Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[Br:1][CH2:2][CH:3]([CH3:7])[CH2:4][CH2:5][O:6][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: CC(CBr)CCO
Reactant: C1=COCCC1
Solvent: ClCCl
Product: CC(CBr)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
16.7 g of 4-bromo-3-methylbutanol was dissolved in 200 ml of anhydrous methylene chloride, and with ice cooling, 10.0 g of dihydropyran was added dropwise. After the addition, the mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off. The residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent to give 16.2 g of 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran. The NMR spectrum of this product was as follows:
Reaction SMILES: [OH:1][C:2]1([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C1C(=O)N([Br:25])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:25][C:15]1[S:14][C:13]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)=[N:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1CCC(O)(c2nccs2)CC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O)(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.7 %

Procedure:
The product of Step 1 (23.5 g, 92 mmol) was dissolved in DMF (94 mL) and then treated with NBS (19.66 g, 110 mmol) and stirred at RT for 10 hours. The reaction was then treated with Na2SO3 (5.8 g, 465 mmol) in H2O (150 mL) and then extracted with EtOAc (100 mL) and the oil was purified by flash chromatography on silica gel to afford ethyl 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylate as an oil (31 g, 77 mmol), which was subjected to chiral chromatography to afford ethyl cis-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexane-carboxylate as an oil (15 g, 33 mmol). MS ESI: [M+H]+ m/z 333.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:15]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20]CC)=O)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.OS(O)(=O)=O>>[OH:20][C:18]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:9]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:15](=[O:16])[C:17]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2cccc(OC)c2)CCOCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(OC)cc2C2(CCOCC2)C1=O
Temperature: 0 °C
Yield: 29.8 %

Procedure:
Diethyl 2-(4-(3-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (2.1 g, see Example 18) was added to 5 mL H2SO4 stirred at 0° C. The mixture was stirred at room temperature for 1 hour, M+1=379. The mixture was then poured into 100 g crushed ice and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 20% EtOAc/hexane to give 0.55 g of the title compound. MS (m/z)=379 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 100 °C
Yield: 70.5 %

Procedure:
A mixture of 5-hydroxy-indan-1-one (5.3 g, 35.7 mmol), KJ (0.6 g, 3.6 mmol) and K2CO3 (6.17 g, 44.6 mmol) and benzyl bromide (4.66 ml, 39.3 mmol) in DMF (50 ml) were heated at 100° C. for 1 hr. Addition of H2O (150 ml) and extraction with EtOAc (3×50 ml), washing the organic phase with satd. NaCl solution (100 ml) and drying with MgSO4 and evaporation afforded a brown solid. This material was recrystallised twice from EtOH to afford 5-benzyloxy-indan-1-one (6 g, 25.17 mmol, 70%) as yellow crystals, Mp. 105-106° C., MS m/e=238.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].[CH:20](O)=O>>[CH3:10][O:9][C:6]1[C:7]2[N:8]=[CH:20][NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:5]=1
Reactant: CCCN(CCC)CCc1ccc(OC)c(N)c1N
Reactant: O=CO
Product: CCCN(CCC)CCc1ccc(OC)c2nc[nH]c12

Procedure:
1.2 g of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dipropylamine is heated under reflux with 20 ml of formic acid for 3 hours. The solution is concentrated. The residue is taken up in water, made alkaline with potassium carbonate, and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated after the drying agent has been removed by filtration. The residue is chromatographed on silica gel with a mixture of dichloromethane/methanol, thus obtaining 0.42 g of 7-methoxy-4-[2-(N,N-dipropylamino)ethyl]benzimidazole as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1.C(OC([N:25]1[C:33]2[N:28]([C:29](=[O:35])[N:30]=[C:31](Cl)[CH:32]=2)[CH2:27][C:26]1([CH3:37])[CH3:36])=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:31]3[CH:32]=[C:33]4[NH:25][C:26]([CH3:37])([CH3:36])[CH2:27][N:28]4[C:29](=[O:35])[N:30]=3)=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1ccc(Oc2cncc(Cl)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4cncc(Cl)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and tert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].CN(C=O)C.[C:19]([C:23]1[C:24]([CH3:45])([CH3:44])[CH2:25][O:26][C:27]=1[C:28]1[CH:42]=[C:41]([OH:43])[C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:34][C:30]=2[CH:29]=1)([CH3:22])([CH3:21])[CH3:20].[Cl-].[Na+]>>[C:19]([C:23]1[C:24]([CH3:45])([CH3:44])[CH2:25][O:26][C:27]=1[C:28]1[CH:42]=[C:41]([O:43][Si:10]([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11])[C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:34][C:30]=2[CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)C1=C(c2cc(O)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)C1=C(c2cc(O[Si](C)(C)C(C)(C)C)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
In nitrogen atmosphere at a room temperature, adding 43 mg (0.63 mmol) of imidazole and 64 mg (0.42 mmol) of TBDMSCl to 2.0 ml of DMF dissolving 102 mg (0.28 mmol) of 4-t-butyl-5-(4-hydroxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [63]), the mixture was stirred for 2 hours. The mixture was added to saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, then dried with magnesium sulfate anhydride and concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=7:1) to obtain 108 mg of 4-t-butyl-5-[4-(t-butyldimethylsiloxy)-2-phenylbenzo[d]oxazol-6-yl]-3,3-dimethyl-2,3-dihydrofuran (Compound [65]) as a colorless oil. Yield 80.6%
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:24]=[CH:23]C(C#N)=[CH:19][C:18]=4[F:25])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:28]([OH:31])(=[O:30])[CH3:29]>C(O)C.O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:24]=[CH:23][C:29]([C:28]([OH:31])=[O:30])=[CH:19][C:18]=4[F:25])=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1

Procedure:
4-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-fluorobenzonitrile (E271) (150 mg, 0.45 mmol) was dissolved in a mixture of ethanol (1 ml) and water (1.5 ml), treated with sodium hydroxide (150 mg, 4.5 mmol) and heated at reflux for 2 hours. The reaction was then treated with acetic acid (0.39 ml, 6.75 mmol) and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (2:18:80) to afford the title compound. MS (ES+) m/e 356 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17](O)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([NH:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)NCC(=O)OC(C)(C)C)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-methoxyquinoline (142 mg, 0.30 mmol) in tetrahydrofuran (THF) (5 mL) was added glycine t-butyl ester hydrochloride (44 mg, 0.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (64 mg, 0.33 mmol), 1-hydroxybenzotriazole (HOBT) (45 mg, 0.33 mmol) and diisopropylethylamine (DIEA) (0.43 g, 0.33 mmol). The reaction was stirred at ambient temperature overnight. The resultant solution was partitioned between water and ethyl acetate. The organic layer was concentrated in vacuo to afford an oil. The crude product was purified by elution through silica gel with 20:1 methylene chloride-methanol to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(((1,1-dimethylethoxycarbonyl)methyl)aminocarbonyl)propyl]aminocarbonyl-4-methoxyquinoline (62 mg, 35%); NMR (CDCl3) 1.25 (t, 3), 1.50 (s, 9), 2.00 (m, 1), 2.15-2.50 (m, 3), 3.31-3.95 (m, 9), 4.10-4.32 (m, 7), 5.40 (m, 1), 759 (t, 1), 7.63 (s, 1), 7.75 (t, 1), 8.14 (d, 1), 8.22 (d, 1), 9.41 (d, 1) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.[C:24](Cl)(Cl)=[O:25].C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N(c2ccccc2)CCN1c1cc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine (100 mg, 0.3 mmol) in DCM (15 mL) at 0° C. under nitrogen, a solution of phosgene in toluene (1.89 M, 0.32 mL, 0.6 mmol) was slowly added. After 20 minutes, the reaction was allowed to warm to RT. After 18 hours, DIEA (0.42 mL, 2.4 mmol) was added and the reaction solution was heated to 40-50° C. for 40 hours. The reaction mixture was evaporated under reduced pressure and the crude product was purified by silica gel chromatography eluting with 70% EtOAc/hexane to give 1-(6-chloro-2-morpholinopyrimidin-4-yl)-3-phenylimidazolidin-2-one as a white solid (94 mg, 87%). LC/MS (m/z): 360.1 (MH+), Rt 3.41 minutes.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[NH:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>S(=O)(=O)(O)O>[CH3:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]=1[NH:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)Nc1ccc(C(F)(F)F)cc1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C(=O)Nc1c(C)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
14.4 g (142.3 mmol) of potassium nitrate are added in small portions to an ice-cooled solution of 32.6 g (118.6 mmol) of ethyl N-(2-methyl-4-trifluoromethylphenyl)oxamate in concentrated sulfuric acid. After stirring at 0° C. for 1.5 hours, the mixture is cautiously poured onto 900 g of ice. The white suspension is extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated under reduced pressure in a rotary evaporator. Crystallization from ethyl acetate/hexane affords 35.5 g of the title compound as white crystals.
Reaction SMILES: CCOCC.Br[C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][C:17]=3Br)[C:12]([CH3:27])([CH3:26])[C:11]=2[CH:10]=[C:9]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:8]=1.[Li]CCCC.[Si:37]([Cl:41])(Cl)([CH3:39])[CH3:38]>CCCCCC>[Cl:41][Si:37]([CH3:39])([CH3:38])[C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][C:17]=3[Si:37]([Cl:41])([CH3:39])[CH3:38])[C:12]([CH3:27])([CH3:26])[C:11]=2[CH:10]=[C:9]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:8]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(C)(C)c1cc(Br)c2c(c1)C(C)(C)c1cc(C(C)(C)C)cc(Br)c1O2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc2c(c([Si](C)(C)Cl)c1)Oc1c(cc(C(C)(C)C)cc1[Si](C)(C)Cl)C2(C)C
Temperature: -65 °C

Procedure:
The reaction outlined in the reaction scheme below is as follows: Et2O (125 mL) and 4,5-dibromo-2,7-di(tert-butyl)-9,9-dimethylxanthene (9.54 g, 19.9 mmol) were combined and cooled to −65° C. A hexane solution of BuLi (19.2 mL, 47.7 mmol) was added dropwise over 5 min and the colorless suspension was allowed to warm to −30° C. over a period of 45 min during which time the starting material dissolved (at about −40° C.). After 15 min at −30° C. the solution was cooled to −80° C. and cold SiMe2Cl2 (20.5 g, 159 mmol) was added in one portion.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][C:3]1=[O:29].Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>C(O)C.O.C(OCC)(=O)C>[OH:32][N:31]=[C:8]([C:6]1[CH:5]=[CH:4][C:3](=[O:29])[N:2]([CH3:1])[CH:7]=1)[CH2:9][C@H:10]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@H](CC(=NO)c1ccc(=O)n(C)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 120 °C
Yield: 97.1 %

Procedure:
To a microwave vial was added (R)-1-methyl-5-(3-(4-(methylsulfonyl)phenyl)-3-o-tolylpropanoyl)pyridin-2(1H)-one (168 mg, 410 μmol), hydroxylamine hydrochloride (85.5 mg, 1.23 mmol) and sodium hydrogencarbonate (103 mg, 1.23 mmol) in ethanol (3 mL) and water (0.2 mL). The vial was capped and heated in the microwave at 120° C. for 15 min. The reaction mixture was diluted with ethyl acetate and poured onto water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to afforded the title compound (169 mg, 97%) as a mixture of the E and Z isomers (ratio ca. 85:15). Light yellow foam, MS (ESI+): m/z=425.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[CH:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[C:13]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([CH:39]([OH:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:7][N:6]=3)[N:17]=[CH:16][N:15]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Reactant: O=Cc1ccccc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(O)c3ccccc3)cn2)cc1

Procedure:
N-[6-{2-(5-Bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide and benzaldehyde are treated in the same manner as in Example 129 to give 4-tert-butyl-N-[6-{2-(5-(α-hydroxybenzyl)primidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]benzenesulfonamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CN(C=O)C>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([O:16][C:29](=[O:30])[N:28]([CH3:32])[CH3:27])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)N(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.8 %

Procedure:
To a solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (2.0 g, 9.04 mmol) in DMF (20 mL) was added sodium hydride (1.0 g, 25 mmol). After stirring at RT for 20 min, a solution of N,N-dimethyl carbamoyl chloride (1.9 g, 17.7 mmol) in DMF (5 mL) was added dropwise into the reaction mixture, which was stirred at RT for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice water (400 mL) and extracted with EtOAc (3×200 mL). The organic layer was washed with water (3×300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-7% MeOH in DCM) to yield N,N-dimethyl-carbamic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl ester (100 mg). 1H NMR (CD3OD, freebase) δ (ppm): 8.5 (d, 2H), 7.34 (d, 2H), 7.31 (d, 1H), 7.21 (s, 1H), 7.00 (d, 1H), 5.96 (t, 1H), 4.53 (dd, 1H), 4.45 (dd, 1H), 3.49 (t, 2H), 2.98 (m, 2H), 2.95 (m, 5H), 2.92 (s, 3H), 2.77 (s, 3H), 2.39 (s, 3H). Separation by chiral HPLC provided enantiomers 141a and 141b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[O:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][CH2:33][CH2:32][CH2:31]1>ClCCl.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:34]2[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:30](=[O:29])[CH2:31][CH2:32][CH2:33]2)=[O:13])=[CH:9][CH:10]=1
Reactant: O=C1CCCNc2ccccc21
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.67 g portion of 2'-methoxybiphen-4-ylcarboxylic acid was dissolved in 17 ml of dichloromethane, 0.95 ml of oxalyl chloride and a catalytically effective amount of dimethylformamide were added to the resulting solution with cooling on an ice bath and then the resulting mixture was warmed up to room temperature. When completion of foaming was confirmed, the reaction solution was concentrated under a reduced pressure and subjected to azeotropic treatment with toluene twice. The thus obtained residue was dissolved in 8.4 ml of dichloromethane and, with cooling on an ice bath, the resulting solution was dropwise added to a solution obtained by dissolving 1.0 g of 5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 1.53 ml of triethylamine in 10 ml of dichloromethane. The reaction solution was warmed up to room temperature and the stirring was continued for 1 hour. The resulting reaction solution was mixed with water and subjected to phase separation to separate dichloromethane layer which was subsequently washed with 0.5N hydrochloric acid and a saturated sodium bicarbonate aqueous solution and dried over anhydrous magnesium sulfate. After removing the solvent by distillation, the thus obtained residue was crystallized from toluene to obtain 1.65 g of 1-(2'-methoxybiphen-4-ylcarbonyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine as crude crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([N:10](C)[CH3:11])=[CH:8][CH:7]=1.N#CBr>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[CH:4]=[CH:5][C:6]1[CH:14]=[CH:13][C:9]([NH:10][CH3:11])=[CH:8][CH:7]=1
Reactant: CN(C)c1ccc(/C=C/c2c(Cl)cccc2Cl)cc1
Agent: N#CBr
Product: CNc1ccc(C=Cc2c(Cl)cccc2Cl)cc1
Yield: 41 %

Procedure:
The procedure used to prepare 4 cc was repeated using 1 g (3.42 mmol) of 4y and 720 mg (6.84 mmol, 2 equiv) of cyanogen bromide to afford a product that was purified by chromatography (multiple times and each time using two developments) using 1:5 EtOAc-hexane to afford 390 mg (41%) of 4ee as a 9:1 E:Z-mixture of isomers that was a yellow oil. 1H NMR (DMSO-d6): δ 7.49 (d, 2H, J=8.4 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.24 (t, 1H, J=8.0 Hz), 6.99 (d, 1H, J=16.4 Hz), 6.82 (d, 1H, J=16.4 Hz), 6.55 (d, 2H, J=8.4 Hz), 6.01 (q, 1H, J=5.2 Hz), 2.70 (d, 3H, J=J5.2 Hz). 13C NMR (DMSO-d6): δ 150.45, 137.40, 134.69, 133.36, 128.86 (two C), 128.28, 127.97 (two C), 123.47, 116.09 (two C), 111.57 (two C), 29.50. HRMS (EI) Calcd for C15H13Cl2N, 277.0425. Found: 277.0425.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2CCc2ccccc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (25 mg, 0.53 mmol), (2-bromoethyl)benzene (7.5 μL, 0.056 mmol, 1.05 equiv), and potassium carbonate (14.7 mg, 0.106 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 9.0 mg (29%). Mass spec.: 576.5 (MH)+.