropwise added thereto in 30 minutes while stirring at room temperature. After heating under reflux for 2 hours, the reaction liquid was cooled down to 20° C. or lower, and crystal was filtered off. The crystal was washed with a small amount of methanol and then dried under reduced pressure, whereby the intended compound (slightly yellow crystal) was obtained. The amount yielded in this reaction was 108.1 g (0.47 mol), and the yield was 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH2:8][C:7](=O)[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[C:7]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:6][CH2:5]2
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(Cl)c(Cl)cc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: Clc1cc2c(cc1Cl)CCC(N1CCCC1)=C2

Procedure:
9.00 g (0.042 mol) of 6,7-dichloro-3,4-dihydro-2(1H)-naphthalenone and 0.3 g of p-toluenesulfonic acid are dissolved in 200 ml of pyridine, 3.5 ml (0.042 mol) of pyrrolidine are added dropwise and the mixture is boiled under reflux for 2 hours. Distillation of the solvent in a vacuum, addition of 200 ml of ether and filtering off the crystals formed yields 1-(6,7-dichloro-3,4-dihydro-2naphthyl)pyrrolidine with melting point 141°-142°.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:21]=[C:22](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:28](=[O:29])/[CH:27]=[CH:26]/[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:31])([F:32])[F:17])[CH:21]=2)=[N:12]1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2cccc(OC(F)(F)F)c2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]=1[O:10]C)([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[CH:1]([C:4]1[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]=1[OH:10])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cc(C(C)C)c(OC)c(C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a solution of methyl 3,5-diisopropyl-4-methoxyphenylacetate (100 mg) in dichloromethane (12 mL) at −78° C. was added a solution of boron tribromide (0.57 mL) in dichloromethane. The reaction mixture was stirred at −78° C. for 1 hour and at 0° C. for 1 hour, quenched by water, and extracted with dichloromethane. The combined organics were washed (brine), dried (MgSO4), filtered, and concentrated. Purification by preparative thin layer chromatography, with ethyl acetate:hexane:acetic acid (90:9:1) gave the title compound (24 mg); 1H-NMR (CDCl3) δ=1.25 (d, 12H, CH(CH3)2), 3.15 (m, 2H, CH(CH3)2), 3.55 (S, 2H, CH2), 3.70 (S, 3H, OCH3), 6.98 (S, 2H, ArH)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1.C([Li])CCC.CCCCCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[C:9]=1[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1
Reactant: COCCc1cnn(C)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 4-(2-methoxyethyl)-1-methyl-1H-pyrazole (0.400 g, 2.85 mmol) in tetrahydrofuran (10 mL) at 0° C. was added 1.6 M n-butyllithium in hexane (6.24 mL, 9.99 mmol). The solution was stirred at room temperature for 1 h and then cooled down to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.70 mL, 3.4 mmol). The reaction was continued at −78° C. for 0.5 h, then warmed up to 0° C. (taking 0.5 h). The reaction mixture was quenched with brine, adjusted to pH=6-7 with 1 N HCl aqueous solution, and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give a brown oil which was further purified to provide 0.33 g (43% yield) of the desired product. LC-MS found: 267.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:26][C:10]3=[CH:11][C:12]4[C:13]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28]>>[CH2:24]([C:13]1([CH2:22][CH3:23])[C:12]2[CH:11]=[C:10]3[NH:26][C:7]([C:3]4[C:2]([NH:1][C:30](=[O:31])[N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[N:15]([CH:18]([CH3:20])[CH3:19])[C:14]1=[O:21])[CH3:25]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(CC)(CC)C(=O)N3C(C)C

Procedure:
3-[3-(7,7-Diethyl-5-isopropyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea was prepared using 2-(4-amino-1H-pyrazol-3-yl)-7,7-diethyl-5-isopropyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.43 mmol) and diethylcarbamoyl chloride (58 mg, 0.43 mmol). 12 mg (6%) %) of the title compound were obtained.