Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)([CH3:9])[CH2:4][C:5](OC)=[O:6].ClCCN(CCCl)C1C=CC(C)=C(C2CNC(=O)C2)C=1>C1(C)C=CC=CC=1>[NH2:16][C:12]1[CH:11]=[C:10]([C:3]2([CH3:9])[CH2:2][NH:1][C:5](=[O:6])[CH2:4]2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CC(C)(CN)c1cccc(N)c1
Agent: Cc1ccc(N(CCCl)CCCl)cc1C1CNC(=O)C1
Solvent: Cc1ccccc1
Product: CC1(c2cccc(N)c2)CNC(=O)C1
Temperature: 100 °C

Procedure:
In a second reaction of the same scale, under comparable conditions, and using comparable procedures, the initially isolated material consisted exclusively of the non-cyclized form (methyl 4-amino-3-(3-aminophenyl)-3-methyl-butanoate) MS (ESI+): m/z=223.20 (M+H)+. The crude material was dissolved/suspended in a sealed tube in toluene (about 25 mL) and heated to about 100° C. (oil bath temperature) for overnight to facilitate lactam formation (TLC reaction control). The organic solution was evaporated under reduced pressure using a rotary evaporator to afford a beige-brown waxy solid that was further purified by silica gel column chromatography using mixtures of dichloromethane (DCM) and methanol (MeOH) as eluent (DCM/MeOH=95:5→93:7) to afford the title compound (4c) as a beige solid. The analytical data corresponded to the proposed structure and was identical to that obtained from the direct lactamization method.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[CH2:8]([O:15][CH2:16][C:17](Cl)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][CH2:16][C:17]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CNCCN(C)C
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N,N,N′-Trimethylethylenediamine (99, 0.17 mL, 1.308 mmol) was dissolved in 5 mL of dichloromethane and cooled to 0° C. in an ice-water bath. 2-Benzyloxyacetyl chloride (100, 0.2 mL, 1.267 mmol) was added to the above solution dropwise and the mixture was allowed to warm to room temperature. After overnight, the reaction was complete and the mixture was concentrated and used in the next step without purification as HCl salt: 1H NMR (400 MHz, CDCl3): δ 2.86 (s, 3H), 2.87 (s, 3H), 3.09 (s, 3H), 3.16 (q, J=5.5, 2H), 3.85 (t, J=6.6, 2H), 4.24 (s, 2H), 4.63 (s, 2H), 7.30-7.39 (m, 5H).
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[NH:8][C:7]2[NH:9][CH:10]=[C:11]([CH2:12][CH2:13][C:14]3[CH:31]=[CH:30][C:17]([C:18]([NH:20][C@H:21]([C:27]([O-:29])=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:16][CH:15]=3)[C:6]=2[C:5](=[O:32])[N:4]=1.[OH-].[Na+].[CH2:35]([OH:46])[C@H:36]([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][OH:45])[OH:43])[OH:41])[OH:39])[OH:37]>O>[Na+:1].[Na+:1].[NH2:2][C:3]1[NH:8][C:7]2[NH:9][CH:10]=[C:11]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:27]([O-:29])=[O:28])[CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[O:19])=[CH:30][CH:31]=3)[C:6]=2[C:5](=[O:32])[N:4]=1.[CH2:44]([OH:45])[C@H:42]([C@H:40]([C@@H:38]([C@@H:36]([CH2:35][OH:46])[OH:37])[OH:39])[OH:41])[OH:43]
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)[O-])cc3)c[nH]c2[nH]1
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
5 grams of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid monosodium salt (purity 99.7% by HPLC) are dissolved in 1 L of distilled water and 5.563 ml of a 2.0 M solution of sodium hydroxide is added to the solution. Mannitol (10 g) is then added to the solution and dissolved. The solution is then filtered through a bacterial filter and dried in a freeze-drier to afford the title compound as a white solid in mixture with mannitol (15.2 g, purity 99.7% area by HPLC).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5](NC(N)=O)=[CH:4][C:3]=1[OH:12].N.Cl.Cl.C[C:17]1[CH:22]=[C:21]([NH2:23])[C:20](OC)=[CH:19][C:18]=1[NH2:26].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.C(O)(C)C>[CH:7]1[C:6](=[N:26][C:18]2[CH:17]=[CH:22][C:21]([NH2:23])=[CH:20][CH:19]=2)[CH:5]=[CH:4][C:3](=[O:12])[CH:2]=1
Reactant: COc1cc(N)c(C)cc1N
Reactant: Cc1ccc(NC(N)=O)cc1O
Agent: Cl
Agent: N
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Temperature: 0 °C
Yield: 121.1 %

Procedure:
There is dissolved 0.5 mole (83 g) of 2-methyl-5-ureido phenol into two liters of isopropyl alcohol to which have been added six liters of ice water and two liters of ammonia (22° Be). To this solution there is added 0.5 mole (112.5 g) of 2-methyl-5-methoxy paraphenylene diamine dihydrochloride in 800 cc of water. Then little by little, and with agitation there is added 1 mole (228 g) of ammonium persulfate in 400 cc of water. The reaction mixture is then filtered to recover the above benzoquinone imine which is then washed with water, yielding 120 g of crude indoaniline. After recrystallizing the same in a mixture of dimethylformamide and water and drying the same in a vacuum at ambient temperature, the resulting product melts with decomposition at 248° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][N:31]3[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=2)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[CH3:7][N:6]([CH3:8])[C:5]1[CH:9]=[CH:10][C:2]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][N:31]3[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:39])[CH3:40])=[CH:27][CH:26]=2)=[CH:3][CH:4]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(N(C)C)cc3)ccc12
Yield: 17.3 %

Procedure:
785 mg of 4-bromo-N,N-dimethylaniline, 646 mg of sodium carbonate, 10 cm3 of water and 196 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 56, in 50 cm3 of dioxane. The medium is then refluxed for 18 hours, the resulting mixture is then allowed to return to room temperature and 75 cm3 of ethyl acetate and 75 cm3 of water are added. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.) to give 1.6 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 170 mg of N-[6-[4-(dimethylamino)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].CCO.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](B(O)O)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[N:37][CH:38]=1)[C:8](=[O:11])[O:9][CH3:10]
Reactant: OB(O)c1cncc2ccccc12
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cncc2ccccc12
Temperature: 97.5 °C

Procedure:
To a solution of methyl [3,5-bis(trifluoromethyl)benzyl](2-iodo-5-trifluoromethyl-benzyl)carbamate (41 mg, 0.070 mmol) (Example 5) in 3:2 EtOH:toluene, 4-isoquinolineboronic acid (18.2 mg, 0.105 mmol) and 2.5 M sodium carbonate (0.175 mmol) were added. The solution was degassed, followed by the addition of a catalytic amount of tetrakis(triphenylphosphine)palladium. The solution was stirred at 95-100° C. until completion of the reaction. Upon cooling, the solvent was removed in vacuo. The desired product was obtained by preparative thin layer chromatography using 25% acetone/hexane. 1H NMR (CDCl3, 500 MHz) δ 9.36 (s, 1H), 8.38 (s, 1H), 8.10-8.13 (m, 1H), 7.68-7.80 (m, 4H), 7.26-7.64 (m, 5H), 4.22-4.48 (m, 4H), 3.64-3.78 (m, 3H). LC-MS (M+1) 587.2 (3.48 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[F:23])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.CCOC(C)=O.[CH3:33][NH:34][CH3:35]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[F:23])[CH2:10][N:34]([CH3:35])[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cccc(Cl)c1F
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
A solution of methanesulfonic acid (S)-2-tert-butoxycarbonylamino-2-(3-chloro-2-fluoro-phenyl)-ethyl ester (690 mg, 1.88 mmol) in 33% dimethylamine in EtOH (5.6 M, 7.5 mL, 42 mmol) was heated at 80° C. for 2 h in a sealed tube. The reaction mixture was concentrated and the crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give a pale yellow oil. TLC, Rf (EtOAc): 0.60; MS (UPLC/MS): 317.3/319.3 [M+H]+; tR (HPLC conditions a): 3.19 min.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(O)C>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCN1CCCCC1
Reactant: Clc1nc2ccccc2s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc2sc(NCCN3CCCCC3)nc2c1

Procedure:
2-Chlorobenzothiazole (10 mmol), 10 mmol of 2-piperidinoethanamine, and 30 mmol of triethylamine in 50 ml of dry ethanol were refluxed for 6 hours. The product was crystallized with hydrochloric acid in 2-propanol and recrystallized in methanol.
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:19]1[N:20]=[C:21]2[CH:29]=[CH:28][N:27]=[CH:26][C:22]2=[N:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:24]1[N:23]=[C:22]2[CH:26]=[N:27][CH:28]=[CH:29][C:21]2=[N:20][C:19]=1[N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[F:2])[CH2:11][CH2:10]1
Reactant: COc1ccc(OC2CCNCC2)c(F)c1
Reactant: Clc1nc2ccncc2nc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (144 mg, 0.550 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol) and DIPEA (260 μL, 1.500 mmol) in DCM (1.0 mL) was stirred at room temperature for 30 min. The mixture was then partitioned between EtOAc and saturated aqueous NH4Cl. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in EtOAc and filtered through a silica pad. The filtrate was concentrated to afford the crude title compound (200.7 mg, 100%) as a yellow oil, which was used without further purification. ESI-MS m/z [M+F]+ 389.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].Cl.[CH:15]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:17]([NH2:26])([CH2:18][CH2:19]3)[CH2:16]1)[CH2:23]2.N1C=CC=CC=1>O>[CH:15]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:17]([NH:26][C:11]([C:2]4[CH:3]=[N:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[O:12])([CH2:18][CH2:19]3)[CH2:16]1)[CH2:23]2
Reactant: NC12CCC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC12CCC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Yield: 57 %

Procedure:
Prepared from 2-quinoxaloyl chloride (135 mg, 0.70 mmol), tricyclo[4.3.1.1(3,8)]undec-3-ylamine hydrochloride (100 mg, 0.60 mmol), pyridine (5 mL), and water (50 mL) yielding 110 mg (57%) of (168):
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[C:10]2[C:11](=[O:23])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][O:14][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1>C1COCC1>[CH3:25][O:24][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[C:10]2[C:11](=[O:23])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][O:14][C:9]=2[CH:8]=1
Reactant: COc1ccc(-c2coc3cc(OC)cc(F)c3c2=O)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2coc3cc(OC)cc(SC)c3c2=O)cc1
Yield: 87.2 %

Procedure:
Sodium thiomethoxide (600 mg) was added to a solution of 5-fluoro-7-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-1-benzopyran (325 mg) in THF (10 mL). The mixture was refluxed for 1 h and cooled. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over MgSO4. Purification by chromatography on silica gel (eluant: ethyl acetate-chloroform, gradient from 0:100 to 5:95) gave the title compound (310 mg) as a pale yellow solid. 1H NMR (CDCl3): 7.81 (s, 1H), 7.50 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=8.7 Hz), 6.67 (d, 1H, J=2.1 Hz), 6.59 (d, 1H, J=2.1 Hz), 3.91 (s, 3H), 3.83 (s, 3H); MS: 329 (MH+); HPLC tR: 2.68 min.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])C=1C(O)=O.CN(C)C=O>ClCCl>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(C(F)(F)F)c1C(=O)Cl
Temperature: 25 °C

Procedure:
Oxalyl chloride (3 mL, 34.27 mmol) was added dropwise to a mixture of 2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6.81 mmol) (prepared according to known method, see: EP0897904B1), N,N-dimethylformamide (0.3 mL), and dichloromethane (40 mL) with stirring at rt. The reaction mixture was stirred overnight. Evaporation of solvent and excess oxalyl chloride and drying under vacuum afforded 2-methoxy-6-(trifluoromethyl)benzoyl chloride as a solid, which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH2:5][OH:6].[OH-].[K+].I[CH3:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][O:6][CH3:21])[CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13]
Reactant: CI
Reactant: C#CCOc1cc(CO)cc(Cl)c1OCC#C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCOc1cc(COC)cc(Cl)c1OCC#C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 3-chloro-4,5-dipropargyloxybenzyl alcohol (1.00 g), potassium hydroxide (1.00 g), iodomethane (1.00 g) and tetra-n-butylammonium bromide (1.00 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 2 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene as an eluent to give 1-chloro-5-methoxymethyl-2,3-dipropargyloxybenzene (0.95 g). nD23.0 1.5450.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.C1(O)CCC1>>[CH:4]1([O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:2][CH2:3][CH2:1]1
Reactant: Nc1cc(OCC2CC2)ncn1
Agent: OC1CCC1
Product: Nc1cc(OC2CCC2)ncn1
Yield: 91 %

Procedure:
This was prepared in a manner analogous to 6-(cyclopropylmethoxy)pyrimidin-4-amine, where cyclobutanol was used as the alcohol. 6-cyclobutoxypyrimidin-4-amine (0.231 g, 1.398 mmol, 91% yield) was obtained as a white solid. m/z (ESI) 166.2 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][NH3+:6].[Cl-].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[C:32]([NH:51][C:52]1[CH:56]=[C:55]([C:57](=O)[C:58]([O:60][CH3:61])=[O:59])[O:54][N:53]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CO>[C:32]([NH:51][C:52]1[CH:56]=[C:55]([C:57](=[N:6][O:5][CH3:4])[C:58]([O:60][CH3:61])=[O:59])[O:54][N:53]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CO[NH3+]
Reactant: COC(=O)C(=O)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)no1
Agent: C[O-]
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Cl-]
Solvent: CO
Product: CON=C(C(=O)OC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)no1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
A solution of sodium methoxide in methanol is added at room temperature, until a pink color persists, to 10.3 mg. (0.12 mmol) of o-methylhydroxylamine hydrochloride in dry MeOH containing a few crystals of phenolphthalein and 3 A molecular sieves. Methyl 2-(3-tritylamino-5-isoxazolyl)-2-ketoacetate (17.8 mg., 0.04 mmol) is then added and the reaction stirred at 65° C. for 5 hours. The sieves are removed by filtration and the filtrate concentrated to dryness under reduced pressure. After chromatography on silica gel (60-200 mesh) using 5:2 hexane:EtOAc as an eluent the title compound is isolated as a mixture of syn- and anti-methyloximes (13.7 mg., 72%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C([Mg]Br)C.[CH3:13][C:14]1([CH3:23])[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[O:22])[CH2:15]1.C(OCC)(=O)C>C1COCC1>[CH3:20][C:18]1([CH3:21])[CH2:19][C:14]([CH3:23])([CH3:13])[CH2:15][C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)([OH:22])[CH2:17]1
Reactant: C#Cc1ccccn1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC(C)(C)CC(O)(C#Cc2ccccn2)C1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
To a solution of 2-ethynylpyridine (1.0 g, 10 mmol) in TBF at −78° C. was added a 1.0 M solution of ethyl magnesium bromide in THF (10 mL, 10 mmol). After stirring at reduced temperature for 30 minutes a solution of 3,3,5,5-tetramethyl-cyclohexanone (1.5 g, 10 mmol) in THF was added rapidly. The mixture was allowed to warm to ambient temperature over 16 hours, then partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The resultant product was purified by flash column chromatography on silica gel eluting with 1:1 hexane:ethyl acetate to afford 3,3,5,5-tetramethyl-1-(2-pyridinylethynyl)cyclohexanol (250 mg, 10% yield) as a white solid. M.p. 126-127° C. 1H NMR (DMSO-d6, 300 MHz) Δ8.57 (m, 1H), 7.64 (m, 1H), 7.39 (d, J=5 Hz, 1H), 7.22 (m, 1H), 1.91 (d, J=9 Hz, 2H), 1.71 (d, J=9 Hz, 2H), 1.26 (s, 2H), 1.14 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccccc1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)CO[SiH2]c1ccc(-c2ccccc2)cc1
Yield: 61 %

Procedure:
A mixture of the 4-(diallylethoxysilyl)bromobenzene (152 mg, 0.49 mmol) obtained in Example 1, Pd(PPh3)4 (16.9 mg, 0.015 mmol), K2CO3 (101 mg, 0.73 mmol), and phenyl boronic acid (71.4 mg, 0.59 mmol) was added with dist.toluene (5 mL). Subsequently, the resultant mixture was stirred under a nitrogen atmosphere at 80° C. for 13 hours to obtain a reaction mixture. Thereafter, a salt formed in the reaction mixture was removed by filtering with celite. The solvent was distilled from the organic layer with an evaporator to obtain a crude product. After that, the crude product thus obtained was separated and purified by silica gel column chromatography (hexane/EtOAc=10/1), and thereby 4-(diallylethoxysilyl)biphenyl was obtained (91.2 mg, 61% yield).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Cl.O>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:12][O:3][CH2:2][CH2:1][OH:4])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(CCl)c1
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(COCCO)c1
Temperature: 60 °C
Yield: 41.7 %

Procedure:
Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol, 95% in oil) in THF (3 mL) (caution: exotherm). m-Methoxybenzyl chloride (0.21 mL, 1.5 mmol) was added to the reaction, and the residual m-methoxybenzyl chloride was transferred to the reaction tube with additional THF (1 mL). (Bu)4NI (55 mg, 0.15 mmol) was then added, and the reaction was heated at 60° C. for 18 h and then cooled to room temperature for 4 h. H2O (2 mL) and EtOAc (2 mL) were added, and the layers were separated via pipette. The aqueous layer was extracted with EtOAc (1×1 mL), and the combined organic layers were concentrated. The crude product was purified on a Biotage 12+M cartridge (8 g silica) eluting with 30% EtOAc/hexanes at 5 mL/min to give the title compound (114 mg, 42%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:45]=[CH:44][C:43]([C:46](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:47])=[CH:42][CH:41]=3)[N:30]=2)=[CH:20][CH:19]=1>>[ClH:15].[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([N:4]4[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][N:9]5[CH2:10][CH2:11][O:12][CH2:13][CH2:14]5)[CH2:6][CH2:5]4)=[O:47])=[CH:42][CH:41]=3)[N:30]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: C1CN(CCN2CCOCC2)CCN1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCN5CCOCC5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A2 and 4-(2-piperazin-1-yl-ethyl)-morpholine as described for compound 8. M.p. 271° C. (decomposes).