Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15](C3CCCCO3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:25][C:40]([C:36]4[O:35][CH:39]=[CH:38][CH:37]=4)=[O:41])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg) in DCM (1 ml) was added DIPEA (131 μl) followed by 2-furancarbonyl chloride (39 mg) (available from ABCR) and the mixture stirred at RT for 1 h, then the solvent was removed. To a mixture of the residue in methanol (2 ml) was added 4M hydrochloric acid in 1,4-dioxane (2 ml) and the mixture stirred at RT for 2 h. Purification of the residue by mass directed preparative HPLC (Method A), followed by freeze drying gave the title compound as an off white solid (13 mg).
Reaction SMILES: [B-](Cl)(Cl)(Cl)[S+](C)C.[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:43])[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35]CC2C=CC=CC=2)=[CH:31][CH:30]=1)[C:24]1[CH:28]=[CH:27][O:26][N:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:43])[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:24]1[CH:28]=[CH:27][O:26][N:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(C[C@@H](c1ccc(OCc2ccccc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[S+](C)[B-](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
Boron trichloride methyl sulfide complex (51 mL, 2.0 M solution in DCM) was added to 7.4 (8.2 g, 17 mmol) in DCM (100 mL) at 0° C. After addition, the ice bath was removed, and the mixture was stirred at room temperature for 7 hours. The mixture was cooled in an ice bath and quenched by adding saturated sodium bicarbonate until the mixture was neutralized. More DCM (400 mL) was added, and the organic layer was separated, washed with brine, dried, and concentrated under vacuum. The crude product (6.5 g) was dissolved in 50 mL of hot MeOH. After cooling, the crystallized product was collected by filtration and washed once with MeOH to give 7.5 (4.2 g). The filtrate was concentrated, and the solid that formed was collected and washed to give an additional 1.2 g of compound 7.5. MS ESI (pos.) m/e: 393 (M+H). 1H NMR (CDCl3) δ 8.29 (d, 1H), 7.30 (m, 3H), 7.20 (d, 2H), 7.15 (d, 2H), 6.95 (d, 2H), 6.14 (d, 1H), 4.71 (dd, 1H), 4.63 (m, 1H), 4.16 (d, 2H), 4.00 (dd, 1H), 3.54 (dd, 1H), 3.21 (dd, 1H), 2.76 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([N:34]=[C:35]=[S:36])[CH2:32][CH3:33]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:35]([NH:34][CH2:31][CH2:32][CH3:33])=[S:36])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Reactant: CCCN=C=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCNC(=S)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 32.5 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 652 mg (2 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.2 ml (1.8 mmol) of n-propyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. The crude product obtained after purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) was crystallized from ethyl acetate. 155 mg (33%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:14]Br.CO.O>C(O)(=O)C.Br>[Br:14][CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(=O)CBr)cc1
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
At 15° C., methyl 4-acetylbenzoate (2.23 g) was dissolved in a hydrobromic acid acetic acid solution (30%, 10 ml). Bromine was gradually added dropwise to the reaction mixture to maintain its temperature at 15° C. After stirring for 10 minutes, the reaction mixture was cooled to 4° C. A mixed solvent of methanol (50 ml) and water (50 ml) was added to the reaction mixture for crystallization, followed by washing with hexane. By the collection through filtration, the title compound (2.29 g, 71%) was obtained as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1>>[C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][O:1][C:2]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:22])#[N:32]
Reactant: Cc1ncc2c(c1O)COC(=O)N2Cc1ccc(C#N)cc1
Reactant: N#Cc1cccc(CBr)c1
Product: Cc1ncc2c(c1OCc1cccc(C#N)c1)COC(=O)N2Cc1ccc(C#N)cc1
Yield: 28 %

Procedure:
The coupling of 4-(5-hydroxy-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1-ylmethyl)-benzonitrile (82) (0.8 g, 2.8 mmol) and α-bromo-m-tolunitrile (5.9 g, 30 mmol), as described in Example 1, gave 4-[5-(3-cyano-benzyloxy)-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1ylmethyl]-benzonitrile (85) (322 mg, 28% yield) as.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[NH2:43][C:44]1[C:45]([Cl:55])=[CH:46][C:47](Br)=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1>C1(C)C=CC=CC=1.O.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>[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:47]3[CH:46]=[C:45]([Cl:55])[C:44]([NH2:43])=[CH:49][C:48]=3[C:50]([F:52])([F:53])[F:51])=[CH:31][CH:32]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1Cl
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: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(N)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (280 mg, 2.0 mmol) was added to a solution of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (200 mg, 0.40 mmol) and 5-amino-2-bromo-4-chlorobenzotrifluoride (110 mg, 0.40 mmol; Preparation 51) dissolved in toluene (1.3 mL) and water (0.43 mL). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.48 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. for 4 h. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce a red solid, which was purified by silica gel chromatography (0-100% ethyl acetate:hexanes) to produce the desired product as a yellow solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[CH2:11]([N:15]1[C:19]([C:20](=O)[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][C:17]([CH3:31])=[C:16]1[CH3:32])[CH:12]=[CH:13][CH3:14].[OH-].[Na+]>ClCCl>[CH2:11]([N:15]1[C:16]([CH3:32])=[C:17]([CH3:31])[C:18]([CH:8]=[O:9])=[C:19]1[C:20]([Cl:3])=[CH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:12]=[CH:13][CH3:14]
Reactant: CC=CCn1c(C(=O)CCc2ccc(F)cc2)cc(C)c1C
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC=CCn1c(C)c(C)c(C=O)c1C(Cl)=CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
0.38 ml (0.00408 mole) of phosphorus oxychloride was added to 0.29 g (0.00397 mole) of dry dimethylformamide and the mixture was stirred at room temperature for 30 minutes. A solution of 0.89g (0.00297 mole) of 1-(2-butenyl)-5-[3-(4-fluorophenyl)propionyl]-2,3-dimethylpyrrole in 4 ml of dichloromethane was added dropwise to the mixture and stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-water and neutralized with an aqueous solution of sodium hydroxide. The aqueous mixture was extracted with 50 ml each of dichloromethane for three times. The extract was washed with 30 ml of a saturated aqueous solution of sodium hydrogencarbonate and 30 ml of a saturated aqueous solution of sodium chloride in turn and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography through silica gel using a 1:12 to 1:9 mixture of ethyl acetate and hexane as an eluent to give 0.41 g of the title compound (cis/trans=22/78) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][N:24]2[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)=[N:25]2)=[N:18][CH:19]=1.O>CC(C)=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][O:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][N:24]2[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)=[N:25]2)=[N:18][CH:19]=1
Reactant: OCC(O)CCl
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC(O)CO)cn4)c3)n2)cn1
Temperature: 80 °C
Reaction time: 120 h

Procedure:
75 mg (0.68 mmol) of 3-chloro-1,2-propanediol and 322 mg (0.99 mmol) of caesium carbonate are added to 150 mg (0.41 mmol) of 2-[3-(5-hydroxy-pyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one, and the mixture is suspended in acetone. The reaction mixture is stirred at 80° C. for 5 days. Water is added to the reaction mixture, which is then extracted a number of times with ethyl acetate, dried over sodium sulfate and evaporated. The crude product is purified by means of column chromatography on silica gel.
Reaction SMILES: [CH3:1][C:2]([C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)=[O:3].Cl.[CH3:17][NH:18][CH3:19].[CH2:20]=O.Cl>C(O)(C)C.C(O)CCC>[ClH:15].[CH3:17][N:18]([CH3:20])[CH2:19][CH2:1][C:2]([C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)=[O:3]
Reactant: CNC
Reactant: CC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCCCO
Product: CN(C)CCC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Yield: 82.7 %

Procedure:
A solution of 22 g. (0.10 mole) of 5-(p-chlorophenyl)-2-furyl methyl ketone, 16 g. (0.20 mole) of dimethylamine hydrochloride, 6 g (0.20 mole) of paraformaldehyde, 100 ml. of n-butanol, and I ml. of concentrated HCl is heated under reflux for 2 hr. Solvent is removed on a rotary evaporator and the yellow, residual solid is partitioned between ether and water. The layers are separated and the water layer is washed with ether. The water layer is made basic with 1N NaOH solution and is extracted twice with ether. The ethereal layers are dried over MgSO4 and are concentrated on a rotary evaporator to give a residual semi-solid. The solid is dissolved in 350 ml. of isopropanol and is treated with ethereal HCl. The solid which is deposited is collected by filtration and is dried in a 60° oven to give 13 g (42%) of product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:6]=1.CO.C(O)(=O)C>[Pd].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:6]=1
Reactant: Nc1nc(C(=O)c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)c2csc(N)n2)cc1
Reaction time: 7 h
Yield: 87.7 %

Procedure:
A mixture of 2-amino-4-(4-nitrobenzoyl)thiazole g) and 10% palladium on carbon (1 g, 50% wet) in a mixture of tetrahydrofuran (50 ml), methanol (50 ml) and acetic acid (5 ml) was hydrogenated under atmospheric pressure for 7 hours. The reaction mixture was filtered and then, the filtrate was concentrated under reduced pressure. The residue was dissolved in water and adjusted to pH using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-4(4-aminobenzoyl)thiazole (0.54 g, yield: 87.7%).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH:22]=2)[O:19][C:18]([CH3:30])([CH3:29])[CH2:17][C:16]3([CH3:32])[CH3:31])=[CH:7][C:6]=1[F:33].[OH-].[Na+]>CO.O1CCCC1>[CH:26]1([N:24]([CH2:23][C:21]2[CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[C:6]([F:33])[CH:7]=3)[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([CH3:29])([CH3:30])[CH2:17][C:16]3([CH3:32])[CH3:31])[CH3:25])[CH2:28][CH2:27]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A solution of (4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-2-fluoro-phenyl)-acetic acid methyl ester (Intermediate 13, 0.060 g, 0.13 mmol) in methanol (1 mL) and tetrahydrofuran (3 mL) was treated with a 1M solution of sodium hydroxide (0.4 mL, 0.4 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo to a residue that was washed with hexane, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow oil (0.056 g, 95%).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[CH2:16]N1C=CN=C1.C[N:26]([CH2:28][CH2:29][N:30]([CH3:32])C)C.[CH:33]12[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[C:34]1=[O:43])[CH2:40]2>C1COCC1.O>[OH:43][C:34]1([CH:16]([C:15]2[CH:14]=[C:13]([CH3:12])[CH:24]=[CH:23][CH:22]=2)[C:32]2[NH:30][CH:29]=[CH:28][N:26]=2)[CH:33]2[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]1[CH2:36]3)[CH2:40]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: Cc1cccc(Cn2ccnc2)c1
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1cccc(C(c2ncc[nH]2)C2(O)C3CC4CC(C3)CC2C4)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
39 ml (60.5 mmol) of 1,55 molar n-butyllithium/hexane solution were added dropwise to a solution of 5.17 g (30 mmol) of N-(3-methylbenzyl)-imidazole and 3.49 g (30 mmol) of TMEDA in 60 ml of absolute THF at -70° C. The mixture was stirred for 30 minutes at -70° C., after which a solution of 4.51 g of adamantanone in 35 ml of absolute tetrahydrofuran was added dropwise at about -70° C., stirring was continued for 20 minutes at -70° C., the mixture was allowed to warm up to room temperature, 300 ml of water were added, while cooling, and the mixture was then stirred for 15 minutes at about 5° C. Thereafter, the crystalline substance which had separated out was filtered off with suction, rinsed with water and hexane, dried and boiled up with about 25 ml of CH3CN for 3 minutes. After cooling, the solid was again filtered off under suction and dried. 3.87 g (=40% yield) of pure (2-hydroxy-2-adamantyl)-1-imidazolyl-(3-tolyl)-methane of melting point 186° C. were obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH3:16].[CH3:17]OC(OC)N(C)C>>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH:16]=[CH:17][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COC(OC)N(C)C
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cccc(F)c1C=CN1CCCC1
Temperature: 25 °C
Yield: 80 %

Procedure:
Pyrrolidine (0.26 mL, 3.22 mmol) was added to a solution of 2-fluoro-6-nitrotoluene (5 g, 32.23 mmol) in N,N-dimethyl formamide dimethyl acetal (50 mL) and refluxed for 48 h. The resulting mixture was cooled to ambient temperature and partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (5×30 mL). The combined organic layers were washed with water (3×30 mL), brine (3×20 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to give 1-[2-(2-fluoro-6-nitro-phenyl)vinyl]pyrrolidine (6.08 g, 80%) as brown liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[O:20][CH2:21][O:22][CH3:23])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[Br:25]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]([Br:25])[C@H:12]1[O:20][CH2:21][O:22][CH3:23])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCO[C@@H]1Cc2ccccc2[C@H]1N(COC)C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCO[C@@H]1C(Br)c2ccccc2[C@H]1N(COC)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A solution of 2.75 g of tert-butyl[(1R,2R)-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate in 55 ml of carbon tetrachloride was heated at an outer temperature of 100° C., and a mixture of 1.53 g of N-bromosuccinimide and 95 mg of 2,2′-azodiisobutyronitrile was added portionwise thereto over 30 minutes at an interval of 5 minutes, followed by stirring at an outer temperature of 100° C. for 1 hour. The insoluble material was filtered, and an aqueous sodium thiosulfate solution and chloroform were added thereto to carry out a layer separation operation. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 984 mg of tert-butyl[(1R,2S)-3-bromo-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[N:44]([CH3:45])[C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([CH2:39][C:40]2[N:44]([CH3:45])[C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2nc3ccccc3n2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2nc3ccccc3n2C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.51 g), sodium hydrogen carbonate (0.82 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-1-[(1-methyl-1H-benzimidazol-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.096 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.08 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 65%).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:14]([Li])CCC.CI.[Cl-].[NH4+]>CCOCC>[CH3:13][O:12][C:3]1[C:2]([CH3:14])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: [Li]CCCC
Reactant: COc1ncc(C(F)(F)F)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: COc1ncc(C(F)(F)F)cc1C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.12 g (0.020 mol) of 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine in 60 ml of ether was cooled to -70° C. and blanketed with nitrogen. A solution containing 0.021 mole of butyl lithium (8.4 ml of 2.5 M) was added slowly with stirring keeping the temperature below about -65° C. and the mixture allowed to react for another 30 min. Methyl iodide (0.62 ml, 0.01 mol) was added to the mixture and stirring continued at -70° C. for about 30 min. The mixture was allowed to warm to about 20° C. and was then poured onto a mixture of ice and saturated aqueous ammonium chloride. The organic layer that formed was recovered. The aqueous layer was extracted with ether and the extract added to the organic layer. The combined organic materials were dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled to obtain 2.1 g (54 percent of theory) of the title compound as a colorless oil boiling at 67°-69° C. at 24 mm pressure. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[CH3:13][NH:14][CH3:15]>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:14]([CH3:15])[CH3:13]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CNC
Product: CN(C)CC(=O)c1ccc(Cl)cc1Cl

Procedure:
In a manner similar to Preparation 40 react 2-bromo-1-(2,4-dichlorophenyl)ethanone with dimethylamine to obtain the title compound.