Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:11][C:12]1(C(O)=O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C([N:30]([CH2:33]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:42])C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:11][C:12]1([N:30]=[C:33]=[O:42])[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cnn(C(C)(C)C)c2Br)(C(=O)O)CC1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Cc2cnn(C(C)(C)C)c2Br)(N=C=O)CC1
Temperature: 120 °C
Yield: 94.4 %

Procedure:
To a solution of 4-((5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (241 mg, 0.54 mmol) in toluene (10 mL) was added triethylamine (91 μL, 0.65 mmol) and diphenylphosphoryl azide (0.14 mL, 0.65 mmol). The mixture was heated at 120° C. for 3 hours, the reaction was cooled and the volatiles were removed under reduced pressure. The resultant oil was purified by flash chromatography (25 g silica, 7-60% ethyl acetate/heptane gradient) to yield 225 mg of tert-butyl 4-((5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)-4-isocyanatopiperidine-1-carboxylate as a clear oil. +APCI (M+H) 385.1; 1H NMR (400 MHz, CDCl3, δ): 7.40 (s, 1H), 4.03 (br. s., 2H), 2.97 (br. t, J=12.3, 12.3 Hz, 2H), 2.70 (s, 2H), 1.74 (s, 9H), 1.67 (m, 2H), 1.62 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]1(=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6]1>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]1[C:5](=[O:6])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCO
Yield: 110.6 %

Procedure:
A solution of 2-aminoethanol (41 g, 0.67 mol) and isobenzofuran-1,3-dione (100 g, 0.52 mol) in toluene (300 mL) was refluxed for 12 hours. Volatiles were distilled out to give a residue, which was purified by re-crystallization from chloroform/hexane (v/v, 1:6) to afford 126 as a white solid (110 g, 85%). (ES, m/z) [M+H]+ 192.0; 1H NMR (300 MHz, CDCl3) δ 7.84-7.90 (m, 2H), 7.71-7.77 (m, 2H), 3.87-3.93 (m, 4H), 2.10 (br, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:41])([F:40])[C:8]1[CH:9]=[C:10]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][C@H:14]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:12].C(N(CC)CC)C>ClCCl>[F:41][C:7]([F:6])([F:40])[C:8]1[CH:9]=[C:10]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][C@H:14]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of methanesulfonyl chloride (1.1 g) in dichloromethane (4 ml) was added to a stirred solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl)piperazine (4.99 g) and triethylamine (1.1 g) in dichloromethane (50 ml) at ice-bath temperature over a 20-minute period. After being stirred at the same temperature for 1 hour, the reaction mixture was diluted with dichloromethane (50 ml) and then washed with water and aqueous sodium bicarbonate solution. The dichloromethane layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane-methanol (30:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (4.31 g) as a powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=1)=[O:14])[CH2:8][CH2:7]2)([O-])=O.CO.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=1)=[O:14])[CH2:8][CH2:7]2
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCN2C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
Under a hydrogen atmosphere 30 mg (0.06 mmol) 1-{1-[6-(5-nitro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 10 mg palladium on charcoal (10%) were hydrogenated in a 1:1 mixture methanol:THF (5 mL each) at RT and 3 bar hydrogen pressure. Then the catalyst was removed by suction filtering and the filtrate was evaporated down i. vac. The residue was dissolved in 1 mL DMF, filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:25][N:9]1[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7](=[O:21])[C:8]1=2
Reactant: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2c(=O)c3cc(Cl)ccc3oc2c1=O
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of ethyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate (0.5 g, 0.0016 mole), methyl iodide (0.5 g, 0.0035 mole) and potassium carbonate (0.23 g, 0.0017 mole) in dimethyl formamide (25 ml) was stirred at 100° for 3 hrs. under nitrogen. The reaction mixture was cooled. The product, which precipitated, was filtered, washed with water and dried. Recrystallization from DMF gave white crystals (0.47 g, 90%), m.p. 295°-297°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][OH:21])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:22][CH3:23])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(NC(C)C)(C)C.[Cl:68][C:69]1[CH:70]=[C:71]([CH:75]=[CH:76][CH:77]=1)[C:72](O)=[O:73]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:68][C:69]1[CH:70]=[C:71]([CH:75]=[CH:76][CH:77]=1)[C:72]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][OH:21])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:22][CH3:23])=[CH:4][CH:3]=1)=[O:73]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCn1cnc2c(Nc3ccc(N)cc3)nc(NCCO)nc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CCn1cnc2c(Nc3ccc(NC(=O)c4cccc(Cl)c4)cc3)nc(NCCO)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
62 mg (0.2 mmol) of 6-(4-amino-phenyl-amino)-9-ethyl-2-(2-hydroxy-ethyl-amino)-9H-purine (prepared according to Example 108), 0.18 g (0.4 mmol) of (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 54 mg (0.4 mmol) of 1-hydroxybenzotriazole (HOBT) and 68 μl of diisopropylamine are stirred in 6 ml of dimethylacetamide at RT for 5 min and then treated with 63 mg (0.4 mmol) of 3-chlorobenzoic acid. After the reaction mixture has been stirred at RT for 30 min, it is diluted with ethyl acetate and washed with water. The crude product is purified by chromatography over silica gel (mobile phase: methylene chloride:methanol=9:1). 6-(4-[3-Chloro-benzoyl-amino]-phenyl-amino)-9-ethyl-2-(2-hydroxy-ethyl-amino)-9H-purine is obtained; FAB-MS: (M+H)+=452; Rf=0.45 (methylene chloride:methanol=9:1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([CH2:33][N:34]([CH3:40])[CH:35]2[CH2:39][CH2:38][O:37][CH2:36]2)[CH2:30]1.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:28]([C:20]1[N:19]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:29]4[CH2:32][CH:31]([CH2:33][N:34]([CH3:40])[CH:35]5[CH2:39][CH2:38][O:37][CH2:36]5)[CH2:30]4)[N:2]3[CH3:1])=[C:7]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:6]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=1)[CH3:41]
Reactant: CN(CC1CNC1)C1CCOC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(CN(C)C4CCOC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.3 %

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (78 mg, 0.2 mmol), (azetidin-3-ylmethyl)methyl(tetrahydrofuran-3-yl)amine (51 mg, 0.3 mmol) and 4 Å molecular sieves (250 mg) in 1,2-dichloroethane (2 mL) was stirred at RT under nitrogen atmosphere for 6 h. Sodium triacetoxyborohydride (85 mg, 0.4 mmol) was added and the resulting reaction mixture was stirred at RT for 36 h. The solvent was reduced in vacuo and the residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PCC, MeOH:DCM: gradient 0:100 to 10:90) to afford 419 as a white foam (80 mg, 73%). LCMS (Method I): RT 2.05 min, [M+H]+ 546. 1H NMR (400 MHz, CDCl3): δ 7.99-7.95 (1 H, m), 7.73-7.70 (1 H, m), 7.23 (2 H, m), 4.32 (4 H, s), 3.92 (1 H, m), 3.82-3.80 (7 H, m), 3.72 (1 H, q, J=8.06 Hz), 3.61 (1 H, m), 3.51 (2 H, t, J=7.19 Hz), 3.31 (2 H, q, J=7.48 Hz), 3.08 (1 H, m), 2.95 (2 H, t, J=6.81 Hz), 2.76-2.44 (2 H, m), 2.14 (3 H, s), 2.03-1.93 (1 H, m), 1.85-1.75 (1 H, m), 1.63 (4 H, br s), 1.41 (3 H, t, J=7.48 Hz)
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26].F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:18][N:17]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added isopropylamine (18 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (0.096 g, 0.30 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4), filtered and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (51 mg, 65%) as a colorless oil. MS: m/e=369.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:22][O:23][C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:27]=1)=[O:25]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12
Temperature: 100 °C
Reaction time: 20 h
Yield: 86.4 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate and 0.695 g (3 mmol) of 4-chloro-7-(trifluoromethyl)quinoline are added to 0.525 g (3 mmol) of 3-methoxycarbonyl-1H-indole in 10 cm3 of dimethylformamide under an argon atmosphere. After stirring at a temperature in the region of 100° C. for 20 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and 100 cm3 of water. The organic phase is separated off by settling and washed with twice 100 cm3 of water and 100 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in an orange-coloured oil. This oil is triturated in 20 cm3 of isopropyl ether and the resulting precipitate is filtered off, giving 0.96 g of 3-methoxycarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a yellow powder. Mass spectrum (EI): m/e 370 (M+•), m/e 339.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([O:25]CC)=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].CO.ClC(Cl)C>C(O)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(Cl)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CO
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1Cl
Reaction time: 8 h
Yield: 40.8 %

Procedure:
Ethyl 1-(3-amino-4-chloro-6-fluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.00 g) was dissolved in 10 ml of acetic acid, 10 ml of methanol and 20 ml of dichloroethane, to which was added a suspension of 132 mg of 10% palladium on carbon in 20 ml of acetic acid. Under a hydrogen atmosphere, the solution was stirred overnight. The palladium on carbon was removed by a membrane filter and 10% sodium hydroxide was added to the filtrate, which was extracted with chloroform. The organic layer was dried, and the solvent was distilled off. The solid was collected by filtration, to give 0.380 g of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1.C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]1([C:9]2[C:10]3[C:2]([B:28]4[O:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[O:27]4)=[CH:3][N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(N3CCOCC3)ncnc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)OC1(C)C
Temperature: 95 °C

Procedure:
To a solution of 5-iodo-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (P1) (500 mg, 1.09 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (543 mg, 4.24 mmol) in 1,4-dioxane (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (99.7 mg, 0.109 mmol), triethylamine (439 mg, 4.34 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 51.8 mg, 0.109 mmol), and the reaction mixture was heated at 95° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 415 mg, 0.901 mmol, 83%. LCMS m/z 461.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.73 (s, 1H), 5.59 (s, 2H), 3.87-3.93 (m, 4H), 3.68-3.74 (m, 4H), 3.49-3.56 (m, 2H), 1.35 (s, 12H), 0.87-0.93 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][C:12]1[N:13]=[CH:14][C:15]([C:18](O)=O)=[N:16][CH:17]=1.N>>[CH3:11][C:12]1[N:13]=[CH:14][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[N:16][CH:17]=1
Reactant: NC(=NO)c1cccnc1
Reactant: Cc1cnc(C(=O)O)cn1
Agent: N
Product: Cc1cnc(-c2nc(-c3cccnc3)no2)cn1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 5-methylpyrazine-2-carboxylic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 2.71 (s, 3H), 7.66 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 8.59 (dt, J=7.9, 1.8 Hz, 1H), 8.74-8.78 (m, 2H), 9.33 (dd, J=2.0, 0.8 Hz, 1H), 9.40 (d, J=1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z 240 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[S:30][C:29]([CH3:31])=[N:28][CH:27]=1)=[O:23])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[S:30][C:29]([CH3:31])=[N:28][CH:27]=1)=[O:23]
Reactant: [H][H]
Reactant: Cc1ncc(CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ncc(CNC(=O)c2nc3n(c(=O)c2O)CCOC3(C)C)s1
Yield: 92.1 %

Procedure:
A solution of 3-(benzyloxy)-9,9-dimethyl-N-((2-methylthiazol-5-yl)methyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.210 g, 0.477 mmol) in a mixture of ethyl acetate (200 ml) and ethanol (50 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (0.25 g) and under one atmosphere of hydrogen for two hours to give 0.154 g (92% yield) of the title compound as white crystals; mp 245° C. (ethanol). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.60 (6H, s, 2×CH3), 2.71 (3H, s, CH3), 4.04 (4H, s, 2×CH2), 4.76 (2H, d, J=6.1 Hz, NCH2), 7.57 (1H, s, CH), 7.82 (1H, broad t, NH), 11.83 (1H, s, OH). Anal. Calcd for C15H18N4O4S: C 51.41; H, 5.17; N, 15.99; Found: C, 51.47; H, 5.29; N, 15.76.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](NC2N=CN=C(NC(C3CC3)=O)C=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29](F)C=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.[H-].[Na+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][CH:39]=1.[CH3:46]N(C)C=O>>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][O:45][C:6]2[C:5](=[O:21])[N:4]3[C:22]4([CH2:27][CH2:32][CH2:31][CH2:30][CH2:29]4)[NH:23][C:24](=[O:25])[C:3]3=[C:2]([CH3:46])[CH:7]=2)=[CH:40][CH:39]=1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: CN(C)C=O
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(COc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Temperature: 0 °C

Procedure:
To a solution of 6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 2.5 g, 8.03 mmol) in dimethylformamide (20 mL), sodium hydride (1.15 g, 48.23 mmol) was added portion wise. The reaction mixture was stirred at 0° C. for 30 m. To the reaction mixture was added (4-methoxyphenyl)methanol (3.34 g, 24.11 mmol) and the reaction was stirred at 80° C. for 16 h. After completion, solvent was evaporated under reduced pressure. Obtained crude was washed with water (50 mL) followed by diethyl ether and dried under reduced pressure to afford 6′-((4-methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3) as yellow solid. Yield: 1.4 g, 48%; MS (ESI) m/z 369.15 [M+1]+.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[CH2:9]1[CH2:19][CH2:18]N2[C:12](=NCCC2)[CH2:11][CH2:10]1.[CH2:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:27][Si:28]([CH3:35])([OH:34])[O:29][Si:30]([CH3:33])([CH3:32])O>C1(C)C=CC=CC=1>[CH2:20]([O:26][Si:30]([CH3:33])([CH3:32])[O:29][Si:28]([O:34][CH2:18][CH2:19][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:35])[CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCO
Reactant: C[Si](C)(O)O[Si](C)(C)O
Reactant: C1CCC2=NCCCN2CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCCCO[Si](C)(C)O[Si](C)(C)OCCCCCC
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A 100-ml four-necked flask equipped with a Dimroth condenser, stirrer and thermometer was thoroughly purged with nitrogen and then charged with 60 ml of toluene, 0.075 g (5.0×10−4 mol) of trifluoromethanesulfonic acid, 0.076 g (5.0×10−4 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene, and 5.1 g (5.0×10−2 mol) of 1-hexanol, which were stirred. Further, 4.15 g (2.5×10−2 mol) of 1,1,3,3-tetramethyldisiloxane-1,3-diol was admitted into the reactor, which was evacuated to a reduced pressure of 4.7 kPa and heated at 35° C. The reactor was kept at the temperature for two hours and resumed atmospheric pressure. Composition analysis by gas chromatography revealed that 1,1,3,3-tetramethyldisiloxane-1,3-diol had completely reacted, and 1,3-dihexyloxy-1,1,3,3-tetramethyldisiloxane was produced at a selectivity of 79.1%. By-products included 1,5-dihexyloxy-1,1,3,3,5,5-hexamethyltrisiloxane and 1,7-dihexyloxy-1,1,3,3,5,5,7,7-octamethyltetrasiloxane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([CH2:41][NH2:42])[CH2:40][CH2:39]1>>[CH:38]1([CH2:41][NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NCC1CC1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclopropylmethylamine according to conditions described in general procedure C. Mp: 117-119° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.10-0.30 (m, 4 H), 0.90 (bs, 1 H), 1.58-1.60 (m, 6H), 3.00 (bs, 2 H), 3.27-3.28 (m, 4 H), 6.29 (bs, 1 H), 6.96 (d, 1 H), 7.15 (d, 1 H), 7.20 (s, 1 H), 7.38 (d, J=8.0 Hz, 1 H), 7.45 (s, 1 H), 7.54-7.58 (m, 3 H), 7.80 (d, 1 H), 7.96 (d, 1 H), 8.20 (s, 1H), 10.41 (s, 1H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:27][OH:28]>>[CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][CH:9]=2)=[N:27][OH:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Reactant: NO
Agent: Cl
Product: ON=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1

Procedure:
In analogy to the procedure of Example IV, the title compound is prepared from 20 g (60.3 mmol) of the compound from Example VIII and 6.3 g (90.7 mmol) of hydroxylamine hydrochloride.