Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)[CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O.C(O)C>[N:28]1([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH:15]=4)[C:10](=[O:27])[C:9]=3[CH:8]=2)=[O:5])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: O=C(CCCl)Nc1ccc2c(=O)c3cc(NC(=O)CCCl)ccc3[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(CCN1CCCC1)Nc1ccc2c(=O)c3cc(NC(=O)CCN4CCCC4)ccc3[nH]c2c1
Temperature: 0 °C

Procedure:
2,6-Bis(3-chloropropionamido)-9(10H)-acridone (AR-ACO-9, 3.00 g, 7.38 mmol) and KI (0.10 g, 0.60 mmol) were suspended in a mixture of dimethylformamide (45 mL) and ethanol (45 mL). Pyrrolidine (12 mL, 10.22 g, 144 mmol) was added in one lot and the whole stirred at reflux for 21 hr. The flask was cooled and all the solvents removed under reduced pressure. Dimethylformamide (100 mL) was added to the flask and this was in turn removed under reduced pressure. The process was repeated with toluene (2×100 mL) and propan-2-ol (2×100 mL). The solid in the flask was dissolved in water (60 mL) and 0.88 s.g. ammonia (10 mL) was added dropwise with stirring to yield an orange-brown precipitate. The flask was chilled with ice-water and the product collected, washed with dilute ammonia (2×10 mL, 1% dilution of 0.88 s.g. ammonia) and ice-cold water (2×10 mL). The product was dried in air and over P2O5 under vacuum to yield a yellow solid AR-ACO-10 (3.11 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:17]C[O-].[Na+].CI>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10](=[O:16])[N:11]=[C:12]([S:15][CH3:17])[NH:13][CH:14]=2)=[CH:6][N:7]=1
Reactant: CC[O-]
Reactant: Cc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Yield: 38 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (210 mg, 234.28 gmol−1, 0.90 mmol, 1 eq) and NaOEt (2 eq, 128 mg) were stirred in 5 ml of absolute ethanol at room temperature for 30 minutes. In the suspension was then added methyl iodide (2.5 eq, 140 μl) and the mixture was stirred for 35 hours. Solvent was then evaporated. In the mixture was added 3 ml of water and pH was adjusted to 5-6 range using 3N HCl water solution. The resulting precipitate was collected and dried to afford 5-(2-methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (85 mg, yield=36.6%, purity=96%) in form of white powder. MS: [M+H]+=249.22 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.45 (s, 3H), 2.54 (s, 3H), 3.57 (s, 2H), 7.87 (br.s., 1H), 8.56 (s, 2H), 12.79 (br.s., 1H).
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]2=[N:8][CH:9]=[C:10]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH:11]=[C:6]2[CH:5]=[CH:4]1.N1C=CC=CC=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:5]1[C:6]2[C:7](=[N:8][CH:9]=[C:10]([N:12]3[C:13](=[O:22])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])[CH:11]=2)[NH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cnc2[nH]ccc2c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1cnc2[nH]cc(Br)c2c1
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
A solution of Br2 (30.2 mg, 0.189 mmol) in CH2Cl2 (2.0 mL) was added dropwise over a period of 4 min. to a stirred and cooled (0° C.) solution of 41 (50 mg, 0.189 mmol) and pyridine (18.0 mg, 0.23 mmol) in CH2Cl2 (2 mL). After additional stirring at 0° C. for 26 min. the reaction mixture was treated with a 1:1 (v/v) solution of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3. Stirring continued for 30 min at 0° C. and the organic phase was separated. The aqueous layer was extracted with CH2Cl2. The combined organic solutions were dried (MgSO4), concentrated and the residue was separated by LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 42 (64.7 mg, quant.). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 7.40 (s, 1H), 7.81 (dd, J=3.1, 5.4 Hz, 2H), 7.94 (d, J=2.3 Hz, 1H), 7.96 (dd, J=5.5, 3.1 Hz, 2H), 8.29 (d, J=2.3 Hz, 1H); MS (ES) m/z 383 (MH++MeCN).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[NH:14][CH3:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)NC)CC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(8-methoxy-3-methylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-ethyl-3-fluoro-benzamide was prepared from 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (52 mg, 25%). LCMS (m/e) 556 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 7.40-7.24 (m, 4H), 6.59 (s, 1H), 6.31-6.23 (m, 1H), 3.84 (s, 3H), 3.45-3.35 (m, 2H), 3.11 (s, 2H), 2.88 (d, 3H, J=4.8 Hz), 2.86-2.78 (m, 2H), 2.71-2.64 (m, 2H), 2.63-2.55 (m, 4H), 1.13 (t, 3H, J=7.3 Hz).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1cccnc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6 g, 28.8 mmol) in toluene (150 ml) at 0° C., trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over 10 minutes and the reaction mixture was heated to 90°-95° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered. The pale yellow amidine (4.5 g, 34%) was used in the next reaction without further purification: mp (DSC) 265° C. Anal Calc'd. for C13H14N3SO2Cl.0.5H2O: C, 48.67, H, 4.71, N, 13.10. Found: C, 48.34, H, 4.26, N, 12.77.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]([C:22]2[N:23]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)=[O:21])=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2)=[O:9])([CH3:6])[CH2:3][S:4][CH3:5].ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:5][S:4]([CH2:3][C:2]([NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]([C:22]2[N:23]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[N:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=2)=[O:21])=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2)=[O:9])([CH3:1])[CH3:6])=[O:46]
Reactant: CSCC(C)(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cn[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)CC(C)(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cn[nH]c12
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a mixture of 144 mg (0.26 mmol) of 6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-1H-indazole-7-carboxylic acid (1,1-dimethyl-2-methylsulfanylethyl)-amide, prepared in example 7 in 2.88 mL of methylene chloride at 0° C. is added dropwise 64 mg (0.26 mmol) of m-chloroperbenzoic acid dissolved in 0.5 mL of methylene chloride. The mixture is stirred and let warm-up to ambient temperature within 1 hour. The reaction is quenched by the addition of an aqueous saturated sodium carbonate solution. The product is extracted with ethyl acetate (3 times) and the combined organic extracts are dried on Na2SO4, filtrated and evaporated. After a flash chromatography with hexanes and ethyl acetate as eluents, 111 mg (0.17 mmol, 75%) of a white solid are obtained; LC/MS: 568/570 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[CH2:11][OH:12])[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C(OCC)(=O)C>[CH2:15]([O:12][CH2:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:4][CH2:3][CH2:2][O:1]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCCCC12OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(COCC2CCCCC23OCCO3)cc1
Reaction time: 1 h

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-6-ylmethanol (2.3 g, 13.3 mmol) in THF (20 mL) and cooled in an ice bath, was treated with a NaH (0.48 g, 20.0 mmol). The reaction mixture was stirred for 1 hour and then benzyl bromide (2.4 mL, 20 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at rt for 5 hours and then diluted with ethyl acetate (100 mL). The organic layer was washed with water, brine and dried over sodium sulfate and concentarted. Purification by silica chromatography using hexane-Et2O 20% linear gradient afforded the title compound as pale yellow solid. MS m/z 263.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Li])(C)(C)C.[CH:19](N1CCOCC1)=[O:20]>C1COCC1.CCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]=[O:20])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-bromo-2-(trifluoromethoxy)iodobenzene (9.93 g, 28 mmol) in THF (150 mL) at -78° C. was added tert-butyllithium (37 mL of a 1.5 M solution in pentane, 56 mmol) dropwise over a period of 20 min. The pale yellow solution was stirred at -78° C. for 1.5 h when N-formylmorpholine (6.5 mL; 58 mmol) was added. The resulting solution was stirred at -78° C. for 15 min and the cooling bath was removed. The mixture was stirred for an additional 1 h, when 0.25 M aqueous citric acid (100 mL) was added. The mixture was diluted with EtOAc (150 mL), the layers were separated, the organic phase was washed with brine (100 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified using pressurized silica gel column chromatography eluting with hexane to give 4-bromo-2-(trifluoro-methoxy)benzaldehyde as a colorless liquid (TLC Rf =0.45 (hexanes)).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].C(Cl)(Cl)Cl>C(O)(=O)C.[Pt]=O>[NH:8]1[CH2:9][CH2:10][CH:5]([CH:1]([OH:4])[CH2:2][CH3:3])[CH2:6][CH2:7]1
Reactant: CCC(=O)c1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC(O)C1CCNCC1
Reaction time: 60 h

Procedure:
A solution of 4-propionyl pyridine (10.0 g) in acetic acid (100 cm3) was hydrogenated over platinum oxide (0.5 g) at 60° and 60 p.s.i. pressure for 60 hours. The mixture was filtered through "Avicel" and volatile material was removed in vacuo to give the crude acetate salt (12.0 g). A portion (1 g) was taken into chloroform (20 cm3), washed with 1M sodium hydroxide solution (10 cm3), dried and evaporated to afford 1-(4-piperidyl)propanol, m.p. 50° (0.70 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7]2.O1CCCC1.[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28]Cl>CN(C)C=O>[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7]2
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOCOc1ccc2cc(C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
3.3 g (83 mmol) of 60% sodium hydride in oil are added portionwise to a solution of 14 g (69 mmol) of methyl 6-hydroxynaphthalene-2-carboxylate in 180 ml of an equivolume mixture of tetrahydrofuran and dimethylformamide. After the evolution of gas has ceased, 8.7 ml (76 mmol) of methoxyethoxymethyl chloride are added dropwise. The reaction medium is stirred at room temperature for 3 hours, immersed into ice-cold water and extracted with ethyl ether. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 17 g of methyl 6-(2-methoxyethoxymethoxy)naphthalene-2-carboxylate are obtained in the form of a colorless oil, in a yield of 85%.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[NH:9][C:8]2=[O:27])=[N:4][N:3]=[N:2]1.[CH3:28][C:29]([CH3:32])([O-])[CH3:30].[Na+].BrCC1CC1>CN(C=O)C>[NH:4]1[C:5]([CH2:6][C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([CH2:28][CH:29]3[CH2:32][CH2:30]3)[C:8]2=[O:27])=[N:1][N:2]=[N:3]1
Reactant: O=C1N[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)C[C@H]1Cc1nnn[nH]1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1[C@H](Cc2nnn[nH]2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Temperature: 0 °C

Procedure:
A solution of (3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 60, Step A) (65 mg, 0.162 mmol) in DMF (1.6 mL) was cooled to 0° C. and sodium tert-butoxide (31.1 mg, 0.323 mmol) was added. The reaction mixture was stirred at 0° C. for ten minutes before adding (bromomethyl)cyclopropane (78 μL, 0.808 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours, quenched with saturated ammonium chloride and diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, washed with 1M LiCl, sat. aq. NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][SiH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[N:16])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1.[C:21]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[OH:33])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([N:16]=[N:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][SiH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])=[CH:10][C:11]=2[N+:17]([O-:19])=[O:18])[C:26]=1[OH:33])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)=C[SiH2]CCCOc1ccc([N+]#N)c([N+](=O)[O-])c1
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Product: COc1cc(N=Nc2ccc(OCCC[SiH2]C=C(C)C)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1

Procedure:
Para-aminophenol is acetylated by reaction with acetic anhydride to form 4-acetoxyacetanilide, which is then nitrated to form 4-acetoxy-2-nitroacetanilide (V). V is then reacted with 3-chloropropyldimethylvinylsilane to form 4-(3'-dimethylvinylsilylpropoxy)-2-nitroacetanilide (VI). VI is hydrolyzed to form VII, which is then reacted with nitrous acid to form a 4-(3'-dimethylvinylsilylpropoxy)-2-nitrobenzenediazonium ion (VIII). The diazonium ion VIII is then reacted with 2-t-butyl-4-methoxyphenol to form 2-t-butyl-6-[4'-(3"-dimethylvinylsilylpropoxy)-2'-nitrophenylazo]-4-methoxyphenol (IX). The azo compound IX is then reacted with glucose and base, and then with zinc to form 2-(3'-t-butyl-2'-hydroxy-5'-methoxyphenyl)-5-(3"-dimethyl-vinylsilylpropoxy)benezotriazole (X).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[CH3:28])=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[BrH:29].N([O-])=O.[Na+]>O>[Br:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[CH3:28])=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Br
Reactant: CCOC(=O)CCc1scc(-c2ccc(N)cc2)c1-c1ccc(C#N)cc1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1scc(-c2ccc(Br)cc2)c1-c1ccc(C#N)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 3-(4-(4-aminophenyl)-3-(4-cyano-2-methylphenyl)thiophen-2-yl)propanoate (180 mg, 0.46 mmol) in a mixture solvent of HBr (48%, 3 mL) and water (1 mL) was added dropwise a solution of NaNO2 (32 mg, 0.46 mmol) in water (0.5 mL). Then the mixture was stirred at 0° C. for 1 hour. Then CuBr (66 mg, 0.46 mmol) was added and the mixture was stirred at 0° C. for additional 1 hour. The reaction mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, concentrated in vacuo to give crude ethyl 3-(4-(4-bromophenyl)-3-(4-cyano-2-methylphenyl)thiophen-2-yl)propanoate, which was used in the next step directly.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[O:8]=[C:9]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]2[C:11]([C:12]([NH2:24])=[CH:13][CH:14]=[CH:15]2)=[N:10]1.N1C=CC=CC=1>O>[O:8]=[C:9]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[C:11](=[C:12]([NH:24][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][CH:15]=2)[NH:10]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1=NC(=O)C=2c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc2c1NC(=O)C2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ten milliliters of acetic anhydride were added to a solution of 2-oxo-3-phenyl-7-aminoindole (0.7 g.) in 40 ml. of pyridine. The reaction mixture was stirred at ambient temperature for 18 hours. Ten milliliters of water were then added and the solvent removed in vacuo. The residue was treated with 100 ml. of 1 N aqueous hydrochloric acid. The resulting solids were separated by filtration and the filter cake washed with water. Recrystallization of the filtered material from methanol yielded N-(2-oxo-3-phenyl-7-indolinyl)acetamide formed in the above reaction melting at 258°-62° C.; yield = 490 mg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>C(Cl)Cl>[F:21][C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([F:2])[C:19]=1[F:20])[CH2:6][CH:7]1[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]1[C:31]([O:32][CH3:33])=[O:34]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2cc(F)c(F)c(F)c2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Methyl 2-(3,4,5-trifluorobenzyl)piperidine-4-carboxylate hydrochloride (3.957 g, 12.22 mmol) and DIPEA (4.68 mL, 26.89 mmol) were dissolved in DCM (20 mL) and methyl carbonochloridate (1.059 mL, 13.45 mmol) was added. The reaction was stirred at room temperature for 18 h, diluted with DCM (200 mL), washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried through a phase separator and evaporated in vacuo to yield dimethyl 2-(3,4,5-trifluorobenzyl)piperidine-1,4-dicarboxylate (4.01 g, 95%) as a brown oil. MS m/z 346 (M+H)+
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]([F:30])([F:29])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([CH:17]([CH3:18])[C:16]([F:15])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:12][CH:13]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: CC(c1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C(F)(F)F)cc3)cc2)C1
Yield: 18 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (15 ml) was treated with 4-(2,2,2-trifluoro-1-methyl-ethyl)-benzenesulfonyl chloride (145 mg, 0.52 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (40 mg, 18%) as a pale yellow gum.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=3)=[CH:16][CH:15]=2)[CH2:19][CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccncc3)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In N,N-dimethylformamide (40 ml), 4-(4-pyridyl)benzoic acid hydrochloride (654 mg) and tert-butyl 1-piperazinecarboxylate (569 mg) were suspended. To the resulting suspension, 1-hydroxybenzotriazole (374 mg) and N-methylmorpholine (336 μl) were added. The resulting mixture was ice cooled, followed by the addition of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (796 mg). After stirring at room temperature for 7 hours, the solvent was distilled off. The residue was purified by chromatography on a silica gel column (2% methanol—dichloromethane), followed by washing with hexane, whereby the title compound (905 mg, 89%) was obtained.