Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][C:13]([OH:15])=[O:14])[CH2:3]1.[Mn]([O-])(=O)(=O)=[O:17].[K+]>O.[OH-].[Na+]>[C:13]([CH2:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:11][C:2](=[O:1])[C:3]1=[O:17])([OH:15])=[O:14]
Reactant: O=C(O)CN1CC(=O)Nc2ccccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a solution of 3.0 g (15 mmol) 1,2,3,4-tetrahydro-3-oxo-quinoxaline-1-acetic acid in 50 ml water was added gradually a solution of 4.0 g (25 mmol) potassium permanganate in aqueous sodium hydroxide (4%, w/v) and the mixture was refIuxed for 4 h. The reaction mixture was cooled, filtered and the filtrate acidified with concentrated hydrochloric acid to pH 2.5. The precipitate was filtered off and washed with water to give 2.2 g (69%) 1-carboxymethylquinoxaline-2,3(1H,4H)- dione. M.p. >300° C. 1H-NMR (DMSO-d6): 12.0 (1 H, broad s), 7.2 (4H, s), 7.0-5.0 (1 H, broad s), 4.9 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[NH2:15][C:16]1[N:21]=[C:20](Cl)[C:19]([C:23]#[N:24])=[C:18]([CH3:25])[N:17]=1.CCN(C(C)C)C(C)C>C(#N)C>[NH2:15][C:16]1[N:21]=[C:20]([NH:10][C@H:8]([C:7]2[N:6]=[C:5]3[CH:11]=[CH:12][N:13]([CH3:14])[C:4]3=[CH:3][C:2]=2[Br:1])[CH3:9])[C:19]([C:23]#[N:24])=[C:18]([CH3:25])[N:17]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2Br)c1C#N
Temperature: 75 °C
Yield: 93.8 %

Procedure:
A microwave vial was charged with (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (2 g, 7.87 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (1.592 g, 9.44 mmol), acetonitrile (40 mL), and DIPEA (5.50 mL, 31.5 mmol). The reaction mixture was heated to 75° C. for 1 hour in an oil bath and then cooled to room temperature. A precipitate was isolated by vacuum filtration and washed with acetonitrile to give the title compound as an off-white solid (2.85 g, 94%). ESI-MS m/z [M+H]+ calc'd for C16H16BrN7, 386. found 386.
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:18]/[C:19](/[CH3:25])=[CH:20]/C(OC)=O>>[CH:1]1([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:15])=[CH:20]/[C:19](=[O:18])[CH3:25])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C2CCCCCC2)cc1
Reactant: COC(=O)/C=C(\C)OC
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCCC2)cc1
Yield: 28 %

Procedure:
(E)-4-(4-cycloheptyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 4'-cycloheptyl-acetophenone (b.p. 120°-125°C at 0.03 mm Hg) and methyl (E)-3-methoxy-crotonate with a yield of 28% of theory. B.p. 132°-135°C at 0.1 mm Hg.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH2:4].[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH2:4].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: Nc1ccc2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-Boc-Dap-2-AQ (11, 68.0 mg, 0.16 mmol) in CH2Cl2 (4 mL) that was stirring at 0° C. under argon was added trifluoroacetic acid (TFA, 2 mL), and stirring was continued for 2 h with warming to rt. The solvent was removed under vacuum, toluene being used to form an azeotrope with the remaining TFA. The residue, a yellow oil, was allowed to stand under diethyl ether for 1 h. Removal of the ether left a yellowish oily solid to which hexane was added and removed under vacuum until a constant weight was reached (99.4 mg; quantitative), and this material was used immediately in the next reaction.
Reaction SMILES: [CH2:1]([C:3]1([C:12]2[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=2)[O:15][C:16]2[CH:23]=[C:22]([C:24]([C:26]3[N:27]([CH3:31])[CH:28]=[N:29][CH:30]=3)=[O:25])[CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])[CH3:2].[CH3:35][Mg+].[Br-]>C1COCC1>[CH2:1]([C:3]1([C:12]2[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=2)[O:15][C:16]2[CH:23]=[C:22]([C:24]([OH:25])([C:26]3[N:27]([CH3:31])[CH:28]=[N:29][CH:30]=3)[CH3:35])[CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])[CH3:2]
Reactant: CCC1(c2cccc(Oc3cc(C(=O)c4cncn4C)ccc3C#N)c2)CCCCN(C)C1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC1(c2cccc(Oc3cc(C(C)(O)c4cncn4C)ccc3C#N)c2)CCCCN(C)C1=O
Temperature: 25 °C

Procedure:
2-[3-(3-Ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(3-methyl-3H-imidazole-4-carbonyl)-benzonitrile (Example 19) (0.216 g, 0.473 mmol) was dissolved in anhydrous THF (10 mL) and a 3.0 M solution of MeMgBr (1.10 mL, 3.30 mmol) was added and stirred at RT. The reaction was quenched with NH4Cl after 1 h, concentrated, diluted with EtOAc, washed with satd. NaHCO3 solution, water, brine, dried (MgSO4), concentrated and purified using SiO2 chromatography (1-3% MeOH/CH2Cl2 w/NH4OH) to give the title compound. FT/ICR MS (M+1)=473.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[C:34]2([CH2:36][CH2:35]2)[CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:32]2[CH2:31][C@@H:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:34]3([CH2:35][CH2:36]3)[CH2:33]2)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Solvent: CS(C)=O
Product: Cc1c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 20.0 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, 28.9 g of (S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane ([α]D20 -47.2° (c=1, MeOH)) and 80 ml of dimethyl sulfoxide was heated at 100° C. for 36 hours. The reaction mixture was poured into 500 ml of ice water. The deposited crystals were collected by filtration, washed with water and isopropanol, and then recrystallized from a mixture of methylene chloride and methanol to give 14.7 g of the desired compound, which was identified as the compound of Example 19.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)C.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>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(CNS(C)(=O)=O)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
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(-c2ccc(C(C)CNS(C)(=O)=O)cc2)cc1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
To a degassed solution of 1.4 g (4.7 mmol) of the product of Example 1, 1.0 g (7.1 mmol) of 4-methylbenzeneboronic acid, 1.0 g (7.1 mmol) of potassium carbonate in 30 mL of toluene, and 10 mL of water was added 0.3 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 2 hr, cooled to ambient temperature and the organic portion was separated. The aqueous portion was extracted three times with ethyl acetate and the combined organic portions were dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (30% ethyl acetate/hexane) to afford an off-white solid. The solid was suspended in diethyl ether, filtered and dried in vacuo to afford 0.6 g (43%) of the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=1.[C:13](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:12])[CH3:13])=[CH:9][N:10]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=Cc1cnc(C2OCCO2)s1
Solvent: C1CCOC1
Product: CC(O)c1cnc(C2OCCO2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole-5-carbaldehyde (2.25 g) in tetrahydrofuran (20 mL) was slowly added a 1.13M methyllithium diethyl ether solution (12.0 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.96 g, yield 80%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). MS: 202 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N:9][C:8]1[C:7]([C:6]=2[NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22][CH2:23]2)=[N:15][C:14]([O:16][CH3:17])=[CH:13][CH:12]=1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Reactant: CCN1CCC(N)CC1
Product: CCN1CCC(Nc2c3ccc(Cl)cc3nc3ccc(OC)nc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 7,10-dichloro-2-methoxypyrido[3,2-b]quinoline and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=371). 1H NMR (DMSO-d6, 400 Hz): 8.43-8.42 (d, 1H, J=9.2 Hz), 8.11-8.10 (d, 1H, J=9.2 Hz), 7.84 (s, 1H), 7.37-7.35 (d, 1H, J=9.2 Hz) 7.25-7.23 (d, 1H, J=9.2 Hz), 6.95 (b, 1H), 4.98 (b, 1H), 4.00 (s, 3H), 2.85 (b, 2H), 2.30 (b, 2H), 2.02-1.99 (m 4H), 1.00-1.97 (t, 3H, J=7.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[CH:15]([NH:17][NH:18][CH:19]=O)=O>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH:19]=[N:18][N:17]=[CH:15]2)=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=CNNC=O
Product: O=[N+]([O-])c1ccc(-n2cnnc2)cc1C(F)(F)F

Procedure:
The following compound m.p. 100°, was prepared similarly to the previous Preparation using 4-nitro-3-trifluoromethylaniline and 1,2-diformylhydrazine as the starting materials: ##STR126##
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:68][C:67]([C:69]([O:71][CH3:72])=[O:70])=[CH:66][CH:65]=1>>[CH3:72][O:71][C:69]([C:67]1[S:68][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)=[O:70]
Reactant: COC(=O)c1ccc(N)s1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)s1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with methyl 5-aminothiophene-2-carboxylate (PrincetonBio) (0.084 g, 0.53 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-thiophene-2-carboxylic acid methyl ester as a off white solid (Yield 0.05 g, 19%).
Reaction SMILES: ClC1C=CC(C2C3C=CC(N)=NC=3C3C(C)=NOC=3C[N:14]=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]3[C:49](F)=[N:48][CH:47]=[CH:46][C:33]=3[C:34]3[C:44]([CH3:45])=[N:43][O:42][C:35]=3[C@H:36]([CH2:38][C:39]([NH2:41])=[O:40])[N:37]=2)=[CH:27][CH:26]=1.ClC1C=CC2C(C3C=CC(Cl)=CC=3)=NCC3ON=C(C)C=3C=2N=1>CS(C)=O.CCO>[NH2:14][C:49]1[C:32]2[C:31]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)=[N:37][C@@H:36]([CH2:38][C:39]([NH2:41])=[O:40])[C:35]3[O:42][N:43]=[C:44]([CH3:45])[C:34]=3[C:33]=2[CH:46]=[CH:47][N:48]=1
Reactant: Cc1noc2c1-c1nc(N)ccc1C(c1ccc(Cl)cc1)=NC2
Reactant: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=O
Agent: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1noc2c1-c1ccnc(N)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=O

Procedure:
A procedure similar to 5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2-amine was followed, except that a solution of 2-((4S)-6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetamide in DMSO was used instead of a solution of 2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine in EtOH. LC/MS m/z 382 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=5.19 Hz, 1H), 7.67 (br. s, 1H), 7.38 (td, J=2.30, 8.70 Hz, 2H), 7.33 (td, J=2.30, 8.70 Hz, 2H), 7.04 (br. s, 1H), 6.95 (d, J=5.19 Hz, 1H), 5.89 (br. s, 2H), 4.40 (dd, J=6.54, 8.00 Hz, 1H), 3.27 (dd, J=8.00 Hz, 15.60, 1H), 3.11 (dd, J=6.65, 15.58 Hz, 1H), 2.49 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(C)(C)C.C(N(CC)CC)C.ClCC(Cl)=O.[H-].[Na+].[C:32]([OH:38])([C:34](F)(F)F)=O>C(Cl)Cl.C1COCC1>[O:14]1[CH2:15][CH2:16][CH:11]([N:10]2[CH2:9][CH2:8][NH:7][CH2:34][C:32]2=[O:38])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCCNC1CCOCC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CNCCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a solution of [2-(tetrahydro-pyran-4-ylamino)-ethyl]-carbamic acid tert-butyl ester (6.60 g, 27.0 mmol) in DCM (100 mL) was added triethylamine (11.3 mL, 81.1 mmol) followed by chloroacetyl chloride (3.64 g, 32.4 mmol) dropwise. The reaction mixture was stirred at RT for 24 h, then partitioned between DCM and saturated NaHCO3 aqueous solution. The organic layer was isolated, dried (Na2SO4) and concentrated in vacuo. To a solution of the resulting residue in THF (50 mL) was added sodium hydride (60% in mineral oil) (1.62 g, 40.6 mmol). The reaction mixture was stirred at RT for 20 h, then partitioned between DCM and water. The organic layer was dried (Na2SO4) and concentrated in vacuo to yield an orange residue. The residue (7.66 g, 27.0 mmol) was dissolved in dichloromethane (15 mL) and TFA (15 mL) was added. The resulting solution was stirred at RT for 4 h before being concentrated in vacuo. The resultant residue was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as yellow oil (4.26 g, 86%).
Reaction SMILES: [OH-:1].[K+].C1(C)C=CC=CC=1.[O:10]([C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19]([C:23]#[N:24])=[N:20][O:21][CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O>[O:10]([C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19](=[N:20][O:21][CH3:22])[C:23]([NH2:24])=[O:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: CON=C(C#N)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 90275.7 %

Procedure:
85% Potassium hydroxide (1.19 g, 0.018 mol) and toluene (30 ml) were added to 2-phenoxy-α-methoxyiminobenzyl cyanide (E/Z=7/93)(3.78 g, 0.015 mmol). The mixture was stirred at 80° C. for 2.5 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with conc. hydrochloric acid, extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (3.66 g, Yield: 90.3%, E/Z=6/94).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[C:16]1(C)C=CC=C[CH:17]=1>FC(F)(F)C(O)=O.CC(OC)(C)C>[CH2:8]([CH:9]1[CH2:10][CH2:5][CH:3]=[CH:2][O:1]1)[CH2:7][CH:6]=[CH:16][CH3:17]
Reactant: Cc1ccccc1
Reactant: O=C(CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC=CCCC1CCC=CO1
Temperature: 50 °C

Procedure:
The cyclic vinyl ether (2 eq.) was added to a suspension of the hydroxy-acetophenone (10 mmol) in toluene (10 ml), followed by trifluoroacetic acid (2 or 3 drops, ˜0.01 eq.). The mixture was heated at 50° C. When the reaction was complete (TLC, 2-3 hours), it was diluted with MTBE and poured into aq. NaHCO3 (sat.). The aqueous phase was separated and extracted with MTBE, and the combined organic layers were washed with brine and dried over MgSO4. The crude, obtained after evaporation of the solvents, was purified by chromatography (SiO2, EtOAc/Hexane) to afford the desired product as a colorless to pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N-:16]=[N+]=[N-].[Na+].O>CS(C)=O>[CH:7]12[CH2:8][CH:4]([CH2:5][CH2:6]1)[C:3]1[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:16][C:2]2=1
Reactant: CCOC(=O)/C=C/C1=C(Cl)C2CCC1C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c([nH]1)C1CCC2C1
Temperature: 105 °C
Yield: 59.8 %

Procedure:
To a solution of 167b (5.0 g, 22 mmol) in DMSO (30 mL) was added NaN3 (2.2 g, 33 mmol). The mixture was heated at 105° C. for 6 hours. Water (13 mL) was added to the reaction mixture after cooling down to room temperature and the resulting mixture was extracted with methylene chloride (3×50 mL). The combined organic phase was dried over Na2SO4 and evaporated under reduced pressure to dryness. The residue was purified by silica-gel column chromatography eluting with 20:1 methylene chloride/methanol to afford 167c as a brown solid (2.7 g, 60%). MS: [M+H]+ 206. 1H NMR (500 MHz, CDCl3) δ 11.51 (s, 1H), 6.45 (s, 1H), 4.16 (q, J=6.5 Hz, 2H), 3.26-3.24 (m, 2H), 1.82-1.79 (m, 2H), 1.74-1.72 (m, 2H), 1.24 (t, J=6.5 Hz, 3H), 0.91-0.89 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][S:22][C:23]1[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][N:24]=1.[NH4+].[Cl-]>C1COCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][CH:29]([OH:30])[C:27]1[CH:26]=[CH:25][N:24]=[C:23]([S:22][CH3:21])[N:28]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CSc1nccc(C=O)n1
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(C(O)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (5.7 mL, 40.5 mmol) in THF (130 mL) is added dropwise n-butyllithium (16.2 mL of a 2.5 M solution in hexanes, 40.5 mmol). The mixture is stirred for 45 min at 0° C., then the solution is cooled to −78° C. tert-Butyl acetate (5.5 mL, 40.5 mmol) is added dropwise to the reaction mixture. After stirring 40 min at −78° C., a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde (5.0 g, 32.4 mmol) is added dropwise. After 30 min at −78° C., the solution is poured into aqueous saturated NH4Cl. The aqueous phase is extracted with EtOAc. The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% EtOAc/hexanes, followed by 20% EtOAc/hexanes) to afford 7.2 g (82% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 5.00 (dd, J=8.4, 3.6 Hz, 1H), 2.93 (dd, J=16.5, 3.6 Hz, 1H), 2.70 (dd, J=16.5, 7.8 Hz, 1H), 2.58 (s, 3H), 1.46 (s, 9H); ESI+ MS: m/z (rel intensity) 271.1 (85, M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([N:12]1[CH2:17][CH2:16]/[C:15](=[N:3]\[N:2]([CH3:4])[CH3:1])/[CH:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)N
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Solvent: CCO
Product: CC1CN(Cc2ccccc2)CC/C1=N\N(C)C

Procedure:
N,N-dimethylhydrazine (3 ml, 39.3 mmol) and 1-benzyl-3-methyl-piperidin-4-one (4 g, 19.7 mmol) are dissolved in 50 ml of ethanol and refluxed for 18 hours. The reaction mixture is evaporated under reduced pressure and dried at high vacuum.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)([OH:25])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of magnesium (1.77 g) and iodine (0.81 g) in THF (60 mL) was added a solution of 1,4-dibromobenzene (8.94 mL) in THF (5 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., a solution of 1-benzylpiperidin-4-one (13.2 mL) in THF (5 mL) was slowly added dropwise thereto, and the reaction mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.19 g).
Reaction SMILES: C(O)C1C=CC=CC=1.C1([Sn](C2CCCCC2)(C2CCCCC2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]([OH:24])[CH3:23])CCCCC1.[Br:37]C1C=CC=CC=1CO>>[Br:37][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([OH:24])[CH3:23]
Reactant: OCc1ccccc1Br
Reactant: CC(O)c1ccccc1[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: OCc1ccccc1
Product: CC(O)c1ccccc1Br
Yield: 75.1 %

Procedure:
17.2 g of o-[tri(cyclohexyl)]tin]benzylalcohol was obtained in the same manner as in the synthesis of tricyclohexyl[o-(1-hydroxyethyl)phenyl]tin of Example 1-(4), with the exception that 9.40 g of o-bromobenzylalcohol (50.2 mmol), prepared in the aforementioned example (1), instead of o-bromo-1-phenyl ethanol (yield=75.1%).