Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]O)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(#N)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:31][C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: OCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: COCCc1nc2c(N)nc3cc(OCc4cccnc4)ccc3c2n1CC(C)(C)O
Reaction time: 0.75 h
Yield: 41 %

Procedure:
4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol, (2.5 g, 7.5 mmol) was slurried in 75 mL of THF to which 3-pyridylcarbinol (350 mg, 3.18 mmol) and triphenylphosphine (1.59 g, 6.06 mmol) were added. To this was added 1.2 g (5.93 mmol) of diisopropyl azodicarboxylate (DIAD) and the reaction mixture was stirred for 45 minutes. Approximately 3 additional equivalents of each reagent were added to complete the reaction. The reaction mixture was then concentrated and partitioned between chloroform and aqueous sodium carbonate. The organic fraction was dried and passed through an ion exchange resin with methanol, followed by 1M ammonia in methanol as the eluents. The solvent was concentrated and the residue was purified by flash column chromatography on silica gel using a gradient of 0-40% CMA in chloroform. The desired fractions were concentrated to produce an oil which was taken up in 20 mL of refluxing acetonitrile. Upon cooling, white crystals formed which were filtered and dried to provide 0.55 g of 1-[4-amino-2-(2-methoxyethyl)-7-(pyridin-3-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, mp 200.0-202.0° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:2].[OH:19]O.[OH-].[Na+].CO>O>[NH2:2][C:1](=[O:19])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCC#N)CC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCC(N)=O)CC1
Yield: 7 %

Procedure:
A stirred mixture of 5.0 g (0.02 mole) of 1-(3-cyanopropyl)-4-(1,1-dimethylethoxycarbonyl)piperazine, 10 ml of 30% hydrogen peroxide solution and 10 ml of 20% NaOH solution warmed spontaneously to 42°. After the initial exothermic reaction had subsided and the temperature returned to room temperature, 50 ml of methanol was added dropwise; a temperature rise to 38° was noted. After heating two hours at 50° the mixture was diluted with 50 ml of water and extracted with CH2Cl2. The organic extracts were dried (Mg SO4), filtered and evaporated on a rotary evaporator. The crude product was recrystallized from ethyl acetatehexane to yield 0.4 g (7%) of 1-(4-amino-4-oxobutyl)-4-(1,1-dimethylethoxycarbonyl)piperazine, 1/4 hydrate, mp-67.5°-71.5°. Calc. for C13H15N3O3. 1/4 H2O (275.87): C, 56.60; H, 9.32; N, 15.23. Found: C, 56.58; H, 9.41; N, 15.23.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][OH:26])[S:18][C:17]=1[C:28]([NH2:30])=[O:29].O[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][O:26][C:32]2[CH:40]=[CH:39][C:35]([C:36](=[O:37])[NH2:38])=[CH:34][CH:33]=2)[S:18][C:17]=1[C:28]([NH2:30])=[O:29]
Reactant: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Reactant: NC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(C(N)=O)cc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (23 mg, 0.116 mmol) was added to a solution of 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (see Example 12) (25 mg, 0.105 mmol), 4-hydroxy-benzamide (15 mg, 0.116 mmol), and Ph3P (30 mg, 0.116 mmol) in THF (2.5 mL) at 0° C. The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was concentrated and triturated with 2:1 EtOAc:MeOH giving the title compound (7 mg, 19%) as an orange solid, m.p.>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=CC=CC=1.Cl.Cl[CH2:18][CH2:19][NH:20]CCCl.[OH-].[Na+]>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[CH2:10][CH2:15][NH:20][CH2:19][CH2:18]1
Reactant: ClCCNCCCl
Reactant: Clc1cccc(Cl)c1Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(Cl)c1N1CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 2,6-dichlorophenylaniline (810 mg, 5 mmol, Aldrich) and bis(2-chloroethyl)amine hydrochloride (823 mg, 5 mmol, Aldrich) was subjected to microwave irradiation at 200° C. for 10 min. The reaction mixture was allowed to cool to room temperature then treated with 5N NaOH (5 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2+1% ammonia (30% in water) to give the title compound. MS (ESI, pos. ion) m/z: 231 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl.[Ni].C(O)C>[N:10]1[CH:11]=[CH:12][C:7]([C@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[OH:21])=[CH:8][N:9]=1
Reactant: C1=C(c2ccnnc2)CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ni]
Solvent: CCO
Solvent: ClCCl
Product: O[C@H]1CCCC[C@@H]1c1ccnnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
To a solution of the 4-(cyclohex-1-en-1-yl)pyridazine (0.15 g, 0.94 mmol) prepared in Example 53a in dichloromethane (9.4 mL), 3-chloroperbenzoic acid (0.76 g, 3.09 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 4 hours. A highly polar compound was removed with a silica gel pad (dichloromethane) to yield crude epoxide. A solution of the crude epoxide and Raney nickel in ethanol (3.0 mL) was stirred at 70° C. for 3 hours under a hydrogen atmosphere. The reaction solution was filtered, and the residue was then purified with silica gel chromatography to yield the title compound (35 mg, 31%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][C:18]([NH2:25])=[N:19][C:20]=3Cl)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CN(C)C.N1C(=[O:40])C2NC=NC=2N=C1N>O.C1COCC1>[CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:40])[NH:19][C:18]([NH2:25])=[N:17][C:16]2=3)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CCOP(=O)(OCC)C1CCC(Cn2cnc3c(Cl)nc(N)nc32)O1
Agent: CN(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)C1CCC(Cn2cnc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To [5-(2-Amino-6-chloro-purin-9-ylmethyl)-tetrahydro-furan-2-yl]-phosphonic acid diethyl ester (100 mg, 0.25 mmol) in water (7 mL) and THF (5 mL) was added trimethylamine (1.6 mL, 6.4 mmol). The reaction mixture was stirred at RT under nitrogen overnight. Conversion to guanine was confirmed by UV spectroscopy. The THF was removed in vacuo and the reaction mixture lyophilized. The sample was chromatographed eluting with 10% methanol/dichloromethane to give [5-(2-Amino-6-oxo-1,6-dihydro-purin-9-ylmethyl)-tetrahydro-furan-2-yl]-phosphonic acid diethyl ester as a white powder (40 mg, 42%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][CH:14]([C:17]4[O:21][N:20]=[C:19]([CH:22]([CH3:24])[CH3:23])[N:18]=4)[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12.[OH:25][C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH:22]([C:19]1[N:18]=[C:17]([CH:14]2[CH2:15][CH2:16][CH:11]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([O:25][C:26]5[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=5)=[C:3]4[CH:10]=[N:9]3)[CH2:12][CH2:13]2)[O:21][N:20]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1noc(C2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Reactant: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCC(c2nc(C(C)C)no2)CC1
Yield: 38.1 %

Procedure:
1-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-4-(2-methyl-pyridin-3-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (60 mg, 76%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 23; 130 mg, 0.375 mmol) with 3-hydroxy-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 42 mg, 0.385 mmol) in the presence of potassium carbonate (114 mg, 0.825 mmol). The compound was purified by column chromatography, eluting with 5% methanol/dichloromethane. Mass spectrum MH+=420.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[C:19]1[N:23]([C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])([O-:3])=[O:2].Br[C:35]1[C:36]([CH3:45])=[N:37][C:38]([O:42][CH2:43][CH3:44])=[CH:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:43]([O:42][C:38]1[N:37]=[C:36]([CH3:45])[C:35]([C:8]2[CH:7]=[CH:6][C:5]([C:19]3[N:23]([C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[N:22]=[CH:21][C:20]=3[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=2)=[C:40]([CH3:41])[CH:39]=1)[CH3:44]
Reactant: CCOc1cc(C)c(Br)c(C)n1
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OCC)nc2C)cc1[N+](=O)[O-]

Procedure:
Ethyl 5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl][(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 7-(2) (200 mg) was dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). 3-bromo-6-ethoxy-2,4-dimethylpyridine obtained in Preparation Example 51 (121 mg), Pd(PPh3)4 (25 mg) and cesium carbonate (428 mg) were added, and the mixture was reacted using a microwave reactor at 130° C. for three hours. The reaction mixture was returned to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 100%) to give the title compound (97 mg).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1.[NH:17]([C:21]1[S:22][CH:23]=[C:24]([CH2:26][S:27][CH2:28][CH2:29][NH2:30])[N:25]=1)[C:18]([NH2:20])=[NH:19]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][C:6]2[C:7](=[O:9])[NH:8][C:3]([NH:30][CH2:29][CH2:28][S:27][CH2:26][C:24]3[N:25]=[C:21]([NH:17][C:18]([NH2:20])=[NH:19])[S:22][CH:23]=3)=[N:4][N:5]=2)[CH:12]=1
Reactant: CSc1nnc(Cc2cccnc2)c(=O)[nH]1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: N=C(N)Nc1nc(CSCCNc2nnc(Cc3cccnc3)c(=O)[nH]2)cs1
Temperature: 140 °C
Yield: 19.5 %

Procedure:
A mixture of 3-methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (0.23 g) and 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole (0.23 g) was heated at 140° C. for 2 hours and then allowed to cool to room temperature. The black solid mass was triturated with a mixture of methanol (10 ml) and dimethylformamide (2 ml) and the resulting pale brown solid was filtered off. This was purified by preparative TLC using Merck Kieselgel GF 254 2 mm preparative plates in chloroform/methanol/ammonia (s.g. 0.880) 8:2:0.3 v/v/v as eluant to give 6-(3-pyridylmethyl)-3-[2-(2-guanidinothiazol-4-ylmethylthio)-ethylamino]-1,2,4-triazin-5-one (0.08 g). The n.m.r. spectrum of the product in d6 dimethyl sulphoxide using tetramethylsilane as an internal standard (δ=0) had the following resonances: 2.7 (2H, triplet); 3.4 (2H, broad multiplet); 3.6 (2H, sharp singlet); 3.8-4.1 (8H, broad multiplet--contains H2O); 6.6 (1H, sharp singlet); 6.9 (4H, broad singlet); 7.3 (1H, multiplet); 7.7 (1H, double triplet); 8.5 (2H, multiplet).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([O-])(=O)C.[K+].Cl[CH2:11][C:12]1[C:13]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[N:14][CH:15]=[C:16]([CH:18]([Cl:20])[Cl:19])[N:17]=1.ClCCl>CS(C)=O>[C:1]([O:4][CH2:11][C:12]1[C:13]([N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])=[N:14][CH:15]=[C:16]([CH:18]([Cl:19])[Cl:20])[N:17]=1)(=[O:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CCl
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)OCc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
50 ml of absolute glacial acetic acid and 35 g of potassium acetate were added to a solution of 57.7 g (0.16 mole) of 65% strength 3-chloromethyl-5-dichloromethyl-2-phthalimidopyrazine in 1,000 ml of dimethyl sulfoxide, and the mixture was then stirred for three days at room temperature. Thereafter, 1,000 ml of dichloromethane and 1,000 ml of ice-water were added to the reaction mixture, the resulting mixture was mixed thoroughly, and phase separation was effected. The aqueous phase was extracted once with 500 ml of dichloromethane and once with 250 ml of dichloromethane. The combined organic phases were washed twice with 1,000 ml of water, dried over sodium sulfate and evaporated down in a rotary evaporator. The blackish brown oil was taken up in 20 ml of methanol at the boil, and the solution was left to crystallize at room temperature. The product was then suspended in a little diethyl ether, filtered off and dried. The crystals were then recrystallized again from methanol. 30.6 g (77% of theory) of 3-acetoxymethyl-5-dichloromethyl-2-phthalimidopyrazine of melting point 117°-118° C. were obtained. 1H-NMR (270 MHz, CDCl3): δ1.9 (s, 3H), 5.3 (s, 2H), 6.9 (s, 1H), 8.1 (m, 4H), 9.1 (s, 1H).
Reaction SMILES: [Cu]C#N.[C:4]1([Mg]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:14][C:15](=[O:37])[C:16](=[CH:22][C:23]1[CH:24]=[N:25][C:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:28]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([CH:22]([C:23]1[CH:24]=[N:25][C:26]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:27][CH:28]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:15]([O:14][CH2:12][CH3:13])=[O:37])[CH3:21]
Reactant: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: Br[Mg]c1ccccc1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.8 %

Procedure:
To a vigorously stirred suspensin of copper(I)cyanide (1.71 g, 19.06 mmol) in dry THF (18 mL) was added a solution of phenylmagnesium bromide (12.7 mL 3 M in ether, 38.11 mmol) at 0° C. under argon. The mixture was allowed to warm to room temperature, giving a dark brown solution. After 150 minutes a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (1.74 g, 4.76 mmol) in dry THF (19 mL) was added at 0° C. The mixture was left stirring for 3 days then aqueous ammonium chloride was added. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine and dried. Removal of the solvent in vacuo gave a residue, which was suspended in hexane. Filtration of the crystals gave 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-malonic acid diethyl ester (1.85 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH3:40])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH3:40])=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:30][CH:29]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.49 mmol, 0.1 g) in THF (1.5 mL) at room temperature was added NaH (50 mg) followed 4-(4-benzyloxy-phenyl)-6-chloro-3-propyl-pyridazine (0.44 mmol, 0.15 g). The mixture was stirred at 70° C. for 4 h. The reaction mixture was cooled to room temperature, quenched with methanol by drop-wise addition, and removed the volatiles under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with 20% ethyl acetate to provide 4-[5-(4-benzyloxy-phenyl)-6-propyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([OH:17])[C@H:12]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([Si:32]([CH3:35])([CH3:34])Cl)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([O:17][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:35])[CH3:34])[C@H:12]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1[C@H](O)[C@@H](F)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C[C@@H]1F
Temperature: 25 °C

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester (1.90 g, 5.09 mmol) in DMF (40 mL) were added tert-butyldimethylchlorosilane (0.844 g, 5.60 mmol), triethylamine (0.709 ml, 5.09 mmol) and DMAP (0.062 g, 0.509 mmol). The reaction mixture was stirred 25° C. for 1 week. Then quenched by addition of a saturated aqueous solution of NaHCO3. The layers were separated and the organic extract was dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1). MS (UPLC): 588.4 [M+H]+, 505.5 [M+NH4]+, 510.4 [M+Na]+; tR (HPLC conditions f): 2.90 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=[C:21]([C:23](=[O:30])[NH:24][C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:46][C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49]Br>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[CH:20]=[C:21]([C:23](=[O:30])[NH:24][C:25]2[CH:29]=[N:28][N:27]([CH2:46][C:47]3[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=3[CH3:49])[CH:26]=2)[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)Nc3cn[nH]c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1cc(NC(=O)c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c2)cn1

Procedure:
Intermediate (2d), 2-[2-oxo-5-(1H-pyrazol-4-ylcarbamoyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (50 mg, 0.091 mmol), Cs2CO3 (45 mg, 0.136 mmol) and 2-methylbenzyl bromide (21 mg, 15 ul, 0.11 mmol) were stirred in N,N-dimethylformamide (5 mL) at ambient temperature for 48 hours. The inorganics were separated via filtration and the filtrate was concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—50% ethyl acetate/hexane (gradient) to afford the desired title compound as a solid, 55 mg, 93%.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=[O:27])[CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[CH:12]1[C:28]([OH:30])=[O:29])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=[O:27])[CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[CH:12]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCOP(=O)(CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1C(=O)O)OCC
Reactant: BrCc1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CN(C)C=O
Product: CCOP(=O)(CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1C(=O)OCc1ccccc1)OCC
Temperature: 25 °C
Yield: 19 %

Procedure:
Dissolve N-carbobenzoxy-3[(diethoxyphosphinyl)acetyl]-piperidine-2-carboxylic acid (36.4 mmol) in dimethylformamide (200 mL) and place under a nitrogen atmosphere. Add benzyl bromide (10.5 mL), 81 mmol) and dicyclohexyl amine (16.2 mL, 89 mmol) and heat to 65° C. Allow to cool slowly to room temperature and filter. Pour the filtrate into water (11/2 L) and extract with ethyl acetate (2×500 mL). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to give a brown oil. Purify by flash chromatography (ethyl acetate) to give the title compound as a yellow oil (3.6 g, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH:7]=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[C:7]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Cn1ccc(=O)c2ccc(Cl)cc21
Reactant: O=S(=O)(O)Cl
Product: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(Cl)cc21
Temperature: 140 °C

Procedure:
7-Chloro-1-methyl-4-quinolone (6.9 g) and chlorosulphonic acid (14 ml) can be stirred and heated at 140° C. for 2 hours. The reaction mixture can be cooled to room temperature and carefully added dropwise to ice water (200 ml). The solid which forms can be collected, washed with water and dried in air to give the compound 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride, m.p. >300° C.