Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl.C1([C@@H]2CCCC[C@H]2[O:20][C:21](=O)[C@H:22]([OH:44])[C@@H:23]([S:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[NH2:43])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)C=CC=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[OH:44][C@@H:22]1[C@H:23]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[S:32][C:33]2[C:42]3[C:37]([CH:36]=[CH:35][C:34]=2[NH:43][C:21]1=[O:20])=[CH:38][CH:39]=[CH:40][CH:41]=3
Reactant: COc1ccc([C@H](Sc2c(N)ccc3ccccc23)[C@@H](O)C(=O)O[C@@H]2CCCC[C@H]2c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)NC(=O)[C@@H]2O)cc1
Yield: 88.7 %

Procedure:
A 10-gallon extractor was charged with 12.0 L of 3N Na2CO3, 575 g (1.02 mole) of (2S,3S)-3-[(2-amino-1-naphthalenyl)thio]-2-hydroxy-3-(4-methoxyphenyl) propanoic acid (1R,2S)-2-phenylcyclohexyl ester hydrochloride and 8.0 L of methylene chloride. The aqueous layer was successively extracted with an additional 4L+2L=6.0 L of methylene chloride. The combined organic layers were dried by filtration through a pad of anhydrous potassium carbonate and evaporated in vacuo to afford the free base which was taken up in 11.5 L of xylene. Then 16 g of p-toluene sulfonic acid.monohydrate was added and this mixture was stirred at reflux under argon for 16 hours (overnight). After cooling, the product was collected by filtration, washed with 500 mL of ethyl acetate, followed by 3×500 mL =1.5 L of ether and air dried overnight to afford 318 g (89%) of (2 S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-naphtho-[1,2-b][1,4]thiazepin-4(5H)-one as colorless needles, m.p. 235-238° decomposition, [α]D20 =+24.87°(c=0.4; acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:13][N:14]([CH3:24])[S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:10][C@H:9]2[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(CC#N)C=CC=1.[CH2:35]([C:42]1[N:46]=[C:45]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[O:44][N:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([C:42]1[N:46]=[C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:11][C@@H:9]3[CH2:10][C@@:8]3([CH2:13][N:14]([CH3:24])[S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:49][CH2:48]2)[O:44][N:43]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: c1ccc(Cc2noc(C3CCNCC3)n2)cc1
Reactant: CN(C[C@@]1(c2cccc(Cl)c2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Agent: N#CCc1cccc(Cl)c1
Product: CN(C[C@@]1(c2cccc(Cl)c2)C[C@H]1CN1CCC(c2nc(Cc3ccccc3)no2)CC1)S(=O)(=O)c1ccccc1

Procedure:
N-{[(1S,2R)-1-(3-chlorophenyl)-2-formylcyclopropyl]methyl}-N-methylbenzenesulfonamide [made from (3-chlorophenyl)acetonitrile via the sequential methods of Preparations 1, 2, 3A, 4A, 5A, 6A, 7A, 8A] and 4-(3-benzyl-1,2,4-oxadiazol-5-yl)piperidine (incorporating by reference as needed WO 00/39125) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, CD3OD) δ 7.70-7.53 (m, 5H), 7.36-7.23 (m, 9H), 4.07 (s, 2H), 3.83 (d, J=14.0 Hz, 1H), 3.39-3.16 (m, 4H), 3.09 (d, J=14.0 Hz, 1H), 2.78-2.61 (m, 3H), 2.57 (s, 3H), 2.28-2.21 (m, 2H), 2.07-1.94 (m, 2H), 1.53-1.48 (m, 1H), 1.33-1.29 (m, 1H), 1.00-0.96 (m, 1H). ES-LCMS m/z 591.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]2C(OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C=CN(C(=O)OCc2ccccc2)C(c2ccc(F)cc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O[C@@H]1CCN[C@H](c2ccc(F)cc2)C1

Procedure:
A mixture of benzyl 2-(4-fluorophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.07 mmol) (reagent preparation 20) and 5% Pd on carbon (0.1 g) in acetic acid:methanol 1:10 (20 mL) was hydrogenated at 45 psi using a Parr apparatus for 16 hours. The catalyst was removed by filtering through Celite, and the filtrate concentrated to give (±)-(2S,4R)-2-(4-fluorophenyl)piperidin-4-ol as an oil. The material was taken into chloroform (100 mL) and di-tert-butyl dicarbonate (0.74 g, 3.4 mmol) was added, followed by the dropwise addition of diisopropylethylamine (1.5 g, 12 mmol). The reaction was warmed to reflux for 10 minutes, then allowed to cool to 25° C. over 30 minutes. The organic solution was washed with 0.1M aqueous hydrochloric acid (45 mL), water (50 mL) and saturated sodium bicarbonate (50 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes, 1:1) to give (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (0.59 g, 65% yield). 1H NMR (400 MHz, d6-DMSO): 7.25 (m, 2H), 7.10 (m, 2H), 4.96 (t, 1H), 4.46 (d, 1H), 3.90 (m, 1H), 3.77 (m, 1H), 3.23 (dt, 1H), 2.06 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H), 1.45 (m, 1H), 1.29 (s, 9H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:11].O>CO>[OH:3][N:2]=[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[NH2:11]
Reactant: NO
Reactant: N#Cc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=NO)c1cccnc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
Hydroxylamine hydrochloride (1.3 g) and sodium carbonate (2.0 g) were added to a mixed solution of 3-cyanopyridine in methanol (10 ml)/water (10 ml) and the mixture was stirred at 100° C. for 2.5 hours. After distilling off the solvent under reduced pressure, water was added to the residue and extracted with tetrahydrofuran, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain N′-hydroxypyridine-3-carboximidamide (1.3 g) as a colorless oily substance.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][O:14][CH2:15][N:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18][C:17]2=[O:23])=[CH:11][CH:10]=1>CO.C(Cl)(Cl)Cl>[OH:7][CH2:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][O:14][CH2:15][N:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18][C:17]2=[O:23])=[CH:11][CH:10]=1
Reactant: O=c1ncc(Cl)cn1COCc1ccc(COC2CCCCO2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ncc(Cl)cn1COCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
Dowex 50W-X8 ion exchanger in the acid form (0.29 g) was added to a solution of 1-[4-(tetrahydropyran-2-yloxymethyl)benzyloxy]methyl-5-chloropyrimidin-2-one (see Example 19) (1.2 mmol) in methanol (2 ml) and chloroform (0.5 ml) and the mixture stirred at room temperature for 2.5 hours. The ion exchanger was then removed by filtration and the filtrate evaporated to dryness at reduced pressure without heating. The residue was the title compound in the form of a non-crystalline material, obtained in 60% yield. 1H NMR (CDCl3): δ4.5-5.0 (2CH2), 5.38 (NCH2), 7.43 (Ph), 8.00 and 8.60 (H-4, H-6, J 4 Hz).
Reaction SMILES: [C:1]([CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:19][C:6]1=2)#[N:2].[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:7]2[O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:5]([S:4][CH2:3][C:1]3[NH:36][N:35]=[N:34][N:2]=3)[C:6]=2[CH:19]=1
Reactant: N#CCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: c1ccc2c(c1)COc1ccc(OCc3ccc4ccccc4n3)cc1C2SCc1nnn[nH]1

Procedure:
11-Cyanomethylthio-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine, ammonium chloride and sodium azide were used and reacted in the same manner as in Example 32 to obtain the title compound.
Reaction SMILES: CC(CCC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(C[C@H](CC2)O)=CC3)CC1)C)C.[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C@@H:49]1[CH2:62][C:61]2[C@@:52]([CH3:75])([C@@H:53]3[C@@H:58]([CH2:59][CH:60]=2)[C@@H:57]2[CH2:63][CH2:64][C@H:65]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH:71]([CH3:73])[CH3:72])[CH3:67])[C@@:56]2([CH3:74])[CH2:55][CH2:54]3)[CH2:51][CH2:50]1)=[O:47]>O>[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C@@H:49]1[CH2:62][C:61]2[C@@:52]([CH3:75])([C@@H:53]3[C@@H:58]([CH2:59][CH:60]=2)[C@@H:57]2[CH2:63][CH2:64][C@H:65]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH:71]([CH3:73])[CH3:72])[CH3:67])[C@@:56]2([CH3:74])[CH2:55][CH2:54]3)[CH2:51][CH2:50]1)=[O:47]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1

Procedure:
Esters such as steroid esters are widely used as an oil phase material or base material of cosmetics for the skin or hair, or of ointments. For example, stearic acid ester or oleic acid ester of cholesterol is contained in stick-like cosmetics such as lipstick, eyeshadow and stick pomade as well as in cosmetic cream, ointment, etc. These linear fatty acid esters of cholesterol are excellent in water-embracing or -encapsulating property and emulsifying property, exhibit affinity with the skin, and are not irritative. These properties render the esters desirable for use as an oil phase material or additive of, for example, cosmetics or ointments. However, these esters are undesirably solidified at temperatures near the human skin temperature. For example, cholesteryl stearate has a melting point of 75° to 85° C., with cholesteryl oleate having a melting point of 40° to 45° C., with the result that the cosmetics containing these esters give uncomfortable feel to the user when applied to the skin. It should also be noted that these esters are decomposed into cholesterol and fatty acids under the action of lipase present on the skin.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1>>[NH:16]1[C:15]([NH:14][C:11]([C:7]2[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[CH:9][N:8]=2)=[O:13])=[N:19][N:18]=[N:17]1
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1ccnc(C(=O)O)c1
Product: CCCCc1ccnc(C(=O)Nc2nnn[nH]2)c1
Yield: 63 %

Procedure:
0.52 g of 4-n-butyl-2-pyridinecarboxylic acid, 0.48 g of N,N'-carbonyldiimidazole and 0.27 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide, water and ethanol, whereby 0.45 g of N-(5-tetrazolyl)-4-n-butyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:23])[CH2:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].[Na+].Br[CH2:27][C:28]1[C:29]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:30]=2[S:31][CH:32]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:35]1[CH:34]=[C:33]([Cl:37])[C:30]2[S:31][CH:32]=[C:28]([CH2:27][O:23][CH:16]([C:10]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=3[Cl:8])[CH2:17][N:18]3[CH:19]=[N:20][CH:21]=[CH:22]3)[C:29]=2[CH:36]=1
Reactant: Clc1cccc2c(CBr)csc12
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(C(Cn2ccnc2)OCc2csc3c(Cl)cccc23)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 0.25 h
Yield: 105.5 %

Procedure:
A 2-L flask was loaded with 308 mL of toluene, 100 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanol (II) (0.389 mol) and 6.67 g of tetrabutylammonium hydrogen sulfate (IV, Z═HSO4) (0.0196 mol). Then, 155 g of sodium hydroxide (purity 49%; 1.905 mol) were added. The mixture was heated at 35-40° C. and stirred for 15 minutes. A solution comprising 111.11 g of 3-bromomethyl-7-chlorobenzo[b]thiophene (III) (0.425 mol) and 595 mL of toluene, maintaining the mass temperature between 37 and 40° C., was added for at least 30 minutes. After the addition, the system was maintained between 37 and 40° C. for 2.5 hours and thereafter water (635 mL) was added. The mixture was cooled to a mass temperature of 5-10° C. and the sertaconazole precipitated was filtered and washed with water and cold toluene (5-10° C.), obtaining 179.7 g of wet sertaconazole free base (161.7 g dry).
Reaction SMILES: [CH2:1]([C@@:4]12[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:20])[CH2:6][CH2:5]2)[CH:2]=[CH2:3].B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([C@@:4]12[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:20])[CH2:6][CH2:5]2)[CH:2]=[CH2:3]
Reactant: C=CC[C@]12CCC(=O)C=C1CCc1cc(OC)ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC[C@]12CCC(=O)C=C1CCc1cc(O)ccc12
Temperature: 0 °C
Yield: 77.4 %

Procedure:
To a solution of (4aR)-4a-allyl-7-methoxy-4,4a,9,10-tetrahydro-3H-phenanthren-2-one (15.0 grams, 55.9 mmol) in methylene chloride (350 mL) at −78° C. was added dropwise boron tribromide (10.6 mL, 112 mmol). The mixture was allowed to warm to 0° C. over 5 hours and was then poured onto a mixture of ice and water. Solid sodium bicarbonate was carefully added to neutralize the mixture which was then extracted with ethyl acetate. After washing with brine, the organic extract was dried (MgSO4) and concentrated under vacuum. The title compound (11.0 grams, 53%) was isolated by flash chromatography eluting with 5 to 10% ethyl acetate in methylene chloride. 1H NMR (CDCl3): δ 7.14 (d, J=8.5 Hz, 1 H), 6.72 (dd, J=2.7, 8.5 Hz, 1 H), 6.58 (d, J=2.7 Hz, 1 H), 5.94 (s, 1 H), 5.62–5.54 (m, 1 H), 5.03–4.98 (m, 2 H), 4.85 (br s, 1 H), 2.95–2.91 (m, 1 H), 2.85–2.63 (m, 5 H), 2.53–2.40 (m, 3 H), 2.08–1.99 (m, 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:10])([CH:6]([OH:9])[CH2:7][CH3:8])[CH3:5].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][CH:6]([CH2:7][CH3:8])[C:4]([CH3:10])([CH3:5])[CH3:3])[N:15]=[CH:14][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCC(O)C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(Oc1cc(Cl)ncn1)C(C)(C)C
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of tetrahydrofuran containing 0.26 g of 2,2-dimethyl-3-pentanol dissolved therein was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.3 g of 4,6-dichloropyrimidine dissolved therein at 0° C., followed by stirring at the same temperature for 1 hour and at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.35 g of 4-chloro-6-(1-ethyl-2,2-dimethylpropyloxy)pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=C(C)C=1.[CH:35]([N:37]1[C:45](=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]1=[O:47])=[CH2:36]>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[NH2:5][C:4]1[CH:3]=[C:2](/[CH:36]=[CH:35]/[N:37]2[C:38](=[O:47])[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]2=[O:46])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cccc(P(c2ccccc2C)c2ccccc2C)c1
Solvent: CC#N
Product: Nc1cc(/C=C/N2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a degassed solution of 3-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.17 mmol) and ACN (40 mL) was added Pd(OAc)2 (0.46 g, 0.20 mmol), bis(2-methylphenyl)(3-methylphenyl)phosphine (0.13 g, 0.40 mmol), and TEA (1.15 mL, 8.25 mmol). After stirring for 1 h, 2-vinyl-1H-isoindole-1,3(2H)-dione (0.72 g, 4.17 mmol) was added. The solution was heated at reflux for 20 h and then allowed to cool to rt and filtered through Celite. The filtrate was washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to yield the title compound as a yellow solid (0.90 g, 62%). LCMS: (FA) ES+ 333.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(O)=O.[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.O>[C:15]([NH:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(N)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C#N)NC(=O)c1ccccc1
Yield: 21.5 %

Procedure:
To a stirred solution of compound ethyl 2-amino-2-cyanoacetate (0.64 g, 5 mmol) in DCM (15 mL) was added a saturate solution of NaHCO3 in water (15 mL). With vigorously stirring, benzoyl chloride (0.84 g, 6 mmol) was added. The reaction mixture was stirred at ambient temperature for additional 30 min at which time it was extracted with DCM (3×15 mL). Combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered, concentrated in vacuo. Resulted residue was purified by silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl 2-benzamido-2-cyanoacetate (0.25 g, 22%) as white solid: 1H-NMR (CDCl3, 500 MHz) δ (ppm): 7.83-7.85 (m, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.49 (t, J=7.5 Hz, 2H), 7.02 (d, J=7.0 Hz, 1H), 5.72 (d, J=7.5 Hz, 1H), 4.40 (q, J=7.5 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 233 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:26](/[CH:27]=[N:28]/[S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:26]([CH2:27][NH:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)/N=C/c1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)NCc1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Yield: 74 %

Procedure:
To a solution of N-[(1E)-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}pyridin-3-yl)methylene]-2-methylpropane-2-sulfinamide (170 mg, 0.34 mmol) in MeOH (1.2 ml) and CH2Cl2 (2.5 ml) was added NaBH4 (78 mg, 2.06 mmol). The reaction was left for 10 minutes, before addition of water (2 mL). The mixture was extracted with CH2Cl2 dried (Na2SO4) and evaporated in vacuo to give the title compound as a solid (125 mg). 1H NMR (400 MHz, d6-DMSO): δ 8.72 (1H, s), 8.43 (1H, t, J=2.3 Hz), 8.38 (1H, s), 8.34 (1H, d, J=8.7 Hz), 8.23 (2H, dd, J=8.2, 10.2 Hz), 8.04 (1H, dd, J=1.8, 8.6 Hz), 7.95-7.91 (3H, m), 7.69 (1H, dd, J=4.6, 8.0 Hz), 7.38 (2H, t, J=8.8 Hz), 5.98 (1H, t, J=6.5 Hz), 4.88-4.78 (2H, m), 1.18 (9H, s). m/z (ES+) 497 [MH+].
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[CH2:15]([S:19]Cl)[CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH3:1][N:2]([S:19][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4]
Reactant: CCCCSCl
Reactant: CNC(=O)Nc1cc(C(C)(C)C)on1
Solvent: c1ccncc1
Product: CCCCSN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 8 h
Yield: 10.9 %

Procedure:
To a solution of 1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (1.97 g) in pyridine (30 ml), butylsulfenyl chloride (1.08 mol equivalent) is added at -30° to -40° C. The resultant mixture is allowed to stand at -30° to -40° C for 6 hours and at room temperature overnight. The reaction mixture is chromatographed on a column of silica gel, whereby 1-methyl-1-butylthio-3-(5-t-butyl-3-isoxazolyl)urea (0.31 g) is obtained as an oil. I.R.: 1698, 1606 cm-1 (CCl4).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Br-:10].[Na+].CN(C)C=O>CC(C)=O>[Br:10][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(=O)oc1CCl
Reactant: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 403 mg of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one and 525 mg of sodium bromide was added 0.8 ml of anhydrous N,N-dimethylformamide, followed by at room temperature for 1.5 hours. To the reaction solution was added 1.2 ml anhydrous acetone, the mixture was further stirred at room temperature for 1 hour, and then insolubles were removed by filtration. Insolubles were washed three times with 0.8 ml of anhydrous acetone, and the resulting pale yellow solution was used in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:12]([N+:20]([O-])=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]>O1CCCC1.[Pd]>[NH2:20][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CCOc1nc2ccccc2c([N+](=O)[O-])c1N1CCOCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1nc2ccccc2c(N)c1N1CCOCC1

Procedure:
The 2-ethoxy-3-morpholino-4-nitroquinoline (1.2 g, 0.004 mol) was dissolved in tetrahydrofuran (10 ml) and subjected to reduction in the presence of 10g palladium-on-carbon (0.3 g). After completion of the reaction, the palladium-on-carbon catalyst was filtered off and the mother liquor was concentrated. Following purification by chromatography on an alumina column using chloroform as a developing solvent, recrystallization from chloroform gas performed to obtain 4-amino-2-ethoxy-3-morpholinoquinoline in an amount of 0.7 g (yield, 60%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1>O>[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:48][C:2]4[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)=[CH:4][N:3]=4)[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: Fc1ccc(OCCCOC2CCCCO2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCCOC5CCCCO5)cn4)cc23)n1
Temperature: 180 °C
Reaction time: 14 h
Yield: 96.5 %

Procedure:
2-Fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (305 mg, 1.10 mmol) and potassium tert-butoxide (140 mg, 1.24 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (120 mg, 0.50 mmol), and stirred at 180° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, then saline water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:3) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-({5-[3-(tetrahydro-2H-pyran-2-yloxy)prop oxy]pyridin-2-yl}oxy)quinazoline-4-amine (230 mg, yield: 97%) as a pale orange amorphous solid.