Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:31][CH2:32][O:33][C:5]2=[CH:4][CH:3]=1.Cl[CH2:35][C:36]#[N:37].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH2:35][C:36]#[N:37])[CH2:29][CH2:30]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:31][CH2:32][O:33][C:5]2=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCCN1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (0.19 g), 2-chloroacetonitrile (0.038 ml), potassium iodide (0.020 g), potassium carbonate (0.139 g) and DMF (2.5 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The crude product was purified by column chromatography on silica using a 93:7 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.13 g) as a solid; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 2.6 (m, 2H), 3.05 (m, 2H), 3.15 (m, 2H), 3.35 (m, 2H), 3.65 (m, 2H), 3.9 (s, 2H), 4.05 (s, 3H), 4.35 (m, 2H), 6.15 (s, 2H), 7.05 (d, 1H), 7.15 (d, 1H), 7.4 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: [M−H]− 509 and 511; Elemental Analysis: Found C, 58.41; H, 5.62; N, 15.93. C25H27ClN6O40.2H2O requires C, 58.35; H. 5.37; N, 16.33%.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][C:21]([CH2:26][C:27]#[N:28])([CH2:23][C:24]#[N:25])[CH2:20]1>O1CCCC1>[C:21]1([CH2:26][C:27]#[N:28])([CH2:23][C:24]#[N:25])[CH2:22][C:19](=[CH:9][C:7]#[N:8])[CH2:20]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: N#CCC1(CC#N)CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC(CC#N)(CC#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (5.1 mL) was added dropwise at 0° C. diethyl cyanomethylphosphonate (0.82 mL, 0.0051 mol). The reaction was warmed to rt and 30 min later cooled to 0° C. again. To the reaction mixture was added a solution of 2,2′-(3-oxocyclobutane-1,1-diyl)diacetonitrile (0.5 g, 0.003 mol) in THF (5 mL). The reaction was allowed to warm up to rt gradually and stirred at rt for 2 h. The reaction was quenched with saturated aq. NH4Cl, then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give a brown oily crude product, which was used directly in the next step.
Reaction SMILES: C[CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][C:6]([CH3:10])=[C:7]([F:9])[F:8].[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>O1CCCC1>[CH3:12][S:13]([O:11][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])=[C:7]([F:9])[F:8])(=[O:15])=[O:14]
Reactant: CC(CCCC(C)O)=C(F)F
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CCCCOS(C)(=O)=O)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To 100 ml of tetrahydrofuran, 5.00 g (33 mmol) of methyl 6,6-difluoro-5-methyl-5-hexenol and 4.20 g (37 mmol) of methanesulfonyl chloride were dissolved, followed by drop-wisely adding 4.40 g (44 mmol) of triethylamine under ice-cooling. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 7.50 g (yield: 99%) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][OH:11])[CH:5]=[N:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: OCC#Cc1cncc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(5-Bromo-pyridin-3-yl)-prop-2-yn-1-ol (Intermediate 218) (1 eq, 2.41 mmol, 510 mg) is dissolved in DCM (5 ml), then TEA (1.5 eq, 3.61 mmol, 0.5 ml) and methanesulfonyl chloride (1.5 eq, 3.61 mmol, 0.28 ml) are added. The resulting mixture is stirred for 30 min at r.t. After addition of water the layers are separated, and the organic layer is dried with MgSO4, filtered, and concentrated under reduced pressure giving the title compound.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH:35]([CH3:37])[CH3:36])[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH:35]([CH3:37])[CH3:36])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1oc(-c2ccccc2OC(C)C)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3OC(C)C)oc2C)c1)C(=O)O
Yield: 60 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(2-isopropoxy-phenyl)-5-methyl-oxazole, the title compound was obtained in 60% yield as a brown oil. MS: (M+H)+ 463.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1
Reactant: C1CCN(CCC2CCNCC2)C1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N1CCC(CCN2CCCC2)CC1
Yield: 49.1 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with 4-[2-(pyrrolidin-1-yl)ethyl]piperidine (230 mg, 1.3 mmol) to afford the desired product (190 mg, 47%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 3.98-3.90 (m, 2H), 3.32-3.23 (m, 2H), 2.58-2.50 (m, 6H), 2.55 (s, 3H), 1.86-1.53 (m, 11H); ESI MS m/z 387 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(Cc3ccccc3)CC2)ncn1
Temperature: 60 °C
Yield: 21.5 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.60 g, 1.84 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in DMF (40 mL) was added benzyl bromide (0.31 g, 0.22 ml, 1.84 mmol) at room temperature. The reaction mixture was heated at 60° C. for one hour and the progress of the reaction was monitored by TLC. The mixture was poured onto ice water and extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with dry diethyl ether and the solid was filtered to obtain 1-benzyl-piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #5A) (0.165 g. 21%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1)C1CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCCC2)cc1)C1CC1
Yield: 53.9 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (49 mg, 0.108 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (46 mg, 0.162 mmol) to afford the desired product (31 mg, 54%) as a yellow solid: 1H NMR (300 MHz, CD3OD+acetic acid-d4) δ 9.31 (s, 1H), 8.06-7.99 (m, 2H), 7.91 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.35-7.26 (m, 4H), 4.41 (s, 2H), 2.93-2.86 (m, 1H), 2.13-2.03 (m, 4H), 1.23-1.06 (m, 4H); ESI MS m/z 532 [C30H27Cl2N3O2H]+; HPLC 94.9% (AUC), tR=11.43 min.
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:31][CH3:32])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:33])C=C.O.I([O-])(=O)(=O)=O.[Na+].CC[O:44][C:45]([CH3:47])=[O:46]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:6]([C@@H:25]([CH2:31][CH3:32])[CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:5](=[O:33])[C@:4]([CH2:47][C:45]([OH:44])=[O:46])([CH3:1])[CH2:9]2)[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CS(C)(=O)=O)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC[C@@H](CS(C)(=O)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)piperidin-2-one (Example 395, Step B, 58 mg, 0.110 mmol) in acetonitrile (1.0 mL), EtOAc (1.0 mL), and water (1.5 mL) was added ruthenium(III) chloride hydrate (0.55 mg, 2.42 μmol) and sodium periodate (144 mg, 0.672 mmol). After 2 hours, the mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH/DCM) to provide the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@:4]([CH3:22])([C:14](=[O:21])[NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][NH:5][C@:4]([CH3:22])([C:14]([NH:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[O:21])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@]1(C)C(=O)Nc1nccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(C(=O)Nc2nccs2)C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2S,4S)-tert-butyl 4-hydroxy-2-methyl-2-(thiazol-2-ylcarbamoyl)pyrrolidine-1-carboxylate (0.49 g, 1.5 mmol) in CH2Cl2 was added TFA (1 ml, excess). The reaction mixture was stirred at RT for 14 h and concentrated. The residue was used for the next step without purification. LC/MS [M+H]+: 228; Ret time (Method F): 0.46 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3C=NC=N3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]N)=[CH:30][CH:29]=1)(=[O:26])[CH3:25].C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:35][CH:34]=3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(CN)cc1
Reactant: Cc1nc(C)n2nc(-c3ccc(Br)cc3)nc(-n3cncn3)c12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(CNc2nc(-c3ccc(Br)cc3)nn3c(C)nc(C)c23)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
2-(4-Bromophenyl)-5,7-dimethyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]-triazine (3.7 mg, 10 mmol) is treated in dioxane (100 μl) with 4-acetylamino-benzylamine (3.3 mg, 20 mmol) and triethylamine (4 μl). The mixture is heated at 80° C. with shaking for 12 h, filtered and washed with DMSO (2×100 μl). The combined filtrates are purified chromatographically by preparative LC-MS.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.C(O)C.[NH2:20][C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C1C=CC=CC=1>[N:20]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:22]2[CH:23]=[CH:24][CH:25]=[N:26][C:21]=12
Reactant: Nc1ncccn1
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2cn3cccnc3n2)cc1
Yield: 46.3 %

Procedure:
A mixture of 48 g of ethyl 4-(chloroacetyl)phenylacetate, 100 ml of ethanol and 38 g of 2-aminopyrimidine is heated under reflux for 3 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried and concentrated to give a brown oil. To the oil is added benzene, and the crystalline precipitate is filtered off and recrystallized from ethyl acetate to give 26 g of ethyl 4-(imidazo[1,2-a]-pyrimidine-2-yl)phenylacetate as pale brown crystals melting at 155°-158°C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Cl:18]Cl>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11]([C:14]([F:17])([F:15])[F:16])(=[O:13])=[O:12])[CH:8]=[C:7]([Cl:18])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: ClCl
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Yield: 95.3 %

Procedure:
In analogy to Example 14, 27 g of 2-nitro-4-trifluoromethylsulphonyl-aniline in 100 ml of acetic acid were chlorinated with 10 g of chlorine. 29 g of 2-nitro-4-trifluoromethylsulphonyl-6-chloro-aniline resulted; melting point 138°-139° C.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27]>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([N:25]([O:26][CH3:27])[CH3:24])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and N,O-dimethylhydroxylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:11][CH2:12][OH:13].[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#[CH:16]>CCN(CC)CC.CN(C=O)C.[Cu]I>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:16]#[C:15][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[N:6]2[CH2:11][CH2:12][OH:13]
Reactant: Nc1ncnc2c1nc(Br)n2CCO
Reactant: C#Cc1cccnc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1nc(C#Cc1cccnc1)n2CCO
Temperature: 60 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
To a solution of 258 mg of 2-(6-amino-8-bromo-purin-9-yl)ethanol in a mixture of Et3N and DMF were added under an atmosphere of argon 35 mg of Pd(PPh)3Cl2, 19 mg CuI and 150 mg 3-ethynylpyridine. The mixture was stirred under argon at 60° C. for 3 hours and over night at room temperature. The precipitate was isolated, washed with water and hot ethanol and dried to give 150 mg (53%) of the desired product.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Br[CH:11]([CH2:14][CH2:15]Cl)[CH:12]=[O:13]>O>[CH:12]([C:11]1([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:15][CH2:14]1)=[O:13]
Reactant: O=CC(Br)CCCl
Reactant: CC(C)(C)S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)SC1(C=O)CC1
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen and while cooling with ice, 112 ml of tert-butyl mercaptan are added dropwise over 10 minutes to a solution, cooled to 5° C., of 80 g of sodium hydroxide in 750 ml of water. Then 50 ml of methanol are added. After 1 hour, 151 g of 2-bromo-4-chlorobutanal (89.5%) are added dropwise over 15 minutes with efficient stirring and cooling, whereupon the temperature of the reaction mixture rises from 5° to 20° C. After 30 minutes, the mixture is extracted 4 times with diethyl ether. The combined organic phases are washed twice with a saturated solution of sodium chloride and dried over magnesium sulfate. The residue obtained after concentrating the residue on a rotary evaporator is fractionated over a 30 cm packed column, affording 89 g of 1-formyl-1-tert-butylthiocyclopropane in 89% purity. Boiling point: 112°-114° C./8 400 Pa.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH:8]3[CH2:13][CH2:14][O:15][C:6]([C:7]=23)=[CH:5][N:4]1[O:16][CH3:17].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>O>[C:18]([CH:10]1[CH2:11][C:12]2[CH:3]([O:2][CH3:1])[N:4]([O:16][CH3:17])[CH:5]=[C:6]3[O:15][CH2:14][CH2:13][CH:8]([C:7]=23)[CH2:9]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Solvent: O
Solvent: c1ccncc1
Product: COC1C2=C3C(=CN1OC)OCCC3CC(C(C)=O)C2
Reaction time: 2 h

Procedure:
A mixture of 1,2,3a,4,5,6-hexahydro-7,8-dimethoxypyrano-[2,3,4-de]isoquinoline (10.0 g), described in Example 23, acetic anhydride (60.0 ml) and pyridine (0.5 ml) is heated on the steam bath for 4 hr. The mixture is poured into water and stirred for 2 hr. The mixture is extracted with chloroform and the extracts are washed with sodium bicarbonate solution and then with brine. The organic solution is dried and evaporated to leave the title compound. A sample, crystallized from isopropanol, had m.p. 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][NH:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][N:14]([CH3:17])[C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(-c2cccnc2)nc2[nH]ccc12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2c(Cl)nc(-c3cccnc3)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.34 mmol, 1.0 eq.) in dry DMF (20 mL) was added Cs2CO3 (221 mg, 0.68 mmol, 2.0 eq.) and iodomethane (54.3 mg, 0.38 mmol, 1.1 eq.) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2.5 h. The reaction mixture was poured into ice water and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 8:1) to give 65 mg of xlvi-a as brown solid (56.7%).
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[CH2:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[S:14].[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:27]=O)=[C:24]([CH3:26])[N:25]=2)[CH:22]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH2:27][NH:1][CH:2]([CH3:15])[CH2:3][N:4]3[C:12]4[N:11]=[CH:10][NH:9][C:8]=4[C:7](=[O:13])[NH:6][C:5]3=[S:14])=[C:24]([CH3:26])[N:25]=2)[CH:22]=1
Reactant: CC(N)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Reactant: Cc1nc2ccc(Br)cn2c1C=O
Product: Cc1nc2ccc(Br)cn2c1CNC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Reaction time: 48 h
Yield: 23.9 %

Procedure:
The title compound was prepared in accordance with the general method described above using 3-(2-aminopropyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (60 mg, 0.18 mmol, obtained from Example 29(c)) and 6-bromo-2-methylimidazo[1,2-a]pyridine-3-carbaldehyde (33.8 mg, 0.14 mmol), with the exception that the imine formation was allowed to run for 48 h, which generated 15 mg (24% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([C:10]2[C:11]([F:20])=[CH:12][C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]=3[CH:19]=2)[C:3]1=[O:21].[H-].[Na+].Cl[CH2:25][C:26]([NH2:28])=[O:27].O>CN(C)C=O>[C:26]([CH2:25][N:15]1[C:14]2[CH:19]=[C:10]([N:4]3[C:5](=[O:9])[CH:6]=[C:7]([CH3:8])[N:2]([CH3:1])[C:3]3=[O:21])[C:11]([F:20])=[CH:12][C:13]=2[S:17][C:16]1=[O:18])(=[O:27])[NH2:28]
Reactant: NC(=O)CCl
Reactant: Cc1cc(=O)n(-c2cc3[nH]c(=O)sc3cc2F)c(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2cc3c(cc2F)sc(=O)n3CC(N)=O)c(=O)n1C
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3.07 g of 1,6-dimethyl-3-(6-fluoro-2-oxo-5-benzothiazolinyl)-2,4(1H,3H)-pyrimidinedione (see Example 79) and 0.48 g of a 55% sodium hydride dispersion are stirred at 25° C. for 1 hour in 50 ml of absolute dimethylformamide. Subsequently, 1.02 g of chloroacetamide are added and the mixture is stirred at 50° C. for 6 hours. The reaction mixture is cooled and treated with 400 ml of water. The precipitated product is filtered off under suction, washed with water and the filter cake is suspended in 200 ml of ethyl acetate at 60° C. The suspension is concentrated to about 50 ml, cooled to 25° C., the solid is filtered off under suction and dried at 50° C. In this manner there is obtained 3-(3-carbamoylmethyl-6-fluoro-2-oxo-5-benzothiazolinyl)-1,6-dimethyl-2,4(1H,3H)-pyrimidinedione, m.p.>260° C.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35]Cl)[CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:30]=1
Reactant: ClCc1cc(Cl)ccn1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cc(Cl)ccn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Tetrahydrofuran (3 mL) and 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridine-3-yl)-isoxazole-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. Next, the reaction solution was concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (36.3 mg, 0.22 mmol) described in Manufacturing Example 51-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature, and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36.6 mg, 83%).