Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: N#Cc1cc(-c2ccc(Cl)c(C(F)(F)F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (89 mg, 88%), MS (ISP) m/z=404.3 [(M+H)+], mp 224.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[N:32][CH:33]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20]([C:28]3[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[N:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(B(O)O)c2)c1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cncc(S(N)(=O)=O)c3)c2)c1

Procedure:
The title compound was prepared from 3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.10) (0.407 g, 1.14 mmol) and commercially available 5-bromo-pyridine-3-sulfonic acid amide (178 mg, 1.14 mmol) according to the general procedure VI. Obtained as a white solid (0.101 g, 19%). MS (ISP) 470.3 [(M+H)+]; mp 217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (10.2 g, 49.0 mmol) in ethyl acetate (80 ml) were added N-bromosuccinimide (9.6 g, 53.9 mmol) and 2,2′-azobis(isobutyronitrile) (161 mg, 0.98 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solution was concentrated and crystals were filtered with hexane. The filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(3-chlorophenyl)-3-oxopropanoate (10.0 g, 44.1 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 1.76 g, 44.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (300 ml), and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give the objective substance (7.5 g, 39%).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:29](=[O:30])/[CH:28]=[CH:27]/[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=3[O:18][CH3:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: COc1cccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1OC

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.06 min; [M+H]+=418.09.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH:17]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:23]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].[NH4+].[OH-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[CH2:21][CH2:20][NH:19][CH:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:17]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CC=C(C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C=C(C2c3ccc(Cl)cc3CCc3cccnc32)CCN1
Temperature: 80 °C
Yield: 26.7 %

Procedure:
Dissolved 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-N-methyl-1,2,5,6-tetrahydropyridine (1.24 g, 3.82 mmol) in 100 mL of dry toluene, and added ethyl chloroformate (0.91 mL, 9.54 mmol) via syringe. Heated at 80° C. for 46 hours under a nitrogen atmosphere. Cooled to room temperature, and added 1N NH4OH. Extracted with ether. Purified crude product by flash chromatography on silica gel eluting with 10% EtOAc-CH2Cl2. Combined appropriate fractions, and evaporated to give 0.39 g (27% yield) of ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1,2,5,6- tetrahydropyridinecarboxylate as an oil. mass spectrum: (Cl, CH4) m/e 383 (M+1) ##STR48##
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:23].C([O-])([O-])=O.[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Br.O>CN(C)C=O>[O:34]1[CH2:33][CH:32]1[CH2:30][O:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:23]
Reactant: BrCC1CO1
Reactant: COc1ccc(-c2coc3c(C)c(O)ccc3c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2coc3c(C)c(OCC4CO4)ccc3c2=O)cc1OC

Procedure:
7-Hydroxy-8-methyl-3-(3,4-dimethoxyphenyl)-4H-1-benzoyran-4-one [see example 12] (3.12 g) is dissolved in dimethylformamide (15 ml) and K2CO3 (3.5 g) is added to the solution. While stirring, epibromhydrine (2.47 g) is dropped into the mixture. After heating for 5 h at 60°, the content of the reaction flask is poured into water (500 ml) and the precipitated product is filtered off and recrystallized from ethanol. The product is dried in vacuo to constant weight to yield 7-(2,3-epoxypropoxy)-8-methyl-3-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one, m.p. 214°.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](F)[N:9]=2)=[C:5]([O:17][CH3:18])[CH:4]=1)[CH3:2].[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([NH:23][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:15]=[CH:16][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[O:17][CH3:18])[N:9]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: CCc1ccc(Oc2cccc(F)n2)c(OC)c1
Product: CCCCNc1cccc(Oc2ccc(CC)cc2OC)n1
Temperature: 80 °C

Procedure:
To 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (94 mg; 0.32 mmol), under argon, was added butylamine (0.5 mL). The reaction was heated to 80° C. for 18 hours. The mixture was concentrated in vacuo. After quenching with saturated NaHCO3 (10 mL), extractions with dichloromethane (3*5 mL), the organic phase was dried over NaSO4, and concentrated in vacuo to give the title compound as a light brown oil used without further purification (87 mg; 0.29 mmol; 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:21][CH2:20][C:15]2(OCC[O:16]2)[CH2:14][CH2:13]1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])cc1N1CCC(=O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a mixture of 8-(2-methoxy-5-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (Preparation Example 495) (795 mg) and dioxane (16 mL), 4M hydrochloric acid (6.8 mL) was added and stirred overnight at 80° C. The reaction liquid was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the concentrate. The concentrate was extracted with chloroform and then washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane) to give 1-(2-methoxy-5-nitrophenyl)piperidin-4-one (296 mg).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([NH:20][C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](C=O)=[CH:34][C:33]=2[CH:39]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([CH:21]=[N:20][N:17]3[CH2:16][CH2:15][N:14]([CH2:13][C@:2]4([CH3:1])[O:6][C:5]5=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]5[CH2:3]4)[CH2:19][CH2:18]3)=[CH:34][C:33]=2[CH:39]=1
Reactant: CC(C)(C)OC(=O)NN1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1cc2cc(Cl)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(CN2CCN(N=Cc3cc4cc(Cl)ccc4o3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a mixture of tert-butyl (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 503 (0.20 g, 0.523 mmol) and 5-chlorobenzofuran-2-carbaldehyde (0.113 g, 0.628 mmol) and methylene chloride (4 ml), trifluoroacetic acid (0.4 ml) was added followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added followed by extraction with methylene chloride. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) to afford (S)-N-(5-chlorobenzofuran-2-ylmethylene)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]amine (0.137 g, yield 59%) as a light yellow powder.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[CH2:10][C@@H:9]2[CH2:11][C@H:6]1[CH2:7][O:8]2.[ClH:14]>O>[ClH:14].[C@H:9]12[CH2:11][C@H:6]([N:5]([CH2:4][CH:3]=[O:2])[CH2:10]1)[CH2:7][O:8]2
Reactant: COC(CN1C[C@@H]2C[C@H]1CO2)OC
Agent: Cl
Solvent: O
Product: O=CCN1C[C@@H]2C[C@H]1CO2

Procedure:
Prepared by treating (1S,4S)-5-(2,2-dimethoxy-ethyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane with conc. hydrochloric acid in water at 80° C. The solution obtained is further reacted directly in Example 2 and 2(5).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:8])[CH:6]=O)(=O)[CH3:2].[C:9]([O:15][CH3:16])(=[O:14])[CH2:10]C(C)=O.CO.ClC(Cl)C>[Fe].O>[CH3:16][O:15][C:9]([C:10]1[CH:6]=[C:5]([CH3:8])[O:4][C:1]=1[CH3:2])=[O:14]
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)OC(C)C=O
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C)oc1C

Procedure:
12.2 parts by weight of anhydrous iron-III chloride followed by 44.9 parts by weight of 85.5 percent strength by weight α-acetoxypropionaldehyde are added to a solution of 34.8 parts by weight of methyl acetoacetate in 36 parts by weight of methanol, during which addition the mixture rises to the boil. The mixture is then refluxed for a further 1-6 hours and, when it has cooled, is mixed with 80 parts by weight of water and 37.5 parts by weight of dichloroethane; the water phase is separated off and is extracted twice, each time with 25 parts by weight of dichloroethane. The dichloroethane is distilled off under atmospheric pressure and the product is then distilled under reduced pressure. 39 parts by weight of 2,5-dimethylfuran-3-carboxylic acid methyl ester of boiling point 92° C./26 mbar are obtained.
Reaction SMILES: [C:1]([C:3]1([CH:9](C(O)=O)[C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]>C1(C)C=CC=CC=1>[C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(C(C(=O)O)C(=O)O)CCCCC1
Solvent: Cc1ccccc1
Product: N#CC1(CC(=O)O)CCCCC1
Temperature: 82.5 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
35.5 g (1-Cyanocyclohexyl)-malonic acid are suspended in 400 mL toluene and heated, while stirring, for about one hour to 80-85° C. In the course of the decarboxylation, an almost clear solution is obtained. After filtration, the toluene is distilled off in a vacuum at 35° C. The crude product is dissolved in a saturated aqueous solution of sodium bicarbonate and stirred with ethyl acetate. After separating off the organic phase, the aqueous phase is acidified with concentrated hydrochloric acid, while cooling with ice to 5° C. The solid product which precipitates out is filtered off with suction and then washed with water. The filter cake is dissolved in ethyl acetate and the solution dried over anhydrous sodium sulphate. After filtration, the ethyl acetate is evaporated on a rotary evaporator at 35° C. The residue is dried to constant weight in a vacuum drying cabinet at 35° C. 19.6 g of the title compound are obtained (70% of theory); m.p. 102° C.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C:12]1([C:25]([O:27]C)=[O:26])[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)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1.CO.CCOC(C)=O>[C:21]([O:20][C:18]([N:15]1[CH2:14][CH2:13][C:12]([NH:11][C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])([C:25]([OH:27])=[O:26])[CH2:17][CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
Lithium hydroxide monohydrate (8.13 g, 193.62 mmol) was added to 1-tert-butyl 4-methyl 4-(tert-butoxycarbonylamino)piperidine-1,4-dicarboxylate (Intermediate 69) (13.88 g, 38.72 mmol) in water (21.51 mL), THF (86 mL) and methanol (86 mL). The resulting solution was stirred at 20° C. for 1 day. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (75 mL). The aqueous was adjusted to pH5 with 1M citric acid solution, then extracted with EtOAc (3×200 mL). The organic extracts were washed with saturated brine (50 mL), then dried over MgSO4, filtered and evaporated to afford desired product 1-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylic acid (10.36 g, 78%) as a fine white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][NH2:12]>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:12][CH3:11])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc(Br)c(OC)n1

Procedure:
5-Bromo-2-chloro-4-methoxypyrimidine [57054-92-9] (8.68 mmol) and methylamine (2M in THF) (19.54 mmol) in THF (15 mL) were stirred at rt for 32 h and the reaction mixture was concentrated. The residue was purified by flash chromatography to afford the title compound as a white solid. ESI-MS: tR=0.81 min, [M+H]+ 218/220 (LC-MS 2).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]3[CH:40]=C[C:38](F)=[CH:37][CH:36]=3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:46]1(C2N=CC(C3C=NC=CC=3)=CN=2)CCNCC1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(Cl)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:42])[C@H:15]([CH2:19][S:20]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:30]=[CH:31][C:32]([C:35]3[CH:40]=[N:46][CH:38]=[CH:37][CH:36]=3)=[CH:33][N:34]=2)[CH2:27][CH2:28]1)(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1cncc(-c2cnc(N3CCNCC3)nc2)c1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 82 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 2-piperazin-1-yl-5-pyridin-3-ylpyrimidine, trihydrochloride (0.292 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.343 g), to yield the title compound as a yellow solid (0.393 g, 82%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N+:13]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1nccn1Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: Nc1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 171.7 %

Procedure:
A suspension of 1-benzyl-2-nitro-1H-imidazole (Step 160.2) (410 mg, 1.16 mmol) and Raney nickel (40 mg) in MeOH (10 mL) was stirred for 3 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated to afford 345 mg of the title compound as a brown solid: ESI-MS: 173.9 [M+H]+; tR=2.02 min (System 1).
Reaction SMILES: [Na].C(O[C:5](=[O:23])[CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C>C(O)C.C1(C)C=CC=CC=1>[O:16]=[C:9]1[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](=[O:23])[CH:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][NH:8]1
Reactant: CCOC(=O)CC(=O)NCC(C(=O)OCC)c1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(=O)NCC(c2ccccc2)C1=O
Reaction time: 1.5 h
Yield: 48.1 %

Procedure:
Sodium (380 mg, 16.52 mmol) was dissolved in anhydrous ethanol (13 mL) and the resulting solution was treated dropwise with 3-(2-ethoxycarbonyl-acetylamino)-2-phenyl-propionic acid ethyl ester (4.23 g, 13.76 mmol) dissolved in anhydrous toluene (35 mL). The reaction was kept at 80° C. for 1.5 hours. After cooling, the mixture was extracted with water. The aqueous extracts were acidified with 2 N HCl, extracted with ethyl acetate and the organic layers were collected, dried over Na2SO4 and evaporated to dryness to obtain ethyl 2,4-dioxo-5-phenylpiperidine-3-carboxylate (1.73 g, Y=48%) which was used for the next step without further purification. Ethyl 2,4-dioxo-5-phenylpiperidine-3-carboxylate (1.73 g, 6.63 mmol) was dissolved in acetonitrile containing 1% of water (30 mL) and the resulting solution was refluxed for 2 hours. After evaporating to dryness, the crude material was chromatographed on silica gel, eluting with methylene chloride/methanol 92/8, to give the title compound (780 mg, Y=62%) as a solid.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4C=C[CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2[O:36]1.O1C=CC=C1B(O)O>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[O:36][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: OB(O)c1ccco1
Product: c1coc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and furan-2-boronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.13 (s, 1H), 7.61 (d, 1H, J=1.8 Hz), 7.12 (d, 1H, J=2.4 Hz), 7.08 (d, 1H, J=2.4 Hz), 6.93 (td, 2H, J=2.4 and 8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 6.68 (d, 1H, J=8.7 Hz), 6.58 (d, 1H, J=2.4 Hz), 6.54 (dd, 1H, J=1.8 and 3.6), 4.24 (s, 4H), 4.20 (bs, 4H); LCMS: ret. time: 15.03 min.; purity: 88%; MS (m/e): 445 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([C:13]2[C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([C:13]2[C:18]([CH2:19][NH:20][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ncccc2CN)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OC)c(-c2ncccc2CNC(=O)OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
[3-(3-Aminomethyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid methyl ester (0.140 g, 0.49 mmol) and triethylamine (0.17 mL, 1.23 mmol) was dissolved in CH2Cl2 (5 mL). Benzyl chloroformate (0.08 mL, 0.54 mmol) was added, and the reaction was stirred for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:30]=[CH:29][C:19]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=2)=[C:4]([O:31][CH3:32])[CH:3]=1.[CH3:33]B1OB(C)OB(C)O1>>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([CH3:33])[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:29][CH:30]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 95.4 %

Procedure:
Following General Procedure J, tert-butyl 4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (52 mg, 0.10 mmol) was reacted with trimethylboroxine (13 mg, 0.10 mmol) to afford the desired product (43 mg, 95%) as a grey solid: ESI MS m/z 451 [C25H26N2O4S+H]+.