Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH2:32][CH3:33])[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (67.6 mg, 0.150 mmol) in tetrahydrofuran (1.0 mL) was added sodium hydride (60% in oil, 7.2 mg, 0.18 mmol) at 0° C. After 15 min iodoethane (60.0 μL, 0.75 mmol) was added. After being stirred for 8 h at 40° C., the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium, hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-300 ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (58.2 mg, 0.122 mmol, 81%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:46])=[N:4][O:5][C:6]=1[N:7]([CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](OC(=O)C)[C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:46])=[N:4][O:5][C:6]=1[N:7]([CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(OC(C)=O)c2cc3c(cc2CCOC(C)=O)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2CCOC(C)=O)OCO3)sc2ncccc12
Yield: 99 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-{α-acetoxy-2-[2-(acetoxy)ethyl]-4,5-(methylenedioxy)benzyl}thieno[2,3-b]-pyridine-3-sulfonamide (0.1 3 g, 0.19 mmoles), CH2Cl2 (3 ml), triethylsilane (0.30 ml, 1.9 mmoles) and boron trifluoride etherate (0.12 ml, 0.95 mmoles), giving 0.12 g (96%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:10][OH:11])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[I-].[K+]>C(#N)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:11][N:10]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:9])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(=NO)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)CON=C(C)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
A mixture of 1-(4-fluorophenyl)ethanone oxime (8.00 g) and caesium carbonate (20.4 g) in acetonitrile was stirred at 20° C. for 30 minutes. Then ethyl bromoacetate (12.2 g) and potassium iodide (8.7 g) were added thereto and the mixture was stirred at 82° C. for 3 hours. Then the reaction mixture was filtered. The solvent was removed from the filtrate under reduced pressure. Purification by column chromatography gave ethyl({[1-(4-fluorophenyl)ethylidene]amino}oxy)acetate (8.7 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].Cl.[O:29]1[CH:33]2[CH2:34][NH:35][CH2:36][CH:32]2[O:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(N(C)C)=O.CN(C=O)C>[CH3:27][O:26][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:35]1[CH2:34][CH:33]3[O:29][CH2:30][O:31][CH:32]3[CH2:36]1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:25])=[CH:19]2
Reactant: C1OC2CNCC2O1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CC2OCOC2C1
Temperature: 80 °C
Yield: 55.3 %

Procedure:
A mixture of 7-(2-chloroethoxy)-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (0.15 g), tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole hydrochloride (0.10 g), potassium carbonate (0.09 g) and potassium iodide (0.1 g) in DMA (1.5 ml) was stirred and heated at 80° C. for 12 hours. The mixture was diluted in DMF (0.8 ml), filtrated and purified by preparative LCMS (Hypersil C18-13-Basic column using a solvent gradient consisting of acetonitrile and water buffered with a 5% ammonium carbonate solution (100 g/L, pH 8.9). The solvent was removed by evaporation under vacuum and the residue was triturated under diethyl ether, filtered and dried to give 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline (0.10 g) as a pale yellow solid.
Reaction SMILES: [Br:1][CH:2]([CH2:7]Br)[C:3]([O:5][CH3:6])=[O:4].C[N+]([O-])(C)C.[CH3:14][O-:15].[Na+].[Na]>CO.C(OCC)C.C(O)(=O)C>[Br:1][CH:2]([CH2:7][O:15][CH3:14])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C[O-]
Reactant: COC(=O)C(Br)CBr
Agent: C[N+](C)(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: COCC(Br)C(=O)OC

Procedure:
Methyl 2,3-dibromopropionate (21.9 g) and trimethylamine N-oxide (0.1 g) in methanol (8 ml) were cooled to −5° C. with stirring under an atmosphere of nitrogen. A solution of sodium methoxide [freshly prepared from sodium (2.25 g) and methanol (24 ml)] was added dropwise over 15 minutes to the mixture, which was maintained below 0° C. by cooling. On completion of the addition, the mixture was stirred for a further 30 minutes and acetic acid (1 ml) was added followed by diethyl ether (100 ml). The mixture was filtered to remove insoluble salts and the filtrate evaporated under reduced pressure to give an oil, which was re-dissolved in a small volume of diethyl ether and re-filtered. The filtrate was evaporated under reduced pressure to give the required product, 17.4 g, as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH3:20])=[CH:10][C:9]=1[C:23]([F:26])([F:25])[F:24].[OH-].[Na+]>ClCCl>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[N:18]=[CH:17][C:16]([N:19]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[CH:15][C:14]=2[CH3:20])=[CH:10][C:9]=1[C:23]([F:26])([F:24])[F:25]
Reactant: CCN(C)C=O
Reactant: Cc1cc(N)cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C)C=Nc1cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
In a 25 ml single-necked round-bottomed flask, ethylmethylformamide (350 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.4 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 1 hour, whereupon a pink-orange solution is obtained. To this solution, 6-(4-Chloro-3-trifluoromethyl-phenoxy)-5-methyl-pyridin-3-ylamine (0.6 g) dissolved in 1.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 1 hour. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 1:2 (v:v) gives 0.52 g of the compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:33])[N:4]([C:19]2[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:20]=2[C:21]([O:23]C)=[O:22])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].Cl.C(#N)C.O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3](=[O:33])[N:4]([C:19]2[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:20]=2[C:21]([OH:23])=[O:22])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNC(=O)c1ccc(C(=O)OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1ccc(C(=O)O)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 60 °C

Procedure:
To a room temperature solution of methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyl]benzoate (1.05 g, 2.02 mmol) in THF (10.0 mL) was added dropwise an aqueous solution of sodium hydroxide (3.0 M, 3.5 mL, 10 mmol). The reaction was then heated to 60° C. for 8.0 hours. The resulting suspension was then diluted with 500 mL of ethyl acetate and neutralized with an aqueous solution of hydrochloric acid (2.0 N, 5.0 mL, 10 mmol). The resulting biphasic solution was separated and the resulting aqueous layer was further extracted with ethyl acetate (2×200 mL). The resulting combined organic extracts were Na2SO4 dried, filtered and concentrated in vacuo to a volume of 50 mL. At this time a white solid began to form and the resulting solid suspension was allowed to sit until precipitation appeared to stop (approximately 1.0 hour). The precipitate was collected and dried in vacuo (1.0 mm Hg) to furnish the solid acid as an intermediate (806 mg, 78%). 1H NMR (400 MHz, d7-DMF) δ 13.19 (s, 1H), 8.63 (app d, J=4.5 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.00 (dd, J=8.0, 1.6 Hz, 1H), 7.71-7.67 (m, 2H), 7.34 (app dt, J=9.6, 1.6 Hz, 1H), 7.16 (app dt, J=8.7, 1.8 Hz, 1H), 6.66 (s, 1H), 5.33 (s, 2H), 3.29 (s, 3H), 1.92 (s, 3H); LC/MS C-18 column, tr=2.15 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0344 (M+H calcd for C22H18BrF2N2O5 requires 507.0362).
Reaction SMILES: [C:1](=[O:38])([O:3][C:4]([CH3:37])([CH3:36])[CH2:5][C@@H:6]([CH2:17][C:18]([N:21]1[CH2:25][CH2:24][C@H:23]2[CH2:26][N:27]([C:29]([C:31]3([C:34]#[N:35])[CH2:33][CH2:32]3)=[O:30])[CH2:28][C@@H:22]12)=[C:19]=[O:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[NH2:2].OO.C(=O)([O-])[O-:42].[K+].[K+].O>CS(C)=O>[C:1](=[O:38])([O:3][C:4]([CH3:36])([CH3:37])[CH2:5][C@@H:6]([CH2:17][C:18]([N:21]1[CH2:25][CH2:24][C@H:23]2[CH2:26][N:27]([C:29]([C:31]3([C:34]([NH2:35])=[O:42])[CH2:32][CH2:33]3)=[O:30])[CH2:28][C@@H:22]12)=[C:19]=[O:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C[C@@H](CC(=C=O)N1CC[C@H]2CN(C(=O)C3(C#N)CC3)C[C@H]21)Cc1cc(F)c(F)cc1F)OC(N)=O
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C[C@@H](CC(=C=O)N1CC[C@H]2CN(C(=O)C3(C(N)=O)CC3)C[C@H]21)Cc1cc(F)c(F)cc1F)OC(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
(R)-4-((3aS,6aS)-5-(1-cyanocyclopropylcarbonyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-carbonyl-1-(2,4,5-trifluorophenyl)butan-2-yltertbutyl carbamate 17a (300 mg, 0.58 mmol) was dissolved in DMSO (5 mL), added 30% of hydrogen peroxide (0.5 mL) and potassium carbonate (160 mg, 1.16 mmol) at 0° C., the temperature of reaction solution was raised to room temperature and stirred for 5 minutes, added water (20 mL), extracted by dichloromethane, dried by anhydrous sodium sulfate, concentrated, residues was purified by column chromatography to give (R)-4-((3aS,6aS)-5-(1-aminocarbonylcyclopropylcarbonyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-carbonyl-1-(2,4,5-trifluorophenyl)butan-2-yltertbutyl carbamate 28a (265 mg, 85%) as white foamy solid. MS m/z (ESI): 539.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[O:12])[S:4][N:3]=1.[H][H]>CO.[Pd]>[NH2:7][C:6]1[C:2]([CH3:1])=[N:3][S:4][C:5]=1[NH:10][C:11]([C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)c1ccccc1C(=O)Nc1snc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1C(=O)Nc1snc(C)c1N

Procedure:
Methyl 2-((3-methyl-4-nitroisothiazol-5-yl)carbamoyl)benzoate was suspended in MeOH (30 mL), Pd/C 10% (477.1 mg, 4.483 mmol) was added and the mixture was hydrogenated at RT under 1 atm of hydrogen (balloon pressure) for 2 h. The catalyst was filtered off and the mixture was concentrated in vacuo, yielding methyl 2-((4-amino-3-methylisothiazol-5-yl)carbamoyl)benzoate. (150 mg, 100%). MS (ES+) 292.1.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][OH:14])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N:20]1[CH:21]=[CH:22][C:17]([O:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:18][CH:19]=1
Reactant: OCc1ccccc1N1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(N2CCNCC2)c(COc2ccncc2)c1
Temperature: 120 °C

Procedure:
(2-piperazin-1-yl-phenyl)-methanol (200 mg, 1.04 mmol) was added to a suspension of 4-chloropyridine hydrochloride (225 mg, 1.50 mmol), tris[2-(2-methoxy)ethyl]amine (32 μL, 0.10 mmol), powdered potassium hydroxide (225 mg, 4.01 mmol) and potassium carbonate (275 mg, 1.99 mmol) in 10 mL of toluene. The reaction mixture was heated to 120° C. overnight. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC. The material was still less than 50% pure, but was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]([CH2:7][C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])(O)C(O)=O.Cl.Cl[O-].[Na+]>C(O)(=O)C>[O:1]=[CH:2][CH2:7][C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9]
Reactant: O=C(O)C(O)(O)C[C@H](O)[C@H](O)CO
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: O=CC[C@H](O)[C@H](O)CO
Reaction time: 1 h

Procedure:
The pH of the resulting reaction mixture containing the 2-hydroxy-3-deoxy-D-gluconic acid was adjusted to 5.0 with 35% hydrochloric acid solution. Into the reaction mixture was dripped 377 g of 13% sodium hypochlorite solution to perform decarboxylation over a period of 1 hour with the reaction temperature adjusted to 35° C. The pH of the reaction mixture at this time was adjusted between 5 and 6 with acetic acid. After adding the sodium hypochlorite solution, the reaction was carried out for 1 hour to yield 69 g of 2-deoxy-D-ribose. The yield from sodium D-gluconate was 86.3%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>[Pd]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc(CN2CCOCC2)cc1N
Temperature: 2.5 °C
Yield: 90 %

Procedure:
A mixture of 4-(3,4-dinitro-benzyl)-morpholine (1 mol. eq.) and 5% Pd/C (0.05 wt. eq.) in IMS (33 vol.) was stirred at 0-5° C. while the vessel was charged with hydrogen. The mixture was carefully warmed to 15-20° C. with stirring until the reaction was complete (<24 hours). The mixture was filtered and the filtrate evaporated to dryness to give 4-morpholin-4-ylmethyl-benzene-1,2-diamine (90%). The material was used immediately in the next step. (LC/MS (basic method): Rt 1.64, [M−N(CH2CH2)2O−]+ 121).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(C)cc1Cl
Product: Cc1ccc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(=O)(=O)NC(C)(C)C)cnn23)c(Cl)c1
Yield: 57.9 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-4-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (11.17 g, 24.0 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (5.93 g, 33.09 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (8.33 g, 63%) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:30]=[C:29]([O:37][CH3:38])[N:28]=3)[CH2:12]1)[C:8](=[O:39])[NH:7]2)=[O:5])C.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:33]([C:31]1[N:30]=[C:29]([O:37][CH3:38])[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:39])[CH2:23]4)[CH2:12]2)[CH:32]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(C(C)(C)C)nc(OC)n3)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Temperature: 60 °C
Yield: 96.4 %

Procedure:
Compound 3i (350 mg, 0.645 mmol) was dissolved in a 2:1:1 mixture of THF:MeOH:H2O (100 ml). LiOH (1 M, 6.5 ml) was added and the reaction mixture was stirred at 60° C. over night. The mixture was acidified by adding citric acid and then extracted three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and evaporated. The afforded residue was purified by column chromatography (DCM/MeOH 98/2→94/6) which gave the title compound (320 mg, 97%), MS (M+H)+515.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11](=[O:13])[CH3:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:51][Mg]Br>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:7]([C:11]([CH3:51])([CH3:12])[OH:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Br
Reactant: CCCCc1nc(Cl)c(C(C)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(C(C)(C)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 0.444 g of the product of Example 4 in 10 ml of tetrahydrofuran, cooled to 0° C. is slowly added 0.656 ml of 3.0 M methylmagnesium bromide. The cooling bath is removed after 0.5 hour and reaction mixture allowed to warm to room temperature and stir for 2 hours. An additional 1.2 ml of 3.0 M methyl magnesium bromide is added and the reaction mixture stirred at room temperature for 0.5 hour. An additional 1.0 ml of 3.0 M methyl magnesium bromide is added an the reaction mixture stirred at room temperature for 0.5 hour. The reaction mixture is quenched with saturated ammonium chloride and diluted with water, followed by extraction with ethyl acetate. The organic layer is dried with MgSO4, filtered and concentrated to give a crude solid which is purified by column chromatography on silica gel with 1:2 ethyl acetate-hexane to give 0.706 g of the desired product as a solid. FAB MASS SPEC 693(M+ H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(Cl)Cl.CCCCCC.CCOCC.CCCCCC>C(OCCO)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: S=C1Nc2cc(Br)ccc2Nc2ccccc21
Reactant: NCc1cccnc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOCCO
Product: Brc1ccc2c(c1)N=C(NCc1cccnc1)c1ccccc1N2
Yield: 60.8 %

Procedure:
A solution of 0.4 g (1.3 mmol) of 8-bromo-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Sahni, S., et al., J. Indian Chem. Soc., 56:625 (1979)) in 10 mL of 2-ethoxyethanol was treated with 0.28 mL (2.1 mmol) of 3-(aminomethyl)-pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Trituration with CH2Cl2 /hexane, then with Et2O/hexane left 0.3 g (61% yield) of the product as a yellow solid, mp 152-155° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =379.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Br)C=C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH2:10][CH:9]=[CH2:8])[CH2:11][CH:6]=[CH2:7])[CH:7]=1
Reactant: COC(=O)COc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C=CCBr
Product: C=CCN(CC=C)c1cccc(OCC(=O)OC)c1
Temperature: 45 °C
Reaction time: 4.5 h

Procedure:
22 g of 3-aminophenoxyacetic acid methylester are solved in 63 g allyl bromide. Subsequently, 10 g of sodium carbonate are added portionwise and the temperature is raised to 45° C. The reaction mixture is stirred at this temperature for 4.5 hours. The insoluble salt is filtered off and washed with 70 g of ethyl acetate. The combined filtrates are kept at 5° C. for 12 h. After the extraction with water, the organic phase is dried with sodium sulfate and the solvent is removed in vacuum (60° C., 28 mbar). Yield: 24 g (dark oil).