Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:17]=[C:18]1OC(=O)[N:20]2[CH:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[S:25][CH2:26][CH:19]12>CS(C)=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:18]([CH:19]3[CH2:26][S:25][CH:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:20]3)=[O:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Reactant: O=C1OC(=O)N2C1CSC2c1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of 40 mg of 1-(3-phenylpropyl)piperazine in 0.5 ml of dimethyl sulfoxide was added to a solution of 50 mg of 1,3-dioxo-5-(3-pyridyl)thiazolidino[3,4-c]oxazolidine hydrochloride in 1 ml of dimethyl sulfoxide at room temperature. The reaction mixture was stirred for 2 hours at room temperature, then diluted with ethyl acetate, washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 70 mg of 1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine. The physicochemical properties of this product were in agreement with those of the compound of Example 108.
Reaction SMILES: O[CH:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5](=[O:19])[N:4]2[CH2:20][CH2:21][C@H:22]([OH:23])[C@H:3]12.C(O)(C)C>CCCCCC>[OH:23][C@@H:22]1[C@H:3]2[N:4]([C:5](=[O:19])[N:6]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=3)[CH2:2]2)[CH2:20][CH2:21]1
Reactant: N#Cc1ccc(N2C(=O)N3CC[C@H](O)[C@@H]3C2O)c2ccccc12
Solvent: CCCCCC
Solvent: CC(C)O
Product: N#Cc1ccc(N2C[C@H]3[C@@H](O)CCN3C2=O)c2ccccc12
Yield: 24 %

Procedure:
The title compound (40 mg) was prepared from compound 42A (176 mg) by procedures analogous to those described in Example 41B. mp 226-228° C. Chiral HPLC: 99% at 7.36 min (retention time) (CHIRALPAK® AD column 4.6×250 mm; 40% isopropanol in hexane over 20 minutes, 1 mL/min, monitoring at 220 nM); MS (ES): m/z 294 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])=[CH:5][N:4]=1.Cl.N1C=CC=CC=1>>[CH3:18][C:10]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=1
Reactant: COc1ccc(-c2cccc([N+](=O)[O-])c2C)cn1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(-c2ccc(=O)[nH]c2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 102.8 %

Procedure:
A 10-mL single-neck round-bottomed flask equipped with a magnetic stirrer, and nitrogen inlet was charged with 2-methoxy-5-(2-methyl-3-nitrophenyl)pyridine (8) (1.00 g, 4.10 mmol) and pyridine hydrochloride (1.90 g, 16.4 mmol) and purged with nitrogen. The flask was place for five min into an oil bath preheated to 165° C. After this time the reaction was cooled to room temperature, and water (70 mL) was added. The resulting suspension was filtered, and the filter cake was washed with water (2×25 mL) and then dried in a 43° C. vacuum oven for 3 h to afford 0.97 g (99%) of 5-(2-methyl-3-nitrophenyl)pyridin-2-one (9) as a white solid: mp 214-216° C.; 1H NMR (300 MHz, DMSO-d6) 11.87 (br s, 1H), 7.85 (dd, 1H, J=8.1, 1.2 Hz), 7.56 (dd, 1H, J=7.8, 1.5 Hz), 7.54 (dd, 1H, J=8.4, 2.4 Hz), 7.53 (d, 1H, J=9.3 Hz), 7.46 (dd, 1H, J=7.8, 1.5 Hz), 6.41 (d, 1H, J=9.3 Hz), 2.30 (s, 3H); MS (ESI+) m/z 231 (M+H).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH:18]([CH2:23][C:24]([NH2:26])=[O:25])[C:19](OC)=[O:20]>C(O)C>[C:2]([NH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]1[CH2:18][C:19](=[O:20])[NH:26][C:24]1=[O:25])(=[O:4])[CH3:3]
Reactant: COC(=O)C(Br)CC(N)=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C1CC(=O)NC1=O
Reaction time: 2 h

Procedure:
In 1 l of ethanol was dissolved 31.6 g of sodium, and following addition of 300 g of diethyl acetylaminomalonate at room temperature, the mixture was stirred for 2 hours. To the reaction mixture, a solution of 144.5 g of methyl 2-bromosuccinamate in ethanol (350 ml) was added dropwise under ice-cooling and the mixture was stirred under ice-cooling for one hour and then at room temperature for an additional one hour. This reaction mixture was concentrated under reduced pressure, followed by addition of 1 l portions of water and ethyl acetate, and stirred. The aqueous layer was separated and the ethyl acetate layer was further extracted with 500 ml of water. These aqueous layers were combined, washed with 1 l of ethyl acetate, adjusted to pH 1.5 with conc. hydrochloric acid and allowed to stand in a refrigerator. The resultant crystals were collected by filtration, washed with water and dried under reduced pressure. Yield 140 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.CN(C)C=[O:43].[OH-].[K+]>CO>[OH:43][CH:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)[N:23]=1)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26]
Reactant: CN(C)C=O
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(CC(=O)N(C)C)n3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(O)C(=O)N(C)C)n3)cc12
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Crude 2-{6-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-N,N-dimethyl-acetamide (0.271 mmol) was dissolved in methanol (1 mL) and dimethylformamide (1 mL) and 50% w/v aqueous potassium hydroxide (0.5 mL) was added. After 30 minutes, the reaction was quenched by addition of acetic acid (0.5 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 2-hydroxy-2-{6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-N,N-dimethyl-acetamide (25 mg, 22.8%, 3 steps). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.32 (s, 3H), 2.78 (s, 3H), 3.79 (s, 3H), 5.37 (m, 1H), 5.61 (m, 1H), 7.03 (dt, J=7.0 Hz, 1H), 7.12 (br d, J=8.5 Hz, 1H), 7.29 (br dt, J=7.5 Hz, 1H), 7.57 (dd, J=7.5 Hz, 1H), 7.79 (br t, 1H), 8.47 (d, 1H), 8.61 (d, 1H), 8.65 (d, 1H), 8.75 (d, 1H). MS: m/z 404 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH3:10])=[C:4]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:3]=1.[OH-].[K+].C([OH:32])(C)(C)C>[Cl-].[Na+].O.C(#N)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:32])=[CH:14][CH:13]=2)[CH3:10])=[C:4]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:3]=1
Reactant: CC(C)(C)O
Reactant: CN(C)Cc1cc(Cl)ccc1OCCN(C)Cc1ccc(C#N)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN(C)Cc1cc(Cl)ccc1OCCN(C)Cc1ccc(C(N)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-{N-[2-(4-chloro-2-dimethylaminomethylphenoxy) ethyl]-N-[methyl]aminomethyl}benzonitrile (10.16 g), powdered potassium hydroxide (20.0 g) and tert-butanol (100 ml) was boiled under reflux for 30 minutes. The mixture was cooled to ambient temperature and poured into saturated brine (300 ml). The mixture was extracted with dichloromethane to give an oil which was dissolved in hot acetonitrile and cooled to yield a precipitate which was collected by filtration and recrystallised from ethyl acetate/petroleum ether b.p. 60°-80° C., to give 4-{N-[2-(4-chloro-2-dimethylaminomethylphenoxy) ethyl]-N-[methyl]aminomethyl}benzamide, m.p. 108°-109° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:38])[C@@H:27]([NH2:37])[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][CH2:21]1)=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:15]([O:17][C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:38])[C@@H:27]([NH:37][C:12]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:14])[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:24][CH2:25]1)=[O:19])[CH3:16]
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.7 g 4-Hydroxy-quinoline-2-carboxylic acid and 5 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 25 ml of DMF, 2.2 g of HOBT and 2.8 g of EDC was added and the reaction mixture was stirred for 3 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by re-crystallisation from n-heptane/ethyl acetate and dried under reduced pressure. Yield: 7.2 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:19])[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Nc2c(C)cccc2C)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)c1ccc(O)cc1
Temperature: -75 °C
Yield: 80 %

Procedure:
A solution of 6.4 g of N-(2,6-dimethylphenyl)-4-methoxybenzamide in methylene chloride was cooled to -75° C. Boron tribromide (25 g) was added over a 15 minute period. The reaction mixture was allowed to warm over 2 hours and then heated at reflux for 2 hours. The reaction was again cooled to -75° C. and 50 ml of water were added. The mixture was allowed to warm and the layers were separated. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from methanol/water affording the desired title product in 80% yield, m.p. 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9](Br)[CH3:10].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[O:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13](=[O:14])[CH3:12])[CH3:10]
Reactant: CC(Br)c1c(Cl)cccc1Cl
Reactant: CC(=O)c1ccccc1N
Product: CC(=O)c1ccccc1NC(C)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
A mixture of 5.5 g of 1,3-dichloro-2-(1-bromoethyl)benzene and 2.9 g of 2-(methylcarbonyl)benzeneamine was stirred for 8 hours at 100° C. After cooling, the reaction mixture was purified by column chromatography (silica gel; CH2Cl2 /hexane 50:50). The eluent of the desired fraction was evaporated and the residue was triturated in hexane. The product was filtered off and dried in vacuo at 60° C., yielding 1.05 g (16.2%) of (±)-1-[2-[[1-(2,6-dichlorophenyl)ethyl]amino]phenyl]ethanone; mp. 122.8° C. (comp. 10).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:21][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2Cl)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (13.5 g, 45.3 mmol), N-bromosuccinimide (10.48 g, 58.9 mmol) and CHCl3 (150 mL). The resulting mixture was stirred at 20° C. overnight and it became a clear solution. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 0-10% EtOAc in petroleum ether, to afford 16.1 g (94%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ: 8.18 (s, 1H), 3.57 (m, 4H), 3.39 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH2:24][CH2:25][O:26][CH2:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.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]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[CH2:28][CH2:27][O:26][CH2:25][CH:24]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCOCC3)c2s1
Temperature: 100 °C
Yield: 37.8 %

Procedure:
To a stirred solution of 600 mg (1.65 mmol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 10 ml dioxane were added 1.23 g (3.30 mmol) tri-n-butyl-(3,6-dihydro-2H-pyran-4-yl)-stannane, 28 mg (0.05 mmol) bis(dibenzylideneacetone)palladium and 61 mg (0.26 mmol) trifurylphosphine. The mixture was heated at 100° C. for 16 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/9-1/3 ethyl acetate/hexane) afforded 200 mg [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester as a light brown solid. ES-MS m/e (%): 319 ([M−H], 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].S(Cl)([Cl:18])=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][Cl:18])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Br)ccc2oc(CO)c(C)c12
Solvent: ClCCl
Product: COc1c(Br)ccc2oc(CCl)c(C)c12
Yield: 92 %

Procedure:
To a solution of (5-bromo-4-methoxy-3-methyl-benzofuran-2-yl)-methanol in 7 mL of dichloromethane was added 0.5 mL of thionyl chloride at room temperature. After 2 h the reaction was concentrated in vacuo, diluted with ethyl acetate and washed with water. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give 216 mg (92%) of 5-bromo-2-chloromethyl-4-methoxy-3-methyl-benzofuran. 1H NMR (400 MHz, CDC3) δ ppm 2.4 (s, 3 H) 3.9 (s, 3 H) 4.7 (s, 2 H) 7.1 (d, J=8.8 Hz, 1 H) 7.4 (d, J=8.6 Hz, 1 H).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.C([C:22]1[CH:27]=[C:26]([S:28]([CH2:31][CH2:32]C)(=[O:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH3:34])#C>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:24]2[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:27]=[CH:22][C:23]=2[CH3:34])[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1C
Product: CCS(=O)(=O)c1ccc(C)c(C#Cc2cc(C#N)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-ethynyl-1-methyl-4-(propylsulfonyl)benzene (Intermediate 40), the title compound was obtained as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH2:10]([C:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]2[C:18](=[O:26])[N:17]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:16][CH2:15][C:14]=2[N:13]=1)[CH3:11].[CH:33]1([C:36]2[C:41]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[C:40]([F:49])[C:39]([O:50][CH:51]([CH3:53])[CH3:52])=[C:38]([CH:54]=O)[CH:37]=2)[CH2:35][CH2:34]1.[Na]>C1COCC1.CC(N(C)C)=O.C(O)(=O)C>[CH:33]1([C:36]2[C:41]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[C:40]([F:49])[C:39]([O:50][CH:51]([CH3:52])[CH3:53])=[C:38]([CH2:54][N:30]3[CH2:29][CH2:28][CH:27]([N:17]4[CH2:16][CH2:15][C:14]5[N:13]=[C:12]([CH2:10][CH3:11])[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=5[C:18]4=[O:26])[CH2:32][CH2:31]3)[CH:37]=2)[CH2:35][CH2:34]1
Reactant: CC(C)Oc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reactant: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCNCC1)CC2
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC1)CC2
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
Triethylamine (2.59 g) was added to a suspension of methyl 2-ethyl-5-oxo-6-(piperidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate dihydrochloride (5.00 g) in THF (60 mL) and DMA (20 mL) at room temperature. After being stirred at the same temperature for 30 minutes, 6-cyclopropyl-2,4′-difluoro-3-isopropoxybiphenyl-4-carbaldehyde (4.86 g) was added to the reaction mixture. The mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. Sodium triacetoxyhydroborate (4.07 g) and acetic acid (769 mg) were added to the reaction mixture at room temperature. The mixture was stirred at the same temperature under nitrogen atmosphere for 16 hours. The mixture was quenched with aqueous saturated sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (ethyl acetate/methanol) to give the title compound (5.80 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[O:18][CH3:19])([O-])=O.[H][H]>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[O:18][CH3:19]
Reactant: COc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: COc1cc(Oc2ccc(Cl)cc2)ccc1N
Yield: 100 %

Procedure:
220 g of 2-nitro-5-(4-chlorophenoxy)-anisole are dissolved in 2000 ml of dioxane and, after addition of 20 g of Raney nickel, the solution is hydrogenated at room temperature and under normal pressure. The theoretical amount of hydrogen is taken up after 12 hours, whereupon the catalyst is filtered off and the solvent evaporated, affording as residue 196.5 g of 2-amino-5-(4-chlorophenoxy)-anisole in the form of a dark brown oil, which is further processed direct.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][C:27]2[CH:28]=[C:29]([NH:35][C@@H:36]3[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]3[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH:30]=[N:31][C:32]=2[C:33]#[N:34])[CH:20]=1>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(Cl)Cl.O1CCOCC1>[C:33]([C:32]1[N:31]=[CH:30][C:29]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:28][C:27]=1[NH:26][C:21]1[CH:20]=[C:19]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=[C:23]([CH3:25])[N:22]=1)#[N:34]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Temperature: 90 °C

Procedure:
Dioxane (1.1 mL), phenylboronic acid (27 mg, 0.22 mmol), and potassium phosphate tribasic (70 mg, 0.33 mmol) were added to a nitrogen purged flask containing tert-butyl [(1S,2R)-2-({5-[(4-chloro-6-methylpyridin-2-yl)amino]-6-cyanopyridin-3-yl}amino)cyclohexyl]carbamate (PrepEx 1.7) (50 mg, 0.11 mmol). The flask was purged and flushed with nitrogen, and then PdCl2(dPPf)-CH2Cl2 (9 mg, 0.01 mmol) was added. The flask was purged with nitrogen, sealed, and heated to 90° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with 10% aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (10-50% ethyl acetate/hexanes, linear gradient) to afford tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-phenylpyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate. MS ESI calc'd. for C29H35N6O2 [M+H]+ 499. found 499.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.[O-:8][N+:9]1[C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:13]=2[N:12]=[C:11]([CH2:22][CH2:23][CH:24]=O)[N:10]=1)[CH2:19][CH2:18][CH2:17]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:2][O:3][CH:4]1[CH2:7][N:6]([CH2:24][CH2:23][CH2:22][C:11]2[N:10]=[N+:9]([O-:8])[C:14]3[CH:15]=[C:16]4[C:20]([CH2:19][CH2:18][CH2:17]4)=[CH:21][C:13]=3[N:12]=2)[CH2:5]1
Reactant: COC1CNC1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC1CN(CCCc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
3-Azetidinyl methyl ether hydrochloride (275) (MacKenzie et al., PCT Int Appl. WO 9605193, 1996) (0.60 g, 4.9 mmol) was added to a stirred solution of propanal 75 (1.2 g, 4.9 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 82 (930 mg, 60%) as a yellow oil: 1H NMR δ 8.24 (s, 1H, H-9), 7.74 (s, 1H, H-5), 4.27-4.39 (m, 3H, CH2N, CHO), 3.49-3.53 (m, 2H, CH2N), 3.30 (s, 3H, OCH3), 3.21-3.27 (m, 2H, CH2N), 3.09-3.16 (m, 4H, H-6, H-8), 3.05 (t, J=7.2 Hz, 2H, CH2), 2.14-2.26 (m, 4H, H-7, CH2); 13C NMR δ 163.9, 155.1, 149.3, 147.3, 132.3, 122.7, 144.2, 68.3, 60.9, 58.7, 56.6, 56.5, 33.5, 33.1, 32.8, 25.7, 23.8; HRMS calcd for C17H22N4O2 (M+) m/z 314.1743, found 314.1742.