Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:16]I.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:9][CH:10]=1)[CH3:16]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of methyl-2-(4-tert-butylphenyl)acetate (1 g, 4.85 mmol) in abs. THF (30 ml) was mixed with a 1 M solution of bis-(trimethylsilyl)lithium amide in THF (5.33 ml, 5.33 mmol) at a temperature of −70° C. within 15 min. The reaction was highly exothermic. The mixture was kept for 20 min at −70° C. and at this temperature methyliodide (0.452 ml, 1.03 g, 7.26 mmol) was added within 5 min. Within 16 h the mixture was heated to RT. For working up, the reaction mixture was mixed with sat. NH4Cl solution (30 ml). There were formed two phases and, as a solid, ammonium chloride which was separated off by filtration and washing with THF (2×8 ml). The filtrate was mixed with DCM (70 ml) and the phases were separated. The aqueous phase was extracted with DCM (2×20 ml). The organic phases were combined, dried and concentrated. There remained a colourless oil (1.08 g) which was purified by chromatography [silica gel 60 (50 g); cyclohexane (800 ml), EtOAc/cyclohexane 1:30 (600 ml)]. 2-(4-Tert-butylphenyl)propionic acid methyl ester was obtained as a colourless oil in a yield of 89% (946 mg).
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.C(O)(=O)C>C1COCC1.O>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
CH3MgBr (3.2M in 2-methyltetrahydrofuran, 3.76 mL, 12.02 mmol) was added dropwise over 10 minutes to a solution of indole (1.42 g, 12.02 mmol) in THF (4.9 mL) at 0° C. The solution was then stirred at 0-2° C. for 0.5 h. A solution of 2,4-dichloro-5-methylpyrimidine (1 g, 6.01 mmol) in THF (3 mL) was then added dropwise to the solution. The ice bath was then removed, then the solution was stirred at r.t. for 1 h then 60° C. for 21 h. While still at 60° C., acetic acid (708 μL, 12.32 mmoles) was added dropwise, followed by water (10 mL). The resulting biphasic suspension was stirred at 60° C. for 0.5 h. The resulting solid was collected by filtration, washed with water (5 mL), and dried in a vacuum oven to give the title compound (805 mg, 50%) as a white solid; 1H NMR: 2.49 (3H, s), 7.20-7.28 (2H, m), 7.52-7.55 (1H, m), 8.20 (1H, d), 8.48 (1H, d), 8.51-8.54 (1H, m), 12.10 (1H, s); m/z: ES+ MH+ 244.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1
Product: NS(=O)(=O)OCCOc1ccc(Cl)cc1
Yield: 48 %

Procedure:
The title compound was prepared by procedures of Example 22 from sulfamoyl chloride and 2-(4-chlorophenoxy)ethanol in 48% yield. A white solid, mp 117°-119° C. was obtained.
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:10])[CH:2]=CC1C=CC=CC=1.CC(C1C=CC(F)=CC=1)=O.FC1C=CC(C(C2C=CC=CC=2)=O)=CC=1>>[C:1]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)=[CH:15][CH:16]=1)(=[O:10])[CH3:2]
Reactant: O=C(C=Cc1ccccc1)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: CC(=O)c1ccc(F)cc1
Agent: O=C(c1ccccc1)c1ccc(F)cc1
Product: CC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 40 %

Procedure:
The 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine used as starting material was prepared as in Example 32, using 4-fluoroacetophenone as starting material in place of 4-fluorobenzophenone to give 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine (40% yield), m.p. 176-177° C.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[CH:11]=1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:45][N:46]1[C@H:50]([CH3:51])[CH2:49][N:48]([C:52]2[S:53][C:54]([C:58](O)=[O:59])=[C:55]([CH3:57])[N:56]=2)[C:47]1=[O:61]>>[F:65][C:63]1[CH:62]=[C:44]([CH:43]=[C:42]([F:41])[CH:64]=1)[CH2:45][N:46]1[C@H:50]([CH3:51])[CH2:49][N:48]([C:52]2[S:53][C:54]([C:58]([NH:16][CH2:15][C:12]3[CH:11]=[C:10]([CH3:9])[O:14][N:13]=3)=[O:59])=[C:55]([CH3:57])[N:56]=2)[C:47]1=[O:61]
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Reactant: Cc1cc(CN)no1
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3C[C@@H](C)N(Cc4cc(F)cc(F)c4)C3=O)nc2C)no1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (5-methylisoxazol-3-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(3,5-difluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid: mp 63-66° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.50 (t, J=5.4 Hz, 1H), 7.17-7.08 (m, 3H), 6.14 (s, 1H), 4.57 (d, J=16.2 Hz, 1H), 4.42-4.36 (m, 3H), 4.25-4.21 (m, 1H), 3.88-3.81 (m, 1H), 3.62-3.57 (m, 1H), 2.48 (s, 3H), 2.37 (s, 3H), 1.23 (d, J=5.9 Hz, 3H); MS (ES+) m/z 462.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([NH2:9])=[O:8])([O-])=O.[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C.[H][H]>CN(C)C=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:16]([O:20][CH3:21])[O:15][CH3:14])[C:7]([NH2:9])=[O:8]
Reactant: [H][H]
Reactant: Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(Cc1ccc(C(N)=O)cc1N)OC
Temperature: 140 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
19.5 g of 3-nitro-4-methylbenzamide and 30 g of dimethylformamide dimethyl acetal were dissolved in 200 ml of dimethylformamide. The obtained mixture was stirred at 140° C. for 20 hours. The mixture was then concentrated under a reduced pressure. Thereafter, 360 ml of methanol and 25 g of chlorotrimethylsilane were added to the residue. The obtained solution was heated to reflux for 16 hours. The reaction solution was cooled and then concentrated under a reduced pressure. Water and ethyl acetate were added thereto, so as to divide an organic layer. The organic layer was separated, and then washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution. It was then dried over anhydrous magnesium sulfate. The mixture was filtered through 100 g of a silica gel layer, and then washed with ethyl acetate. Thereafter, the filtrate was concentrated under a reduced pressure. 0.9 g of 10% palladium carbon was added to 150 ml of a methanol solution containing the obtained crude product, and the mixture was intensively stirred in a hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under a reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), so as to obtain 11.5 g of the subject compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16].CCN(CC)CC.O>C(Cl)(Cl)Cl>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[F:13])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1nc(Cl)c(C=O)c(Nc2ccc(F)cc2F)n1
Yield: 114.4 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-45] (4.0 g, 18.0 mmol) in CHCl3 (50 mL) was added 2,4-di-fluoroaniline (2.02 mL, 19.8 mmol) followed by Et3N (3.76 mL, 27 mmol, 1.5 eq). The reaction mixture turned yellow and was heated to reflux for 6 h, H2O (50 mL) was added and the layers were separated. The organic layer was evaporated to give 6.5 g (>100%) of the crude title compound which is pure enough to be used in the next step. LC MS (m/e)=316 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH:7][CH:6]=2)[CH3:2].N[C:24]1C=C2C(=CC=1)NC(CCC)=C2>>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3]([CH2:1][CH2:2][CH3:24])=[CH:11]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CCCc1cc2cc(N)ccc2[nH]1
Reactant: CCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1
Product: CCCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1

Procedure:
Refer to 45a) using 5-amino-2-propylindole.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[N:12][C:13]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:14][C:15]=1[CH3:16]
Reactant: CNc1ccccc1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccccc2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 40.1 %

Procedure:
After N-methylaniline(0.84 ml, 7.8 mmol) was added to a mixture solution of 5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.0 g, 3.6 mmol) and dimethylformamide(5 ml), 0.55 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:13]=[N:14][C:15]3[CH:16]=[C:17]4[CH:24]=[N:23][NH:22][C:18]4=[CH:19][C:20]=3[N:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:25](OC(=O)C)(=[O:27])[CH3:26].O>C1COCC1>[C:25]([N:22]1[C:18]2=[CH:19][C:20]3[N:21]=[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([F:3])[CH:5]=4)[CH:13]=[N:14][C:15]=3[CH:16]=[C:17]2[CH:24]=[N:23]1)(=[O:27])[CH3:26].[C:25]([N:22]1[C:18]2=[CH:19][C:20]3[N:21]=[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([F:3])[CH:5]=4)[CH:13]=[N:14][C:15]=3[CH:16]=[C:17]2[CH2:24][NH:23]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2cnc3cc4cn[nH]c4cc3n2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3cc4c(cc3n2)N(C(C)=O)NC4)cc1F
Product: COc1ccc(-c2cnc3cc4cnn(C(C)=O)c4cc3n2)cc1F
Reaction time: 0.08 h

Procedure:
To an ice-colded suspension of NaH (0.029 g) in 30 ml of anhydrous THF under N2 is added 7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (0.30 g). The orange-red mixture is stirred at the same temperature for 5 minutes, then acetic anhydride (0.122 g) is added dropwise to the mixture. A yellow solid forms during the acetic anhydride additions. The resulting mixture is stirred at room temperature overnight. The mixture is poured into water. The yellow solid is filtered, washed with water then with ether and dried. The product is purified by column chromatography eluting with 15% ethylacetate in hexane, 25% ethylacetate in hexane then 5% ethylacetate in methylene chloride to obtain 1-acetyl-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 261°-265° C.) and 1-acetyl-7-(3-fluoro-4-methoxyphenyl)-2H-pyrazolo[3,4-g]quinoxaline.
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:11](OC)(=[O:15])[C:12]([CH3:14])=[CH2:13].C[O-].[Na+]>>[C:11]([O:4][CH2:3][CH2:2][N:1]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)OC
Reactant: OCCN(CCO)CCO
Agent: C[O-]
Agent: [Na+]
Product: C=C(C)C(=O)OCCN(CCO)CCO

Procedure:
Triethanolamine is reacted with methyl methacrylate and sodium methoxide at ambient temperature until the unreacted mono-, di- and trimethacryloxy substituted products reached the desired distribution as determined by gas chromatography. The resulting solution is stripped of excess reagent under reduced pressure. Next, N-(2-methacryloxyethyl)diethanolamine is separated from the solution by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([C:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)=[O:38])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: O=C(Cl)c1cccs1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added triethylamine (261 mg, 2.58 mmol), thiophenylcarbonyl chloride (227 mg, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 480 mg (81%) of the product as a solid. HR-MS: m/z Calculated for C22H23NO6S2 462.1040; Found 462.1039.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: COc1ccc(N)cc1
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OC)cc3)cc21
Reaction time: 8 h
Yield: 57 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol) and p-anisidine (160 mg, 1.3 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (1.2 mL, 1.8 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a brown residue that was purified by silica gel chromatography eluting with 1:1 EtOAc hexanes then EtOAc. The product fractions were pooled and concentrated to a solid that was crystallized to give 1-ethyl-7-(4-methoxyphenylamino)-1H -[1,6]naphthyridin-2-one (87 mg, 57%): mp (2-propanol) 165-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:20][CH2:19][CH2:18][C:17]3[N:16]([CH3:21])[N:15]=[CH:14][C:13]2=3)=O)=[N:4][CH:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.CN(C=O)C>CC#N>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:20][CH2:19][CH2:18][C:17]4[N:16]([CH3:21])[N:15]=[CH:14][C:13]3=4)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cn1ncc2c1CCCC2C(=O)NCc1nccnc1Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cn1ncc2c1CCCC2c1ncc2c(Cl)nccn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
To a solution of N-((3-chloropyrazin-2-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxamide (1.5 g, 4.9 mmol) in MeCN (50 mL) was added POCl3 (1.2 g, 7.9 mmol) dropwise and DMF (0.1 mL). The mixture was stirred at 60° C. for 4 hours. After cooling, the mixture was poured into ice-water and extracted with EA three times. The EA layer was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel (DCM/methanol=40/1 v/v %) to afford 8-chloro-3-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)imidazo[1,5-a]pyrazine (1.0 g, 70.4%). MS-ESI (m/z): 288 (M+1)+ (Acq Method: 10-80AB_2 min_220 &254.1 cm; Rt: 0.85 min)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](=[S:24])[NH2:23])=[CH:18]2)(=[O:11])=[O:10].[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:24][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:23]=1)=[CH:18]2)(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of 7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carbothioamide (2.3 g), ethyl but-2-ynoate (1.5 mL), tributylphosphine (1.5 mL), toluene (25 mL) and tetrahydrofuran (25 mL) was stirred for 3 hr at room temperature. The reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-5:5) to give the title compound (1.23 g, yield: 41%) as a pale-brown amorphous solid.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:6]=1[F:20])[CH2:3][OH:4].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24](O)=O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24]1[O:4][CH2:3][CH:2]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:6]=2[F:20])[N:1]=1
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CCCCCCCCCc1ccc(C(N)CO)c(F)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(C2COC(c3c(F)cccc3F)=N2)c(F)c1
Temperature: 25 °C

Procedure:
To a mixture of 2.81 g (10 millimoles) of 2-amino-2-(2-fluoro-4-n-nonylphenyl)ethanol, 1.77 g (10 millimoles) of 2,6-difluorobenzoic acid and 20 ml of toluene, 3 g (30 millimoles) of concentrated sulfuric acid was added and refluxed for 7 hours with stirring. After cooling again to room temperature, the reaction mixture was washed successively with 30 ml of a 10% aqueous sodium hydroxide solution and then 30 ml of a saturated sodium chloride solution, desiccated over anhydrous sodium sulfate and concentrated under reduced pressure. This concentrate was purified by silica-gel column chromatography using a 8/2 solvent mixture of n-hexane/ethyl acetate to obtain 2-(2,6-difluorophenyl)-4-(2-fluoro-4-n-nonylphenyl)-2-oxazoline (Compound Number 42).
Reaction SMILES: [NH2:1][C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[C:11](=[S:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4][CH:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Nc1coc2ccccc2c1=S
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2coc3ccccc3c2=S)cc1
Temperature: 10 °C
Yield: 93.9 %

Procedure:
In order to do this, 3-aminothiochromone (7.4 g) is suspended in anhydrous pyridine (25 ml), the mixture is cooled to about 10° C. and para-toluenesulphonyl chloride (8.6 g) is then added, whist stirring. After dilution with distilled water (100 ml), precipitation, filtration, washing with ethanol and drying, 3-(p-toluenesulphonylamino)-thiochromone (13 g), which melts at 212° C., is obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.Cl[C:20]1[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:18][C:20]4[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:13]([C:14]([F:16])([F:17])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=Cc1cccnc1Cl
Reactant: Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-ol (9-5, 35 mg, 0.14 mmol, 1 equiv.) and 2-chloropyridine-3-carbaldehyde (29 mg, 0.20 mmol, 1.5 equiv.) were dissolved in N,N-dimethylacetamide (1.5 mL) and treated with cesium carbonate (89 mg, 0.27 mmol, 2 equiv.). The mixture was irradiated at 100° C. in a microwave reactor for 30 minutes, cooled to ambient temperature and poured into water (30 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound 417.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].[Cl-].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.[CH3:34]N(C)C=O>>[CH:5]1([CH:34]=[CH:13][C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:1]1
Reactant: CC(C)(C)[O-]
Reactant: CN(C)C=O
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: C(=CC1CC1)c1cccs1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
Potassium tert-butoxide (1.81 g, 16.2 mmol) was suspended in N,N-dimethylformamide (50 mL), thiophen-2-ylmethyl triphenylphosphonium chloride (6.38 g, 16.2 mmol) was added while stirring at room temperature under a nitrogen stream, and the mixture was stirred at room temperature for 30 minutes. Then, cyclopropanecarboxyaldehyde (1.13 g, 16.2 mmol) was added dropwise to the reaction solution, and the solution was stirred for 1 hour. Water (100 mL) was added to the reaction solution, which was then extracted with hexane (50 mL). The organic layer was passed through silica gel (10 g) for filtration, the filtrate was evaporated in vacuo, and the title compound (1.27 g, 8.47 mmol, 52.3%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].O.[C:8]1(C)[CH:13]=CC(S(O)(=O)=O)=C[CH:9]=1>CC(C)=O>[CH3:9][C:8]1([CH3:13])[O:4][CH:3]([CH2:5][OH:6])[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)CO
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(CO)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 6265.8 %

Procedure:
In a pear-shaped flask equipped with a calcium tube, a condenser, and a Dean-Stark trap, 100 g of glycerine, 300 ml of acetone, 3 g of p-toluenesulfonic acid monohydrate, and 300 ml of petroleum ether were placed, and heated to reflux in an oil bath set at 50° C. After 12 hours, when about 23 ml of water was collected and no further formation of water was confirmed, the reaction mixture was cooled to room temperature. 3 g of sodium acetate was added, and the mixture was stirred for 30 minutes. Petroleum ether and acetone were distilled off in an evaporator. The resulting crude product was purified by vacuum distillation to give 130.6 g of 2,3-O-isopropylideneglycerol in the form of colorless, transparent liquid at 91% yield. 1H-NMR spectral data are shown below: