Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.[CH3:23][N:24]=[C:25]=[O:26]>C(Cl)Cl>[CH3:23][NH:24][C:25](=[O:26])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CN=C=O
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=NCc2ccccc2)CC1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (2.0 g) in CH2Cl2 (40 ml) was added 1,8-diazabicyclo[5.40]undec-7-ene (0.16 g) followed by the dropwise addition of methyl isocyanate (0.39 g) in CH2Cl2 (10 ml). The reaction was monitored via TLC and after 3 hours the solution was concentrated and the precipitate was collected and recrystallized from acetonitrile to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.85 grams).
Reaction SMILES: [N:1]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:5]([C:6]([O:8]CC2C=CC=CC=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12>CO.[OH-].[OH-].[Pd+2].[C]>[C:22]([O:21][C:19]([N:1]1[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of the product from Example 123A (0.56 g, 1.6 mmol) in MeOH (8.0 mL) was added Pd(OH)2/carbon. The mixture was evacuated and a H2 atmosphere was introduced via a balloon. The mixture was stirred overnight then filtered and the solvent was removed under reduced pressure to provide the title compound (0.42 g, 102% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1.[ClH:19].[C:20](OCC)(=O)[CH3:21]>CN(C)C=O.O1CCOCC1.ICC>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:20][CH3:21])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: COc1ccnc(-c2cccc(NC(N)=S)c2)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCI
Solvent: CN(C)C=O
Product: CCSC(=N)Nc1cccc(-c2cc(OC)ccn2)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of N-(3-(4-methoxypyridin-2-yl)phenyl)thiourea (171 mg) in N,N-dimethylformamide (4 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.33 ml) and iodoethane (0.263 ml), and the mixture was stirred at 50° C. for 1.5 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration. The precipitate was dissolved in water, and to the solution was added a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(3-(4-methoxypyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride (204 mg).
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[CH:5]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cccc(-c2cscn2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cscn2)c1

Procedure:
3-Thiazol-4-yl-benzoic acid methyl ester (0.91 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-(3-thiazol-4-yl-phenyl)-propionic acid tert-butyl ester (1.54 g) as a pale-yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+]([O-])(O)=O.[C:11]1([NH:17][C:18]([NH2:20])=[NH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:21][C:22]1[O:29]C(=O)[CH:26]([C:30]([CH3:32])=O)[C:24](=O)[CH:23]=1.Cl>CN(C)C=O>[NH:17]([C:18]1[N:20]=[C:30]([CH3:32])[CH:26]=[C:24]([CH2:23][C:22]([CH3:21])=[O:29])[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Reactant: N=C(N)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Product: CC(=O)Cc1cc(C)nc(Nc2ccccc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
Into a 500 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 200 ml of dimethylformamide, 13.8 g (0.1 mol) of potassium carbonate, 39.6 g (0.2 mol) of phenylguanidine nitrate and 33.6 g (0.2 mol) of dehydroacetic acid were charged, and the reaction was conducted at 140° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and put into ice water. Then, the reaction solution was extracted with toluene and washed with water. Then, 21 g (0.2 mol) of concentrated hydrochloric acid was dropwise added thereto. Precipitated crystals were collected by filtration, washed with toluene, then neutralized with an aqueous sodium carbonate solution and again extracted with toluene. This toluene layer was washed with water and concentrated to obtain 24.1 g of 2-anilino-4-methyl-6-acetonyl-pyrimidine having a melting point of from 77° to 80° C. The yield was 50%.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7](C)([CH3:9])[CH3:8])(C)([CH3:3])[CH3:2].C(N)(C)C.C(N(CC)CC)C.C(Cl)(=O)C(C)C>>[CH:1]([NH:5][C:6](=[O:11])[CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)N
Product: CC(C)NC(=O)C(C)C
Yield: 94 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of isopropylamine (9.0 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with isobutyryl chloride (10.8 mL, 100 mmol) afforded LiPr,iPrH as white crystalline solid (12.14 g, 94%) upon sublimation at 55° C./0.05 Torr: mp 104-106° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][N:17]=1>>[CH2:22]([C:20]1[CH:19]=[CH:18][N:17]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:21]=1)[CH3:23]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: CCc1ccnc(Br)c1
Product: CCc1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Yield: 51 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-4-ethylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 74 mg, 51%) which was obtained as a yellow oil. MS: m/e=289.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[OH:16])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc(I)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(I)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94.6 %

Procedure:
To a mixture of (2-hydroxy-5-iodo-phenyl)-phosphonic acid diethyl ester (14.7 g, 41.2 mmol) and cesium carbonate, (17.4 g, 53.5 mmol) in DMF (150 mL) was added benzyl bromide (6.40 mL, 54 mmol). The reaction was allowed to stir for 2.5 days at rt at which point the reaction was concentrated under reduced pressure, the residue diluted in 0.5 N HCl (30 mL) and extracted twice with EtOAc. The pooled organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 17.4 g (91%) of a colorless solid after recrystallization (EtOAc-hexanes). Rf 0.36 (1:1 EtOAc-hexanes). Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 447 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].[S:13]([O-:17])([O-:16])(=[O:15])=[S:14]>>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])=[CH:5][C:6]=1[S:14][S:13](=[O:16])(=[O:15])[OH:17]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: O=S([O-])([O-])=S
Product: CCN(CC)c1ccc(N)c(SS(=O)(=O)O)c1

Procedure:
In this step, an N,N-diethyl-1,4-diamino-benzene, 15, is oxidized in the presence of a thiosulfate to give a thiosulfuric acid S-(2-amino-5-diethylamino-phenyl) ester, 16, as illustrated in the following scheme:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:33]2[CH2:34][CH2:35][CH:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH2:31][CH2:32]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Yield: 78.3 %

Procedure:
A dispersion of 0.5 g (2.3 mmol) of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (J. Heterocycl. Chem. 1971, 8, 445-453) and 0.65 g (5.0 mmol) of N-ethyl-diisopropylamine in 40 ml of dioxane was treated at room temperature with 0.54 g (5.0 mmol) of 4-(4-fluorophenyl)-piperidine hydrochloride during 18 h. For the working-up, the reaction mixture was evaporated, and, thereafter, the residue obtained was directly chromatographed on silica gel using toluene as the eluent yielding 660 mg (1.8 mmol, 80% of theory) of 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=363.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.ClC(Cl)(Cl)C(Cl)(Cl)Cl>>[CH2:1]1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Product: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reaction time: 3 h

Procedure:
A 10.0 gram (75.6 mmol) amount of dicyclopentadiene was added to a 20 ml scintillation vial. A 5.0 milligram (7.2 μmol) amount of RuClH(H2)(PCy3)2 was added. One equivalent of hexachloroethane was charged per equivalent of RuClH(H2)(PCy3)2 via the addition of 0.1 mls of a 72 mM hexachloroethane solution. The ring opening polymerization of dicyclopentadiene was observed slowly by a gradual thickening of the solution to a rubbery viscous material after three hours. After 24 hours, the material was a soft rubbery material.
Reaction SMILES: [OH:1][C@H:2]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:23]1[CH:24]=[C:25]([C:29]#[N:30])[CH:26]=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:1][C@H:2]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH:24]=2)[C:29]#[N:30])=[CH:7][CH:6]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: OB(O)c1ccc(OC[C@H](O)CCc2cccnc2)cc1
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: [Na+]
Product: N#Cc1cncc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 90 °C
Yield: 55.4 %

Procedure:
Prepared according to the method described in Example 21b) from (2R)-4-(2-hydroxy-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 28a)), 5-bromopyridine-3-carbonitrile (0.19 g), 2M aqueous sodium carbonate (0.60 ml) and tetrakis(triphenylphosphine)palladium(0) (0.014 g) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.10 g).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][N:6]1[C:12]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][C:7]1=[O:20]>CO.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:20])[N:6]([CH3:5])[C:12]=2[CH:13]=1
Reactant: CN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1C(=O)CCCc2ccc(N)cc21
Temperature: 80 °C
Yield: 120.6 %

Procedure:
696 mg of ammonium formate and 581 mg of Pd/C (10%) are added to a solution of 405 mg of 1-methyl-8-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 39 ml of methanol. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel, and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure, so as to give 422 mg of 8-amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:45][CH2:44][CH2:43][N:40]3[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:36])[CH2:38][CH2:39]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc(Nc2ncnc3cc(O)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Product: COc1cc(Nc2ncnc3cc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Yield: 72.5 %

Procedure:
Using an analogous procedure to that described in Example 12, 4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.109 g) was reacted with 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (0.074 g) to give 4-(2,4-dichloro-5-methoxyanilino)-7-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.12 g).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[C:27](=[O:28])[C:16]4[CH:17]=[N:18][C:19]5[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=5[C:15]=4[N:14]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:13]3=[O:35])=[CH:11][C:6]=2[O:5][CH2:4]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[C:27](=[O:28])[C:16]4[CH:17]=[N:18][C:19]5[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=5[C:15]=4[N:14]([CH:29]4[CH2:34][CH2:33][N:32]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:31][CH2:30]4)[C:13]3=[O:35])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)OCO4)c(=O)n(C3CCNCC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)OCO4)c(=O)n(C3CCN(S(C)(=O)=O)CC3)c12

Procedure:
3-Benzo[1,3]dioxol-5-yl-1-(1-methanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (45 mg) was prepared according to general procedure H from 3-Benzo[1,3]dioxol-5-yl-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and methanesulfonyl chloride. LCMS: m/z 525 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.52 (s, 1H), 7.15 (m, 1H), 7.08 (m, 1H), 6.92 (m, 1H), 6.86 (m, 1H), 6.70-6.76 (m, 2H), 6.19 (s, 1H), 6.12 (s, 1H), 5.09 (m, 1H), 4.38 (m, 1H), 4.18 (m, 2H), 4.07 (s, 3H), 3.26 (m, 2H), 2.91 (m, 2H), 2.68 (m, 2H), 1.78 (m, 2H), 1.14 (t, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:30]C(=O)C)[CH:5]=[C:6]([F:29])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=[C:17]([CH3:18])[C:10]=12.[OH-].[Na+]>C(O)C>[F:29][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12)[NH2:30]
Reactant: CC(=O)Nc1cc(F)c(Oc2ccnc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c[nH]c2nccc(Oc3c(F)cc(N)cc3F)c12
Temperature: 90 °C

Procedure:
690 mg (1.46 mmol) of N-[3,5-difluoro-4-({3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)phenyl]acetamide are dissolved in 25 ml of ethanol. 12.5 ml of 20% strength aqueous sodium hydroxide solution are added, and the reaction mixture is heated at 90° C. for 4.5 hours. The reaction solution is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The product is reacted without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][O:17][CH2:18][CH2:19]Br>>[CH3:16][O:17][CH2:18][CH2:19][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: COCCBr
Product: COCCOc1c(C(=O)OC)ccc2ccccc12

Procedure:
By alkylating methyl 1-hydroxy-naphthalene-2-carboxylate analogously to Example 1 (g) with 2-bromoethyl methyl ether there was obtained methyl 1-(2-methoxy-ethoxy)-naphthalene-2-carboxylate, which was subsequently converted analogously to Example 5 (b)-(c) firstly into [1-(2-methoxy-ethoxy)-naphthalen-2-yl]-methanol and then into 2-chloromethyl-1-(2-methoxy-ethoxy)-naphthalene, which was finally obtained as a beige solid; MS: 250 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C1(=O)C2C(=CC=CC=2)CCC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(F)cc1
Agent: O=C1CCCc2ccccc21
Product: O=C1CCCc2ccc(F)cc21
Temperature: 100 °C
Yield: 63.2 %

Procedure:
A stirred mixture of 4-(p-fluorophenyl) butanoic acid (23g; 0.126 mole) and 85% polyphosphoric acid (200g) was heated at 100° C for 4 hrs., cooled, and poured onto ice-water (800g). After through stirring the precipitated tetralone was filtered off, washed well with water, and recrystallised from ethanol to give 13.07g (63%) of material of m.p. 56°-57° C. (Found; C, 73.31; H, 5.72; C10H9FO requires; C, 73.13; H, 5,53%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=C[C:18]=3Cl)=[O:16])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1[N:36]=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC(C1C=NC=CC=1)=O>>[C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]([C:17]3[CH:18]=[N:36][CH:20]=[CH:21][CH:22]=3)=[O:16])[N:13]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3Cl)nc2n1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: O=C(CBr)c1cccnc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3cccnc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 2-[5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl]-1-(2-chloro-phenyl)-ethanone (example 47), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide and isolated as light yellow solid. MS (m/e): 402.3 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:19]([O:21][CH2:22][CH2:23]O)[CH3:20].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:20][CH2:19][O:21][CH2:22][CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc(NCC2C=CCCC2)cc1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOCCOC(=O)Cc1ccc(NCC2C=CCCC2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(cyclohex-2-enylmethylamino)phenylacetic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-(cyclohex-2-enylmethylamino)phenylacetate.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[Na]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ncccn1
Reactant: NCCCN
Agent: [Na]
Solvent: CCO
Product: NCCCNc1ncccn1

Procedure:
Reaction of 2-bromopyrimidine with 1,3diaminopropane in ethanol containing sodium ethoride gives 2-(3-aminopropylamino)pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10](O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[N:40]=[C:39]([SH:45])[N:38]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH:10]([S:45][C:39]1[N:38]=[C:37]([O:36][CH3:35])[CH:42]=[C:41]([O:43][CH3:44])[N:40]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
11 g (25 mmol) of methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate (compound 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise while stirring. Stirring is continued for 2 hours at room temperature, and the mixture is washed with water, dried over magnesium sulfate and evaporated down under reduced pressure. The residue is taken up in dimethylformamide and the solution is added dropwise at 0° C. to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium bicarbonate in 100 ml of dimethylformamide. After stirring has been carried out for 2 hours at room temperature and for a further 2 hours at 60° C., the mixture is poured onto 11 of ice water and the resulting precipitate is filtered off with suction. After drying, 3.2 g of a white powder remain.