Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:41])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([O:42][CH2:43][CH2:44][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[O:41])[CH2:38][CH2:39]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(OCCN1CCOCC1)C1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(=O)N2CCC(C(=O)OCCN3CCOCC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.26 mmol) in DMF (2 mL) was added 2-(morpholin-4-yl)ethyl piperidine-4-carboxylate hydrochloride (140 mg, 0.50 mmol), DIEA (101 mg, 0.78 mmol), HATU (119 mg, 0.31 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 10% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (31.0% MeCN up to 38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 31.0% in 2 min); Detector, UV 254/220 nm. This resulted in 35.6 mg (20%) of the formic acid salt of 2-(morpholin-4-yl)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as a off-white solid. LCMS (Method 28) [M+H]+=687.2, RT=0.86 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.27-5.22 (m, 2H), 4.20-4.15 (m, 3H), 3.89-3.82 (m, 1H), 3.58-3.55 (m, 4H), 3.26-3.17 (m, 1H), 2.89-2.78 (m, 1H), 2.69-2.59 (m, 1H), 2.53-2.51 (m, 2H), 2.40-2.32 (m, 4H), 1.91-1.80 (m, 2H), 1.69-1.41 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: OC[C@H]1CCCCN1
Reactant: COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CCCC[C@@H]2CO)cc1
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine [prepared by a process described in Japanese Patent Unexamined Published Application (hereinafter referred to as “J. P. KOKAI”) No. Sho 48-19597] (600 mg, 5.22 mmol), 4-methoxyphenethyl tosylate (1.76 g, 5.74 mmol), sodium carbonate (608 mg, 5.74 mmol) and sodium iodide (100 mg, 0.67 mmol) were added to acetonitrile (50 ml), and they were heated under reflux at 90° C. for 3.5 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and dichloromethane (1:1), then with dichloromethane and finally with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(4-methoxyphenethyl)piperidine in the form of a light yellow oil (617 mg, 47%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]12([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2>CN(C)C=O>[Cl:1][C:30]1[CH:31]=[C:19]([C:9]23[CH2:10][CH:11]4[CH2:12][CH:13]([CH2:14][CH:15]([CH2:17]4)[CH2:16]2)[CH2:18]3)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: CN(C)C=O
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1Cl
Temperature: 0 °C

Procedure:
3.22 g of N-chlorosuccinimide are added to a solution of 7 g of 4-[4-(1-adamantyl)-phenoxy]-butyric acid in 40 ml of absolute dimethylformamide whilst stirring in an anhydrous atmosphere at 0° C. The mixture is then stirred for a further 15 minutes at 0° C, 30 minutes at about 25° C and 9 hours at 50° C. The reaction solution is cooled to 0° C, filtered and treated with 40 ml of ice water. The precipitate formed is filtered off and washed with ice water. It is then recrystallised twice from ethanol. 4-[2-Chloro-4-(1-adamantyl)-phenoxy]-butyric acid of melting point 164°-166° C is thus obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].CN1CCCC1=O.F[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([S:10][CH2:7][CH2:8][CH3:9])=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCSc1ccc(F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Potassium carbonate (5.0 g, 36.2 mmol) and 1-propanethiol (2.7 g, 35.5 mmol) were added to a N-methylpyrolidone (NMP) solution (15 ml) of 2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), and the mixture obtained was stirred at 90° C. for 2 hours. After the reaction mixture was cooled to room temperature, water (50 ml) was added, and the reaction product was extracted with ethyl acetate (100 ml). The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 6.7 g of powdery yellow 4-fluoro-2-nitro-1-propylsulfanylbenzene (yield: 99%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(O)[C:4]=2[CH:3]=1.[I-].[K+].O.[PH2](=O)[O-].[Na+].[PH2](=O)O>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:6]3[C:11]([C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: OC1(c2ccccc2)c2ccccc2C(O)(c2ccccc2)c2cc(Br)ccc21
Agent: O=[PH2]O
Agent: O=[PH2][O-]
Agent: [I-]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
About 7.6 g (17 mmol) of the obtained 2-bromo-9,10-diphenyl-9,10-dihydroanthracene-9,10-diol, 5.1 g (31 mmol) of potassium iodide, 9.7 g (92 mmol) of sodium phosphinate monohydrate, and 50 mL of glacial acetic acid were put into a 500 mL three-neck flask, and the mixture was refluxed at 120° C. for two hours. Thereafter, 30 mL of 50% phosphinic acid was added to the reactive mixture, and the mixture was stirred for one hour at 120° C. After the reaction, the solution was washed with water, and the aqueous layer was extracted with ethyl acetate. The extracted solution and an organic layer were dried with magnesium sulfate, filtered by suction filtration and the obtained filtrate was concentrated to obtain a solid substance. The solid substance was dissolved in toluene, and the solution was filtered through Celite (manufactured by Celite Co., Ltd.), Florisil (manufactured by Floridin Company), and alumina. The obtained filtrate was concentrated to obtain a solid substance, and the solid substance was recrystallized with a mixed solvent of chloroform and hexane, giving 5.1 g of 2-bromo-9,10-diphenylanthracene as a light yellow powdered solid substance. The yield of the two stages (ii) and (iii) was 74%.
Reaction SMILES: [OH-].[Na+].O.[I-].[CH2:5]([N:7]([CH2:28][CH3:29])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][CH:26]=[O:27])=[N+:14]([CH3:16])[CH:15]=1)=[O:9])[CH3:6].[BH4-].[Na+]>CO>[CH2:28]([N:7]([CH2:5][CH3:6])[C:8]([CH:10]1[CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][CH:26]=[O:27])[N:14]([CH3:16])[CH2:15]1)=[O:9])[CH3:29]
Reactant: CCN(CC)C(=O)c1ccc(CCc2ccccc2NC=O)[n+](C)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)C1CCC(CCc2ccccc2NC=O)N(C)C1
Reaction time: 2 h

Procedure:
A 50% sodium hydroxide solution (9.6 g., 0.12 mole) in 45 ml. of water is added to a solution of 5-diethylcarbamyl -2-(o-formamidophenethyl)-1-methylpyridinium iodide (46.7 g., 0.1 mole) in 300 ml. of methanol. Sodium borohydride (4.56 g., 0.12 mole) is added in portions with stirring to the reaction mixture. After 2 hr. the mixture is evaporated and water (500 ml.) is added to the resulting residue. This mixture is extracted with ether, the ethereal extracts washed with water, dried over magnesium sulfate and the other evaporated. The resulting residue consisting of N,N-diethyl-6-(o-formamidophenethyl)-1-methyltetrahydropyridine-3-carboxamide hydrogenated in a Parr apparatus in 200 ml. of ethanol employing 4 g. of 10% palladium on carbon as the catalyst at a temperature of 50°-70° C. provides N,N-diethyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].Cl[CH2:59][CH2:60][CH2:61][CH2:62]C>CN(C)C=O>[CH2:59]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:14])=[O:16])[C:18]([CH:53]([CH3:55])[CH3:54])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:44]([OH:45])[CH:41]1[O:40]3)[O:36]2)[CH2:60][CH2:61][CH3:62]
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg of compound (6) was dissolved in 0.5 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 5 mg of sodium hydride under cooling with ice. After 30 minutes, 78.7 μl of 1-chloropentane was added, and the reaction solution was stirred at room temperature for 4 hours. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with n-hexane-ethyl acetate (5:1). The fraction containing the desired product was concentrated to dryness to give 22.0 mg of compound (38).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[C:29]([CH3:30])=[N:28][C:27]([CH3:31])=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[C:29]([CH3:30])=[N:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: Cc1cnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)c(C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-3,5-dimethyl-pyrazine. MS (ESI) mass calcd. for C25H26N4O, 398.50; m/z found, 399.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C(C)=C1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[Si:41]([O:48][CH2:49][C@@H:50]1[C:55]([CH:56]([CH3:58])[CH3:57])=[CH:54][C@H:53](O)[CH2:52][N:51]1[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>>[CH2:1]([O:4][N:5]([C@H:53]1[CH2:52][N:51]([C:60]([O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[O:61])[C@H:50]([CH2:49][O:48][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[C:55]([CH:56]([CH3:58])[CH3:57])=[CH:54]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)C1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Product: C=CCON([C@@H]1C=C(C(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 78 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (0.928 g, 78%) was prepared as described in Intermediate 80 as a pale yellow oil, using (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 90, 0.731 g, 1.90 mmol) as a starting material.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[C:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)Cl)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CCc2ccc(O)cc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)C(=O)CC2)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A mixture of 6-hydroxy-1-indanone (250 g, 1687 mmol) (634549, commercially available from Sigma-Aldrich, St. Louis, Mo., USA), t-butyldiphenylchlorosilane (487 g, 1772 mmol) and imidazole (138 g, 2025 mmol) in degassed DMF (900 mL) was heated at 60° C. for 16 hours. The mixture was then concentrated to remove most of DMF, diluted with ether (3000 mL), filtered, and concentrated to give the initial product H1.1 (674 g, 100% yield) which was used in the next step reaction without further purification. MS ESI (pos.) M/E: 409 (M+Na).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([CH3:12])[CH:4]=1.[Br-].[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)=O>O1CCCC1.BrCCBr>[Br:23][C:19]1[CH:18]=[C:17]([C:15]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([CH3:12])[CH:4]=2)=[CH2:14])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOc1ccc(Br)cc1C
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(c1cccc(Br)c1)c1ccc(OCC)c(C)c1
Temperature: 0 °C

Procedure:
To a suspension of magnesium turnings (963 mg, 39.6 mmol, 1.2 eq) in 5 mL of dry tetrahydrofuran, 0.1 mL of 1,2-dibromoethane were added followed by 5 mL of a tetrahydrofuran solution of 4-bromo-1-ethoxy-2-methyl-benzene (7.8 g, 36.3 mmol, 1.1 eq in 25 mL tetrahydrofuran). The resulting mixture was gently heated to initiate the reaction. The remaining solution of bromide was added dropwise at such a rate that the reaction could reflux without external heating. After the addition the reaction mixture was heated at reflux for further 2 hours. The mixture was cooled to 0° C. and a solution of 3-bromoacetophenone (6.56 g, 33.0 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise. After 2 hours LCMS showed complete conversion to the desired product. 50 mL of water were added followed by 35 mL of 1M aqueous HCl. The organic fraction was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in 10 mL of acetic acid. 0.3 mL of 98% sulfuric acid were added and the dark solution was stirred at room temperature. After 30 min LCMS showed complete conversion to the desired product. Crushed ice was added to the reaction mixture which was then extracted with dichloromethane. The organic fraction was collected, washed with water, saturated sodium bicarbonate solution and dried with over sodium sulfate. The crude product was purified by flash chromatography eluting with cyclohexane. 7.5 g of clean product was obtained as colorless liquid (yield: 63%)
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])C(O)=O.[BrH:26].FF>>[F:1][C:2]([Br:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: Br
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Yield: 35.6 %

Procedure:
Perfluorooctanoic acid 18.6 g (0.045 mole), 48% hydrobromic acid 9.1 g (0.054 mole) and Freon 113 (400 ml) were mixed and treated with fluorine. The solution immediately turned to dark red. When the dark red color disappeared, fluorine was terminated and the reaction mixture was poured into dilute hydrochloric acid solution. The lower phase was separated and dried over magnesium sulfate. After removing the solvent, 7.2 g (36% yield) of perfluoroheptyl bromide was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1CCC(N2Cc3c(NCc4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (1.04 g, 4 mmol) was dissolved in acetic acid (7 ml) with heat. The mixture was cooled slightly and methylene chloride (50 ml) was added slowly followed by 3-chlorobenzaldehyde (0.91 ml, 8 mmol) and sodium triacetoxyborohydride. (2.54 g, 12 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 h, diluted with methylene chloride (100 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give a white solid. The solid was recrystallized from methylene chloride/methanol to give 0.48 g (31%) of product as a white solid: mp 253-255° C.; 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 7.45 (s, 1H), 7.37-7.19 (m, 4H), 6.95 (d, J=7.4 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.45 (t, J=5.9 Hz, 1H), 5.14 (dd, J=5.1 and 13.1 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 4.34 (d, J=17.3 Hz, 1H), 4.20 (d, J=17.2 Hz, 1H) 3.01-2.87 (m, 1H), 2.66-2.60 (m, 1H), 2.42-2.25 (m, 1H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.90, 171.24, 168.74, 143.03, 142.59, 133.08, 132.16, 130.19, 129.12, 126.80, 126.70, 125.73, 112.27, 110.55, 51.54, 45.73, 45.47, 31.25, 22.79; Anal. Calcd. For C20H18ClN3O3: C, 62.58, H, 4.73; N, 10.95. Found: C, 62.32; H, 4.61; N, 10.80.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH:37]1[CH2:42][CH2:43][OH:44]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH:37]([CH2:42][CH2:43][OH:44])[CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN1CCNCC1CCO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1CCO

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[3-(2-hydroxy-ethyl)-4-methyl-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(1-Methyl-piperazin-2-yl)-ethanol following General Procedure B.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH:15]([C:16]([O:18]CC)=[O:17])[S:14][CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+]>CO.O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH:15]([C:16]([OH:18])=[O:17])[S:14][CH2:13][C:12](=[O:21])[C:11]=2[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc2c(c1)C(=O)CSC2C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCc1ccc2c(c1)C(=O)CSC2C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
In methanol (150 ml) was suspended ethyl 6-hexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (41 g) followed by addition of 2N-KOH (150 ml). The mixture was stirred at room temperature for one hour. The reaction mixture was poured in water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6-hexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (27.5 g, yield 74%). Recrystallization from ether-hexane gave colorless plates.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([C:9]([O:11][CH3:12])=[O:10])[N:5]=[C:4](C(O)=O)[N:3]=1>Cl>[OH:8][C:7]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:4]=[N:3][C:2]=1[OH:1]
Reactant: COC(=O)c1nc(C(=O)O)nc(O)c1O
Agent: Cl
Product: COC(=O)c1ncnc(O)c1O

Procedure:
A solution of the product of Step 1 in HCl 1N solution was stirred for 6 hours at 90° C. Reaction mixture was filtered and the solid washed with HCl 1N. Evaporation of the filtrate afforded the title product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cc(Cl)ccc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2cc(Cl)ccc2n(C)c1=O
Reaction time: 2 h

Procedure:
A mixture containing 7.1 g. of 4,6-dichloro-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester, 2.36 g. of N-methylpiperazine and 2.5 g. of sodium carbonate in 25 ml. of dimethyl formamide was heated under reflux with stirring for 2 hours. The reaction mixture was cooled in ice and the resulting precipitate collected. Recrystallization from ethanol gave 4.2 g. of the title compound, m.p. 163°-165° C.