Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([CH3:26])[CH3:25]
Reactant: N#Cc1cccc(N)c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N(c1cccc(C#N)c1)[Si](C)(C)C
Yield: 96.8 %

Procedure:
About 5.87 g of 3-aminobenzonitrile, 11.57 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 25.41 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 12 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 3-[bis(trimethylsilyl)amino]benzonitrile (3-BTMSABZN) as a brown oil (12.62 g, 97% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.00 (multiplet, 1H, aromatic proton), 6.81 (multiplet, 1H, aromatic proton), 6.67 (multiplet, 1H, aromatic proton), 6.59 (multiplet, 1H, aromatic proton), −0.10 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7]1.Cl>C1COCC1>[O:2]=[CH:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7]1
Reactant: COC(=O)c1cccc2ccn(CCC(OC)OC)c12
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cccc2ccn(CCC=O)c12
Yield: 20.7 %

Procedure:
A mixture of methyl 1-(3,3-dimethoxypropyl)-1H-indole-7-carboxylate (1.6 g, 5.8 mmol) from Step A above, 2 N HCl (15 mL) and THF (15 mL) were heated at reflux for 4 h. The reaction was quenched with solid sodium bicarbonate and adjusted to pH 8 and the aqueous phase was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 80:20 hexanes/ethyl acetate) to give methyl 1-(3-oxopropyl)-1H-indole-7-carboxylate (278 mg, 21%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.18 (d, J=3.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.57 (d, J=3.0 Hz, 1H), 4.72 (t, J=6.5 Hz, 2H), 3.96 (s, 3H), 2.99 (t, J=6.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[CH:10]([NH:13][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: Clc1cc(Cl)nc(Cl)n1
Product: CC(C)Nc1cc(Cl)nc(Cl)n1

Procedure:
400 (2.18 mols) of 2,4,6-trichloro-pyrimidine are dissolved in 2000 cc of alcohol. 280 g (4.75 mols) of isopropyl amine in 200 cc of alcohol are added to the solution while stirring and cooling, the temperature being maintained below 30°. The mixture is subsequently stirred at room temperature for a further 60 minutes and the alcohol is then removed by evaporation in a water jet vacuum until the mixture hardens to a solid mass. The solid residue is washed with water and subjected to steam distillation. This distillation is continued until only traces of the steam-volatile 2-isopropylamino-4,6-dichloro-pyrimidine are deposited in the receiver. The steam-nonvolatile 4-isopropylamino-2,6-dichloro-pyrimidine is obtained. After distillation in a vacuum (B.P. 124°/0.1 mm of Hg) the pure product, having a M.P. of 69°-70° after recrystallization from water/alcohol, is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:15]([C:14]3[CH:18]=[CH:19][C:11]([OH:10])=[CH:12][CH:13]=3)[O:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Nc1ccc(Br)cc1O
Product: Oc1ccc(-c2nc3ccc(Br)cc3o2)cc1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-hydroxybenzoic acid
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.Cl.Cl.[NH2:13][C:14]1([CH2:19][NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:13][C:14]1([CH2:19][NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[CH2:18][CH2:17][N:16]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([NH2:1])[N:3]=[CH:4][N:5]=2)[CH2:15]1
Reactant: NC1(CNC(=O)c2ccc(F)cc2F)CCNC1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1c(N)ncnc1N1CCC(N)(CNC(=O)c2ccc(F)cc2F)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (72.0 mg; 0.47 mmol; 1.02 eq.), N-[(3-aminopyrrolidin-3-yl)methyl]-2,4-difluorobenzamide dihydrochloride (150.0 mg; 0.46 mmol; 1.0 eq.), potassium carbonate (126.3 mg; 0.91 mmol; 2.0 eq.) in DMSO (2.00 ml) was stirred at 60° C. for 2 h. The reaction mixture was workup and the crude was purified by reverse phase pre-HPLC (Waters, acetonitrile/0.1% NH4OH in water) to afford the title compound in 70% yield. LC-MS: (M+1=374, obsd.=374).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH3:20].[OH-].[K+].C1COCC1>O>[NH:1]([C:8]1[N:13]=[C:12]([N:19]([CH3:20])[CH3:18])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#Cc1cc(Cl)nc(Nc2ccccc2)n1
Reactant: CNC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC#Cc1cc(N(C)C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
2-Anilino-4-chloro-6-(1-propynyl)pyrimidine (1.7 g) prepared in Example 2, 1.9 g of 54% aqueous solution of dimethylamine and 0.7 g of KOH were added to 20 ml of THF and the mixture was stirred at room temperature for 24 hours. The reaction liquid was poured in water and extracted with benzene. Then, the benzen layer was dried over Glauber's salt and concentrated, the residue was recrystallized from n-hexane-ethanol to afford 1.5 g of 2-anilino-4-dimethylamino-6-(1-propynyl)pyrimidine (yield: 85%). Melting point: 150°-152° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[CH3:11][O:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31]
Reactant: COCOCCCCCCCCCCCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCOCCCCCCCCCCCCCCCC=O
Reaction time: 0.17 h

Procedure:
To a solution of 1.23 ml of oxalyl chloride in 60 ml of dichloromethane was added dropwise at -78 ° C. a solution of 2.0 ml of dimethyl sulfoxide in 2 ml of dichloromethane. After stirring for 10 minutes, a solution of 2.13 g of 16-methoxymethoxyhexadecanol in 30 ml of dichloromethane was added dropwise and the mixture was allowed to slowly rise up to -20° C. and then stirred for 15 minutes. 5.9 ml of triethylamine was added and the mixture was stirred at 0° C. for one hour. To the reaction solution was added a saturated aqueous solution of ammonium chloride and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, distilled under reduced pressure and chromatographed over a silica gel column to afford the title compound as a colorless oily substance.
Reaction SMILES: C1(C2(C)COC(C)(C)C2)C=CC=CC=1.[CH3:15][C:16]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)([CH2:19][C:20]([CH3:22])=[CH2:21])[CH:17]=[O:18].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:15][C:16]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)([CH2:19][C:20]([CH3:22])=[CH2:21])[CH2:17][OH:18]
Reactant: C=C(C)CC(C)(C=O)c1ccc(C)cc1
Agent: CC1(C)CC(C)(c2ccccc2)CO1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C=C(C)CC(C)(CO)c1ccc(C)cc1
Yield: 94 %

Procedure:
Following the procedure of part (a) of Example I a 353.5 g sample of 2,4-dimethyl-2-(4-methylphenyl)-4-pentenal was reduced with 30 g of lithium aluminum hydride in 1100 ml of anhydrous ether. Usual workup and distillation afforded 335 g (94% yield) of the desired 2,4-dimethyl-2-(4-methylphenyl)-4-penten-1-ol (bp 136°-138° C./0.7 mm Hg) with a purity of 95%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(CO)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (68 mg, 82%), MS (ISP) m/z=332.5 [(M+H)+], mp 265° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[O:23][C:22]([CH3:24])=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)=[C:5]2[CH:18]=[N:17][NH:16][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:2].[OH-].[Li+].O.Cl>O1CCOCC1.O>[C:1]([C:3]1[C:4]([C:19]2[O:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=2)=[C:5]2[CH:18]=[N:17][NH:16][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:2]
Reactant: COC(=O)c1cc(-c2c(C#N)c(-c3ccc(O)cc3)nc3[nH]ncc23)oc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc(-c2c(C#N)c(-c3ccc(O)cc3)nc3[nH]ncc23)cc1C(=O)O
Reaction time: 5 h
Yield: 8.3 %

Procedure:
To a suspension of 0.066 g (0.10 mmol) of methyl 5-(5-cyano-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-2-methylfuran-3-carboxylate in 2 ml of dioxane/water (80:20) are added 0.011 g (0.4 mmol) of lithium hydroxide. The mixture is brought to 50° C. for 5 h. After return to room temperature, the mixture is poured onto 20 ml of iced water and adjusted to pH=1-2 with 0.1N hydrochloric acid solution. The solution is left to stand for 18 h at 4° C. The precipitate obtained is filtered. The residue obtained is purified by preparative reverse-phase HPLC (acetonitrile/water eluent) to yield 3 mg (6%) of 5-(5-cyano-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-4-yl)-2-methylfuran-3-carboxylic acid in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.ClCCl.ClC1C=C(C=CC=1)C(O)=O.[Br:25]Br>CC(C)=O>[Br:25][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)cc1

Procedure:
A 6.6 g. portion of p-chloropropiophenone is dissolved in 150 ml. of dichloromethane and 100 mg. of m-chlorobenzoic acid are added. The solution is stirred as a mixture of 6.0 g. of bromine in 50 ml. of dichloromethane is added dropwise. The solution is stirred for 2 hours, taken to dryness in vacuo and the oil is dissolved in 100 ml. of acetone and clarified, providing an acetone solution of 2-bromo-4'-chloropropiophenone. A 50 ml. portion of this acetone solution is added to a stirred solution of 3.0 g. of hexahydro-1,3-diazocine-2(1H)-thione in 500 ml. of acetone. The mixture is stirred for 18 hours, the solid is collected, washed with 100 ml. of acetone and dried in vacuo, giving 1.6 g. of the desired product, m.p. 212°-213° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]([F:19])([F:18])[C:5]([F:17])([F:16])[O:6][C:7]([F:15])([F:14])[CH2:8][O:9][CH2:10][CH2:11][CH2:12]Cl.BrCCCCl.[CH2:27]([O:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)=[N:38][CH:39]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH2:27]([O:33][C:34]1[CH:39]=[N:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:12][CH2:11][CH2:10][O:9][CH2:8][C:7]([O:6][C:5]([F:17])([F:16])[C:4]([F:19])([F:18])[O:3][C:2]([F:21])([F:20])[F:1])([F:15])[F:14])=[CH:44][CH:45]=2)=[N:36][CH:35]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCl
Agent: ClCCCBr
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (4.5 g, 11.7 mmol; prepared by combining 1-bromo-3-chloropropane with 3-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2-difluoroethanol) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 11.0 mmol). The resulting product was isolated by addition of water (50 mL) to the reaction mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by distillation using a Kugelrohr apparatus (b.p. 180-183° C. at 0.1 torr; yield of 3.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]2)[CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Br)cc1N1CCN(CCO)CC1
Temperature: 110 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a suspension of 4-bromo-2-fluorobenzaldehyde (281 μL, 2.37 mmol) and potassium carbonate (328 mg, 2.37 mmol) in 5 mL of dry N,N-dimethylformamide was added 4-(2-hydroxyethyl)piperazine (463 mg, 3.56 mmol) at room temperature. After being stirred at 110° C. for 12 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol=98/2 to 90/10) to obtain the title compound as a pale yellow powder (364 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:18].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1([CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][CH2:12]1)[CH2:6][C:5]2=[O:18]
Reactant: O=C1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC2(CCC(O)CC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24 %

Procedure:
In a 25 mL round bottom flask was placed 6-bromospiro[chroman-2,1′-cyclohexane]-4,4′-dione (240 mg, 0.779 mmol) and it was dissolved in THF (7.8 mL). To this solution was added NaBH4 (30 mg, 0.789 mmol) and the reaction was allowed to stir at room temperature for 5 minutes. At that time, TLC indicated total consumption of the diketone. The reaction was diluted with water (10 mL) and ethyl acetate (10 mL) and it was allowed to stir for 15 minutes. The phases were separated and the aqueous phase was back-extracted with ethyl acetate twice (5 mL/each). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). A 3:1 mixture of separable isomers formed. The less-polar product (judge by TLC) was cleanly separated by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate/hexanes as the eluents) and use for further development. The corresponding fractions for less-polar product were combined and concentrated under reduce pressure yielding one of the isomers of 6-bromo-4′-hydroxyspiro[chroman-2,1′-cyclohexan]-4-one (58 mg, 0.187 mmol, 24% yield).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:11][CH:10]=1)C=C.Cl[C:23]1[CH:28]=CC=C[CH:24]=1>>[CH2:28]([C:14]1[CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:11]=[CH:10][C:9]=1[OH:8])[CH:23]=[CH2:24]
Reactant: C=CCOc1ccc(-c2ccccc2C)cc1
Reactant: Clc1ccccc1
Agent: ClB(Cl)Cl
Product: C=CCc1cc(-c2ccccc2C)ccc1O
Reaction time: 1 h

Procedure:
To a stirred solution of BCl3 (1M in p-xylene; 6.7 mL, 6.7 mmol) in chlorobenzene at -15° C. was added the allyl ether from step B (1.48 g, 6.6 mmol) in 5 mL of chlorobenzene. After 1 h at -15° C., the mixture was poured into ice/MeOH, extracted with Et2O (3×), washed with saturated NaHCO3, water then brine. The dried solution was evaporated to give the title compound as an oil.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)C>CN(C=O)C>[I:1][C:2]1[N:3]=[CH:4][N:5]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: Ic1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a solution of 4-iodoimidazole (1 eq) in DMF at room temperature was added triphenylmethyl chloride (1.2 eq). After stirring at room temperature for 24 h, the solution was poured into ice water and left stirring for 30 min. The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether was added to the crude compound and the solution was filtered to yield 4-iodo-1-trityl-1H-imidazole (92%) as a white solid. MH+(437).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]3)[O:16][C:15]2=[O:26])[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][Si](C)(C)C.[OH-].[K+].Cl>CO>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]3)[O:16][C:15]2=[O:26])=[CH:3][C:2]=1[F:1])#[CH:9]
Reactant: Cc1cn(C[C@H]2CN(c3ccc(C#C[Si](C)(C)C)c(F)c3)C(=O)O2)nn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(N2C[C@H](Cn3cc(C)nn3)OC2=O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
(5R)-3-{3-Fluoro-4-[(trimethylsilyl)ethynyl]phenyl}-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Intermediate 10, 1.4 g, 3.76 mmol) was dissolved in methanol (10 ml) and cooled to 0° C. 1N potassium hydroxide aqueous solution (4 mL) was added and the mixture was stirred for one hour. 2M HCl (4 mLl) was added and the reaction mixture was stirred for 30 minutes. It was extracted with dichloromethane (30 mL), the organic phase was concentrated to dryness. The product was preciptitated from dichloromethane (10 mL) by the additon of hexanes (50 mL) to give the product as a colourless solid (0.91 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(Cl)(Cl)Cl>[CH2:28]([NH:32][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH3:31]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCCCN
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -15° C. during 15 minutes. After stirring for 5 minutes, 6.43 g (0.088 mol) of butylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -10° C. and -15° C. during 50 minutes. The reaction mixture is stirred for 1 hour at the same temperature and then let to stand under cooling by ice. For working up, the mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate and evaporated to give 14.9 g (71.8%) of the named product as yellow crystals, m.p.: 127°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].[NH4+].[OH-]>>[NH:1]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(C)nc(N[N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
2-Amino-4,6-dimethylpyridine (10.0 g, 81.8 mmol) was added portion-wise to 65 mL of H2SO4 (conc. d=1.84) which was stirred (mechanical) at 0° C. After complete addition, the mixture was warmed to room temperature until the mixture became homogeneous. The solution was then cooled to -10° C. and a pre-cooled (0° C.) mixture of conc HNO3 (11.5 mL, d=1.40) and H2SO4 (8.2 mL, d=1.84) was added at such a rate as not to raise the internal reaction temperature above -9° C. Ten minutes after the addition was complete this cooled (-10° C.) mixture was poured onto 400 g of crushed ice. The resulting slurry was neutralized by the addition of conc NH4OH (to pH 5.5) while cooling (ice bath). The solid was isolated by filtration, and dried at room temperature to give 13.3 g of the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1)#[N:2].[CH2:18](N)[CH2:19][NH2:20]>C(=S)=S>[NH:2]1[CH2:18][CH2:19][N:20]=[C:1]1[CH2:3][C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:6][CH:5]=1
Reactant: NCCN
Reactant: CS(=O)(=O)Nc1ccc(CC#N)c2ccoc12
Solvent: S=C=S
Product: CS(=O)(=O)Nc1ccc(CC2=NCCN2)c2ccoc12
Yield: 93.7 %

Procedure:
A mixture of N-(4-cyanomethyl-benzofuran-7-yl)-methanesulfonamide (1.0 g, 4.0 mmole), ethylene diamine (8 mL, 119.7 mmoles), and carbon disulfide (one drop) was microwaved at 140° C. for 30 minutes in a Smith creator™. The reaction mixture was transferred into a large beaker (1 L) and the reaction vessel was rinsed with methanol (5 mL). Ether (600 mL) was added to the reaction mixture and insoluble material settled at the bottom of the container. The ether solution was removed by decantation. The residue was purified by flash column chromatography over silica gel eluting with 8% methanol in dichloromethane with 0.1% concentrated ammonium hydroxide to give N-[4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-benzofuran-7-yl]-methanesulfonamide as a solid (1.1 g, 85%).