Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH:11]1([C:5]2[CH:6]=[CH:7][C:8]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])=[CH:9][CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(C2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(C2CCCCC2)cc1
Reaction time: 15 h
Yield: 75 %

Procedure:
67 g (0.5 mol) of aluminium chloride are added in portions to a mixture of 80 g (0.5 mol) of cyclohexylbenzene 70 g (0.5 mol) of benzoyl chloride and 500 ml of methylene chloride at room temperature. After 15 hours, the reaction mixture is poured onto ice/hydrochloric acid. The organic phase is washed with water until neutral, dried over sodium sulphate and evaporated. The crude product is purified by distillation. 93.3 g (75% of theory) of 4-cyclohexylbenzophenone of boiling point 160° to 175° C./0.1 mm are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.O.O.O.C([O-])(=O)C.[Na+].[Br:17]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:17])=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnc(N)c(Br)n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To acetic acid (1500 ml.), 2-amino-5-methylpyrazine (1 mole) and 326.5 g. sodium acetate trihydrate are slowly added 1.1 mole bromine in 180 ml. acetic acid at 2° C. in the absence of light. The mixture is stirred about 15 hours at 20° C., stripped of acetic acid in vacuo, poured into ice, made alkaline with sodium hydroxide, filtered, the residue extracted with ether, the extract stripped and the 2-amino-3-bromo-5-methylpyrazine crystallized from a suitable solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][NH2:8].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][C:20](Br)=[O:21].O>ClCCl>[Br:18][CH2:19][C:20]([NH:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=1)=[O:21]
Reactant: NCCOc1cccc(F)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)NCCOc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(3-fluorophenoxy)ethylamine (0.93 g) and potassium carbonate (1.24 g in dichloromethane (20 mL) at 0° C. was treated with bromoacetyl bromide (1.04 mL). The reaction mixture was stirred at 0° C. for 30 mins then at room temperature for 6 h. Water was added and the mixture was stirred until effervescence ceased. The organic layer was separated and the organic layer was evaporated to afford the crude product which was purified by silica gel chromatography eluting with 0-50% EtOAc/pentane to give the sub-titled compound (1.17 g) as a brown oil.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[CH3:10][C:11]1[NH:16]C(=O)[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>ClCCl>[CH3:6][O:7][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[N:16]=1
Reactant: C[O+](C)C
Reactant: Cc1cccc(=O)[nH]1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cccc(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.3 %

Procedure:
Trimethyloxonium tetrafluoroborate (10.0 g, 67.6 mmol) was added portionwise to a suspension of 6-methylpyridin-2-one (7.3 g, 67.0 mmol) in dichloromethane (100 ml), and once addition was complete, the reaction was stirred at room temperature for 24 hours. Dichloromethane (50 ml) and aqueous sodium hydroxide solution (50 ml, 2N) were added and the layers separated. The aqueous phase was extracted with dichloromethane (2×50 ml), the combined organic solutions washed with brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of pentane: dichloromethane (66:34 to 0:100) to afford the title compound (2.25 g, 27%) as a colourless oil.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]\[CH3:10])/[CH:4]=[CH:5]/[C:6]([OH:8])=O)[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([NH:28][C:6](=[O:8])/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:9]/[CH3:10])[CH2:25][CH2:26][CH3:27]
Reactant: C/C=C(/C=C/C(=O)O)CC
Reactant: CCCCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C/C=C(/C=C/C(=O)NCCCC)CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E,E)-4-Ethyl-2,4-hexadienoic acid (5 g) was dissolved in tetrahydrofuran (300 ml) and triethylamine (5 ml) was added to the solution. The mixture was stirred at room temperature for 30 minutes and then ethyl chloroformate (3.4 ml) was added dropwise thereto at -20° C. with stirring. The resulting mixture was stirred at the same temperature for 60 minutes. n-Butylamine (3.6 ml) was added to the reaction mixture at -20° C. The resulting mixture was stirred at the same temperature for 60 minutes. The reaction mixture was concentrated and the concentrate was diluted with water, and then extracted with two portions of ethyl acetate (100 ml×2). The combined extracts were washed with successively an aqueous sodium carbonate solution and brine, dried over magnesium sulfate and then evaporated to dryness to given an oil (6.5 g) which was subjected to column chromatography on silicagel, eluting with chloroform containing 2% methanol, to give (E,E)-N-n-butyl-4-ethyl-2,4-hexadienamide (5.8 g).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:15][C:16]1[C:21]([CH3:22])=[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)[CH2:25][CH2:24]2)[N:19]=[N:18][C:17]=1[CH2:39][C:40](O)=[O:41].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:15][C:16]1[C:21]([CH3:22])=[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)[CH2:25][CH2:24]2)[N:19]=[N:18][C:17]=1[CH2:39][C:40]([NH:5][NH:4][C:1](=[O:3])[CH3:2])=[O:41]
Reactant: CC(=O)NN
Reactant: Cc1c(CC(=O)O)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)Cc1nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c(C)c1C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Acetic acid hydrazide (20.6 mg, 0.28 mmol) is added to a round-bottom flask under N2 followed by DMF (5 mL). Diisopropylethylamine (0.25 mL) is added and the reaction is stirred for 30 min. {4,5-Dimethyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazin-3-yl}-acetic acid (110 mg, 0.28 mmol) is added and the reaction is stirred for 1 h. HOBT (42 mg, 0.311 mmol) and HBTU (116.8 mg, 0.31 mmol) are added and the reaction is allowed to stir for 16 h. The crude reaction mixture is purified via flash chromatography on silica gel (0-30% methanol in dichloromethane) to afford the title compound (114 mg, 90%).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:41]4[CH2:42][CH2:43][N:38]([CH:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH2:39][CH2:40]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCN(C3CCCCC3)CC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 40.4 mg (0.24 mmol) 1-cyclohexylpiperazine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 16 mg (22%) product as an orange powder. MS (ESI) m/z 599.35 (M+1).
Reaction SMILES: C(Cl)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][C@@H:16]2[CH3:32])=[O:14])[CH:10]=[CH:11][CH:12]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>CN(C=O)C>[CH2:33]([NH:35][C:36](=[O:37])[N:25]([C@H:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([C:13](=[O:14])[C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=2)[C@@H:16]([CH3:32])[CH2:17]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:34]
Reactant: CCN=C=O
Reactant: COc1cccc(C(=O)N2c3ccccc3[C@H](Nc3ccccc3)C[C@@H]2C)c1
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CCNC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2cccc(OC)c2)c2ccccc21
Temperature: 90 °C

Procedure:
(±)-Cis-3-ethyl-1-[1-(3-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-1-phenyl-urea was synthesized using general procedure A, substituting ethyl isocyanate for acetyl chloride using the following procedure. To a solution of (±)-cis-(3-methoxy-phenyl)-(2-methyl-4-anilino-3,4-dihydro-2H-quinolin-1-yl)-methanone in DMF was added ethyl isocyanate and reaction mixture was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and concentrated. Crude mixture was purified by flash chromatography on silica gel using gradient elution hexane-ethyl acetate (5-20%).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])[CH:21]=[CH:22][CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)=[O:30])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(F)c3)n2)n1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>C(#N)C>[Cl:38][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(C1=CN(C)CS1)c1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(C1=CN(C)CS1)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a mixture of 1.24 g (5.3 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylthiazole and 10 ml of acetonitrile was added 1.67 g (6.36 mmol) of triphenylphosphine and 1.23 ml (12.7 mmol) of carbon tetrachloride under ice-cooling and stirred at room temperature overnight. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-(2-chloromethyl-α-methoxybenzyl)-3-methylthiazole (1.03 g, 77.2%) as colorless oil.
Reaction SMILES: C([O:3][P:4]([C:9]([F:25])([F:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:8])[O:5]CC)C.C(Cl)Cl>>[F:25][C:9]([P:4](=[O:3])([OH:5])[OH:8])([F:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCC(F)(F)P(=O)(OCC)OCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(F)(F)P(=O)(O)O
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a solution of vacuum dried 10 (225 mg, 0.585 mmol) in methylene chloride (5 mL) bromotrimethyl silane (895 mg, 5.85 mmol) was added and the mixture was stirred at room temperature. TLC showed completion of the reaction after 6 h. Solvents were removed under reduced pressure, and the residue was stirred in 95% methanol (3 mL) for 1 h. The mixture was concentrated under reduced pressure, dried under vacuum to give 150 mg (78%) of 11 as light yellow solid. mp 66–69° C.; 1H NMR (CD3OD): δ 2.03 (m, 2H), 1.59 (m, 2H), 1.24 (br s, 22H), 0.90 (t, J=6.6 Hz, 3H); MS: [M−H]— at m/z 327.3. Anal. (C15H31F2O3P.0.2H2O) C, H.
Reaction SMILES: [CH:1]([CH:3]([C:5](=[O:8])[CH2:6][CH3:7])[CH3:4])=[O:2].[C:9](OC(C)=C)(=[O:11])[CH3:10]>S(=O)(=O)(O)O>[C:9]([O:2][CH:1]=[C:3]([CH3:4])[C:5](=[O:8])[CH2:6][CH3:7])(=[O:11])[CH3:10]
Reactant: C=C(C)OC(C)=O
Reactant: CCC(=O)C(C)C=O
Agent: O=S(=O)(O)O
Product: CCC(=O)C(C)=COC(C)=O
Yield: 70.5 %

Procedure:
A mixture of 11.4 g of 2-formyl-3-pentanone and 17 g of isopropenyl acetate was brought to reflux in the presence of 0.1 g of sulfuric acid. After removal of the acetone formed at ambient pressure, the desired product was distilled under vacuum. In this manner 11 g of 1-acetoxy-2-methyl-1-pentene-3-one was obtained under conditions of 104° C. and 16 mm of mercury, which is a yield of 70%.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(=O)(O)[O-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:12]1([S:18]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)NN
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)NNS(=O)(=O)c1ccccc1

Procedure:
180 g. (0.2 mole) of methyl carbazate (from hydrazine and dimethyl carbonate) is placed in a liter flask. 20.0 g (0.24 mole) of sodium bicarbonate and 100 ml. water are added. The mixture is stirred and dropped in 35.2 g. (0.2 mole) of benzene sulfonyl chloride. Then the mixture is stirred for 16 hours. The crystals that have formed are filtered off, washed with water, and dried in air. Yield = 34.5g.; m.p. 149°-154° C. Upon recrystallization from ethanol 26 g. of material is recovered which melts sharply at 155° C.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[C:12]=1I)([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH:33]=[O:34])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]>>[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH:33]([OH:34])[C:12]3[N:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]4=[N:5][C:4]=3[CH:1]([CH3:3])[CH3:2])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: CC(C)c1nc2ccccn2c1I
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C(C)C)nc4ccccn34)cc2COc2cc(F)ccc21
Yield: 45.2 %

Procedure:
[step 3] Using 2-isopropyl-3-iodoimidazo[1,2-a]pyridine (366 mg, 1.28 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (250 mg, 0.853 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[hydroxy(2-isopropylimidazo[1,2-a]pyridin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (175 mg, 45%) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[Cl:14][CH:15]=[CH:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:14]/[CH:15]=[CH:16]/[CH2:17][N:2]([CH3:1])[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1cccc2ccccc12
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C/C=C/Cl)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of 9.84 g (57.5 mmol) of N-methyl-1-naphthalenemethanamine in 60 ml of dimethyl sulfoxide were added 5.5 ml (60 mmol) of 1,3-dichloropropene (E/Z=9/1) and 8.28 g (60 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 6 hours at room temperature, poured into 250 ml of ethyl acetate, washed with 150 ml×3 of water and 150 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 10.86 g (yield: 77%) of the above identified compound as an oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][OH:18])[CH:11]=[CH:10]2)(=[O:5])=[O:4].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[F:19][C:2]([F:1])([F:20])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]=[O:18])[CH:11]=[CH:10]2)(=[O:4])=[O:5]
Reactant: O=S(=O)(Oc1ccc2cc(CO)ccc2c1)C(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Yield: 93.8 %

Procedure:
To a mechanical stirred solution of 6-trifluoromethanesulfonyloxy-naphthalen-2-yl-methanol (70.0 g, 0.228 mol) in CH2Cl2 (600 mL) under an atmosphere of argon was added PCC (54.20 g, 0.25 mol, crushed prior to addition) over a few minutes. After 2 hours the resulting black suspension was poured onto a silica gel column and purified using CH2Cl2 to give a yellow oil that slowly crystallized upon standing to afford 65.1 g (94%) of 6-trifluoromethanesulfonyloxy-naphthalene-2-carboxaldehyde. 1H NMR (300 MHz; CDCl3) 7.50 (dd, J1=9.0 Hz, J2=2.0 Hz, 1 H), 7.83 (d, J=2.0 Hz, 1 H), 7.99 (d, J=8.4 Hz, 1 H), 7.07 (dd, J1=9.0 Hz, J2=2.0 Hz, 1 H), 8.12 (d, J=9.0 Hz, 1 H), 8.40 (brs, 1 H), 10.19 (s, 1 H), 13C NMR (75 MHz, CDCl3) 118.7 (q, J=318 Hz), 119.5, 120.9, 124.5, 129.1, 131.6, 132.2, 133.6, 134.9, 136.4, 148.9, 191.4.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]([O:37][C:38](=[O:47])[NH:39][C@H:40]1[CH2:45][CH2:44][C@@H:43]([NH2:46])[CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:47])[NH:39][CH:40]1[CH2:41][CH2:42][CH:43]([NH:46][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:31])[CH2:44][CH2:45]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
{4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-cyclohexyl}-carbamic acid tert-butyl ester was prepared starting from intermediate M and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester. MS calcd. for C28H34ClN4O4 [(M+H)+] 525.2, obsd. 525.1.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20]>C(O)C>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:19][C:17]2[N:16]=[C:15]([S:20][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N:3]([CH3:12])[CH3:2])=[CH:5][CH:6]=3)[C:14]([CH3:21])([CH3:13])[N:18]=2)=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc(CCl)cc1
Reactant: CC1(C)NC(=S)NC1=S
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(CSC2=NC(C)(C)C(SCc3ccc(N(C)C)cc3)=N2)cc1

Procedure:
Initially, 3.2 g of 4-dimethylaminobenzylchloride hydrochloride was added to a solution of 1 g of 5,5-dimethyl-2,4-dithiohydantoin in 50 mL of ethanol (EtOH). The reaction mixture was treated following the procedure used in Example 62, and purified by column chromatography (CHCl3). Recrystallization form diethyl ether-n-hexane gave the desired compound in the form of a needle-like crystal. The yield of this compound was 1.9 g with a yield ratio of 71.2%, and the melting point was 91°-92° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: c1ccc2[nH]ccc2c1
Product: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 2,4,5-trichloropyrimidine and 1H-indole. m/z 265.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: OC1CCCCC1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)=cyclohexanol (150 mg), and sodium hydride (43 mg, 60% dispersion in oil) and n-octyl bromide (180 ml) in dry N,N-dimethylformamide (1 ml) was stirred for 3 hrs at room temperature. The mixture was allowed to cool to 0° C., and the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)=cyclohexyl octyl ether (222 mg, 89% yield) as a colorless oil.
Reaction SMILES: CO[C:3](=[O:7])[C:4]([CH3:6])=[CH2:5].[NH:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11]>C[O-].[Na+].O>[OH:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][OH:14])[C:3](=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: OCCNCCO
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)N(CCO)CCO

Procedure:
N,N-bis(2-hydroxyethyl)methacrylamide was prepared by the alcoholysis of methylmethacrylate with diethanolamine in the presence of sodium methoxide catalyst, following the general procedure of Gast, Schneider and Cowen (J. Am. Oil Chem. Soc. 43 418 (1966)). The crude product was stripped of volatile materials in vacuo, and then dissolved in water and treated with a strong acid ion-exchange resin, sold under the trade mark Dowex X 50, to remove unchanged diethanolamine and any basic by-products. After removing the water in a rotary vacuum evaporator, a colourless oil was obtained which was shown by NMR analysis to be the desired compound in a satisfactory state of purity.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:11][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]2=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn2cccc12
Solvent: ClC(Cl)Cl
Product: Cc1nccn2c(Br)ccc12
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
5.0 g of 1-methylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 2 was dissolved in 60 ml of chloroform; and 6.7 g of N-bromosuccinimide was added thereto at 0° C. The reaction mixture was stirred for 30 minutes at the same temperature; and the resulting solution was concentrated. The residue was chromatographed over silica gel to obtain 6.3 g of title compound (yield: 80%).