Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:56])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:55])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:54])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:53])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:52])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:51])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:50])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:49])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:48])=[CH:35]/[CH2:36][CH2:37]/[C:38](/[CH3:47])=[CH:39]/[CH2:40][CH2:41]/[C:42](/[CH3:46])=[CH:43]/[CH2:44][OH:45].[C:57](Cl)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>N1C=CC=CC=1.CCCCCC>[C:57]([O:45][CH2:44][CH:43]=[C:42]([CH3:46])[CH2:41][CH2:40][CH:39]=[C:38]([CH3:47])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:48])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:49])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:50])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:51])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:52])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:53])[CH2:13][CH2:12][CH2:11][C:10]([CH3:54])=[CH:9][CH2:8][CH:7]=[C:6]([CH3:55])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:56])[CH3:1])(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCC=C(C)CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 Grams of undecaprenol were dissolved in 30 ml of pyridine and the solution was added with a solution of 1.3 g of benzoyl chloride in pyridine dropwise over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for one hour to complete the reaction. The reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 50 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain a white waxy final product. Yield: 3.6 g.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.[I-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH2:32][CH2:31]1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
5.0 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril and 7.5 g of sodium iodide were dispersed in 120 ml of anhydrous dimethylformamide and the mixture was stirred at 50°-60° C. for 2 hours. To this reaction mixture were added 10 g of 4-(3-chlorophenyl)piperazine and 5 ml of triethylamine and was stirred at 50°-60° C. for 6 hours, then stirred at a room temperature for 24 hours. The reaction mixture was concentrated under a reduced pressure to obtain a residue. To the residue thus obtained was added 80 ml of 5%-sodium hydrogencarbonate solution and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was crystallized with ether to obtain crude crystals and the crude crystals were recrystallized from ethanol to obtain 6.5 g of 6-{1-oxo-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[NH2:21][C:22]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C1COCC1.C1OCCOCCOCCOCCOCCOC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:30][C:28]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([NH2:21])[CH:29]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1N
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(C#N)c(N)c2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
(2-Oxopyrrolidin-3-(S)-yl) carbamic acid tert-butyl ester (1 g, 5 mmol) is dissolved in THF (100 mL) under nitrogen, and cooled to 0° C. Potassium-tert-butoxide (0.62 g, 5.5 mmol) is added in one portion to the vigorously stirring solution, followed by 18-crown-6 (10 mg, 0.038 mmol), and the reaction mixture allowed to warm to room temperature and stirred for 1 hour. The solution is cooled to 0° C. and 2-amino-4-(bromomethyl)benzonitrile (1.16 g, 5.5 mmol) added dropwise as a solution in THF (10 mL), before leaving the reaction mixture to warm to room temperature and stir overnight. The reaction is quenched with 0.25M HCl (20 mL), then neutralized with saturated aqueous NaHCO3, and brine added. The solution is extracted with ethyl acetate, and the organic phase dried over MgSO4, concentrated, and purified by column chromatograph on silica with 0.5-5% methanol/dichloromethane. The product fractions are combined, concentrated, and the semi-solid oily residue triturated with hexanes/dichloromethane=100/1 (25 mL). The product is isolated as a pale yellow powder (1.24 g, 3.75 mmol).
Reaction SMILES: Br[C:2]1[N:7]2[C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[C:8](=[O:23])[N:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:26]1
Reactant: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(Br)n12
Reactant: C1COCCN1
Product: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(N3CCOCC3)n12
Temperature: 120 °C
Yield: 84.9 %

Procedure:
In a 5 mL microwave vial was placed 2-4 (221 mg, 0.599 mmol) and morpholine (2.0 g, 2.0 mL, 23 mmol). The mixture was heated at 120° C. under microwave irradiation for 20 min. After cooling, the reaction mixture was purified by reversed phase HPLC to give 191 mg (85%) of 6-1. 1H NMR (500 MHz, DMSO-d6): δ 8.51 (d, J=8.2 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.69-7.60 (m, 2H), 7.00 (t, J=8.1 Hz, 1H), 6.67 (d, J=9.3 Hz, 1H), 5.72 (d, J=7.0 Hz, 1H), 4.32 (t, J=7.0 Hz, 2H), 3.63 (m, 4H), 3.10 (s, 1H), 2.99 (s, 1H), 2.93 (s, 4H). HRMS (ES) 376.1765 (M+H) found, 376.1771 required.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CN(C)C=O.[CH2:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13]>O>[CH:1]([NH:4][CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: C=C(C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCC(C(F)(F)F)C(F)(F)F

Procedure:
To a mixture of isopropylamine (5.65 g) and dimethylformamide (DMF, 5 mL) was added HFIB in several portions over a period of about 0.5 h until a gentle reflux of HFIB was observed which did not dissipate. A dry-ice condenser was used to obtain the gentle reflux of HFIB at 25° C. for 15 h. The reaction mixture was poured into water (100 mL) and the bottom layer separated, washed with water (10 mL) and dried over sodium sulfate to provide N-isopropyl N-(2-trifluoromethyl-3,3,3-trifluoropropyl)amine (15 g): MS (m/e) 223 (M+, 1.2%), 208 (100%), 72 (7.8%); 1H NMR (CDCl3) 1.06 (d, J=6 Hz, 6H), 1.12 (m, 1H), 2.81 (m, 1H), 3.07 (m, 3H) ppm; 19F NMR −67.0 (d, J=9 Hz) ppm.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: BrC1C(NC(=O)C(=O)CC(C)(C2C=CC=CC=2)C)=CC=C2C=1COC2=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:33](=[O:34])[O:32][CH2:31]2.[I:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:53])([CH3:52])[CH2:46][C:47](=[O:51])[C:48](O)=[O:49])=[C:41]([O:54][CH3:55])[CH:40]=1>>[I:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:53])([CH3:52])[CH2:46][C:47](=[O:51])[C:48]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C:33](=[O:34])[O:32][CH2:31]3)=[O:49])=[C:41]([O:54][CH3:55])[CH:40]=1
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Reactant: Nc1ccc2c(c1)COC2=O
Agent: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Product: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid as a foam.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C[O-].[Na+].Cl[CH2:16][C:17]#[N:18]>CO>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[S:4][CH2:16][C:17]#[N:18])([O:10][CH3:11])=[O:9]
Reactant: N#CCCl
Reactant: COC(=O)c1ccccc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1SCC#N
Temperature: 0 °C
Yield: 69.8 %

Procedure:
A solution of methyl thiosalicylate (164 g, 0.975 mol) in methanol (1.1 L) was added in one portion to a cold solution of freshly prepared sodium methoxide (from 25.5 g, 1.1 mol Na-metal in methanol, 1.1 L). The salt solution was cooled to 0° C. and a cold (0° C.) solution of chloroacetonitrile (83.7 g, 1.1 mol) in methanol (0.5 L) was added in one portion with stirring. After several minutes a strong precipitate appeared. After standing for several days at room temperature, the precipitate was collected, washed with ice-cold methanol, then washed well with water and dried to give 141.0 g of 2-(2-carbomethoxyphenylthio)acetonitrile, mp 120°-122° C. [described by K. Gorlitzer, Arch. Pharmaz., 308, 700 (1975)].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[C:6]([C:12](=[O:13])[CH2:11][Cl:10])[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 4-bromoanisole (17.4 ml, 138 mmol) in dichloromethane (150 ml) was added chloroacetyl chloride (32 ml, 400 mmol) followed by aluminium chloride (60 g, 450 mmol) keeping the temperature below 30° C. The yellow solution was heated to reflux for 8 hours, cooled down to ambient temperature, then ice water was added very carefully. The organic layer was separated and the aqueous extracted once with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give an oil which was purified by crystallisation from hexane. The title compound was obtained as a yellow solid (18 g, 52%). mp 80-82° C. 1H NMR (250 MHz, CDCl3) δ 4.69 (2H, s), 6.95 (1H, d, J=9 Hz), 7.60 (1H, dd, J=1 and 9 Hz), 7.80 (1H, d, J=2 Hz), 11.59 (1H, s).
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.O/[N:47]=[C:48](/[NH2:55])\[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[C:49]1([C:48]2[N:55]=[C:13]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)[O:15][N:47]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Reactant: N/C(=N/O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2noc(C3(c4ccccc4)CCCCC3)n2)cc1
Temperature: 95 °C
Yield: 4 %

Procedure:
A solution of 1-phenylcyclohexanecarboxylic acid (1 g, 4.9 mmol), EDAC (1.032 g, 5.39 mmol), HOBT (825 mg, 5.39 mmol), and N,N-diisopropylethylamine (2.57 mL, 14.69 mmol) in DMF (5 mL) was stirred at room temperature for 30 min under an argon atmosphere. (E)-N′-hydroxybenzimidamide (733 mg, 5.39 mmol) was added and the reaction mixture was heated to 95° C. for 8 h. The reaction mixture was cooled to room temperature and a portion (˜10%) was purified by automated preparative HPLC (PHENOMENEX® Luna Axia 21.2×100 mm 5 μm, Flow rate 20 mL/min, Gradient time 15 min, Mobile Phase: solvent A: 5% aq. MeOH, 0.05% TFA; solvent B: 95% aq. MeOH, 0.05% TFA). HPLC: tR=3.95 min, Waters Sunfire C18 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.1% TFA; Final solvent: 90% aq. MeOH-0.1% TFA to obtain 3-phenyl-5-(1-phenylcyclohexyl)-1,2,4-oxadiazole (60 mg). LC/MS: m/e 305.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.95-8.14 (2 H, m), 7.47-7.66 (3H, m), 7.31-7.44 (4 H, m), 7.17-7.31 (1H, m), 2.57-2.75 (2 H, m), 2.01-2.18 (2 H, m), 1.71 (2H, bs), 1.51-1.65 (1H, m), 1.27-1.51 (3 H, m).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:11]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15]>>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([NH:9][NH:10][C:22]([C@H:19]2[CH2:20][CH2:21][C@H:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]2)=[O:23])=[O:8])=[CH:3][CH:4]=1
Reactant: CCCCCC1CCC(C(=O)O)CC1
Reactant: NNC(=O)c1ccncc1
Product: CCCCC[C@H]1CC[C@H](C(=O)NNC(=O)c2ccncc2)CC1

Procedure:
Isonicotinic acid hydrazide was reacted with 4-pentylcyclohexane carboxylic acid in a similar fashion to that described in Preparation 16 to afford the title compound: RT=4.79 min; m/z (ES+)=318.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1.C1C=C([O:23]O)C(C(O)=O)=C(C(O)=O)C=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])[CH:6]=[C:7]([F:9])[CH:8]=1)=[O:23]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CSc1cc(F)cc(C(=O)c2nccs2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1cc(F)cc(C(=O)c2nccs2)c1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 144.4 %

Procedure:
To a solution of sulfide from Step 1 (0.76 g, 2.99 mmol) in MeOH (1.5 mL) and CH2Cl2 (6 mL) at 0° C. was added the magnesium salt of monoperoxyphthalic acid (1.11 g, 1.80 mmol). The mixture was stirred at 0° C. for 1.25 h and then sat. aqueous NaHCO3 was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with H2O and dried over anhydrous MgSO4. Evaporation of the solvent and chromatography using toluene:EtOAc (25:75) gave 0.70 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][CH3:20]>CC(C)=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:17][CH2:18][O:19][CH3:20])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCn1ncc(Cl)c(Cl)c1=O
Temperature: 55 °C
Reaction time: 24 h

Procedure:
To a suspension of 4.00 g (24.2 mmol) of 4,5-dichloro-2H-pyridazin-3-one and 6.70 g (48.5 mmol) of potassium carbonate in 40 ml of acetone were added 4.55 ml (6.74 g, 48.5 mmol, 2 eq.) of 2-bromoethylmethylether. The suspension was stirred for 24 h at 55° C. Then 1 ml (1.48 g, 10.6 mmol) of 2-bromoethylmethylether were added and the mixture was stirred for another 24 h. The reaction was then allowed to cool to room temperature, the solids were filtered off and washed twice with ethyl acetate. The filtrate was concentrated in vaccuo, taken up in methylene chloride and purified by flash chromatography (SiO2, heptane:ethyl acetate 85:15 v/v) to yield the title compound as a white crystalline solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:8](Cl)[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:20]([NH2:23])[CH:21]=[CH2:22]>O>[CH2:20]([NH:23][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=1)[CH:21]=[CH2:22]
Reactant: C=CCN
Reactant: CCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCCCC)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To 170 mg (0.67 mmol) of 4-butylamino-2-chloro-6-nitroquinazoline was added 1.52 g (26.66 mmol) of allylamine, followed by stirring at room temperature overnight. To the reaction solution was water added, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 166 mg (yield: 82.1%) of the title compound.
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@@H:16]([CH3:20])[C:17](Cl)=[O:18])[CH:13]=[CH:14][CH:15]=1.C([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)CC>O>[CH:30]1([C:27]2[CH:26]=[CH:25][C:24]([C:17](=[O:18])[C@@H:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH3:20])=[CH:29][CH:28]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COc1cccc([C@@H](C)C(=O)Cl)c1
Reactant: CCC[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc([C@@H](C)C(=O)c2ccc(C3CCCCC3)cc2)c1
Reaction time: 0.25 h

Procedure:
To a methylene chloride suspension of aluminum chloride, a methylene chloride solution of (R)-2-(3-methoxyphenyl)propionic acid chloride was added dropwise under ice cooling. After stirring at the same temperature for 15 minutes, a methylene chloride solution of trans-4-propylcyclohexylbenzene was added dropwise. After the completion of the reaction, the reaction system was added to iced water and the organic layer was separated by adding methylene chloride. The organic layer was washed twice with water and then washed with saturated brine. The aqueous layer was washed with methylene chloride and, after combining the organic layer, the solvent was concentrated to obtain a crude product of (R)-1-(4-cyclohexylphenyl)-2-(3-methoxyphenyl)-propan-1-one. To an ethylene glycol solution of the resulting crude product, hydrazine monohydrate was added and the solution was stirred at 110° C. while removing water as a by-product. After efflux of water has nearly terminated, excess hydrazine was distilled off by stirring at 120° C. The temperature of the reaction system was reduced and potassium hydroxide was added, followed by heating to 160° C. After the completion of the reaction, the temperature of the reaction system was reduced and water and toluene were added, followed by stirring. After separating the organic layer, the aqueous layer was washed with toluene and the organic layer was combined and then washed three times with water. The residue was washed with saturated brine and concentrated to obtain a crude product of a compound represented by the formula (XI-a). The resulting crude product was purified by column chromatography and recrystallized from ethanol to obtain (S)-1-{2-(3-methoxyphenyl)propyl}-4-(trans-4-propylcyclohexyl) benzene (S-isomer of the compound represented by the formula (XI-a)).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:16][C:11]1[CH:10]=[C:9]([Br:8])[CH:15]=[CH:14][C:12]=1[NH:13][C:5]([CH3:6])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Br)ccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Br)cc1C
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
Acetic anhydride (15.2 ml, 0.16 mol) was added dropwise to a stirred mixture of 4-bromo-2-methylaniline (10.0 g, 0.054 mol) and sodium acetate (2.52 g, 0.056 mol) in toluene (150 ml). Once the addition was complete the mixture was warmed to 85° C. and stirred for 40 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic solution was evaporated in vacuo, a further quantity of toluene was added and then the solvent was evaporated to give 4-bromo-2-methylacetanilide (12.3 g), as a colourless solid.
Reaction SMILES: [C:1]([NH:4][C:5](=[N:7]/[N:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[C:18]([CH3:19])=[N:17][NH:16][C:13]2=[N:14][CH:15]=1)[SH:6])(=[O:3])[CH3:2].C(OO)(=O)C>C(O)(=O)C>[CH3:19][C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:9]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:7][N:8]=3)[CH:11]=2)[NH:16][N:17]=1
Reactant: CC(=O)NC(S)=N/N=C/c1cnc2[nH]nc(C)c2c1
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)Nc1nnc(-c2cnc3[nH]nc(C)c3c2)s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
The starting material 1-acetyl-3-((E)-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyleneamino)isothiourea (5 g) (80 mg, 0.22 mmol) was taken up in 5 ml acetic acid and 1.2 ml peracetic acid in a round bottom flask. The mixture was heated to 60° C. After 15 min, the product was precipitated out. The solid was filtered off and washed with ether (50 ml). The yield for this reaction was quantitative and the product was used for the next step without turther purification.
Reaction SMILES: [C:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[Cl-].[Na+]>C(OCC)C>[CH3:9][C:5]1[N:6]=[CH:7][O:8][C:4]=1[C:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:3])[CH3:2]
Reactant: [Li]c1ccccc1
Reactant: CC(=O)c1ocnc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1ncoc1C(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5-Acetyl-4-methyloxazole (5g) in dry diethylether (25ml) at -70° C. under a nitrogen atmosphere was treated dropwise with phenyllithium (1.8M solution in cyclohexane-diethylether, 27ml). After 45 minutes the mixture was allowed to warm to room temperature and water (10 ml) was added. The mixture was poured into saturated aqueous sodium chloride and extracted with dichloromethane. The product thus obtained was crystallised from diethylether to give 1-(4-methyl-5-oxazolyl)-1-phenylethanol, m.p. 102-104° C.