Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].[H-].[Na+]>CN(C=O)C>[CH3:12][N:13]([CH3:17])[C:14]([O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[S:15]
Reactant: CN(C)C(=S)Cl
Reactant: COc1cc(O)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(OC(=S)N(C)C)c1

Procedure:
3,5-Dimethoxyphenol is reacted with N,N-dimethylthiocarbamoyl chloride in the presence of sodium hydride in DMF to give 1-dimethylaminothiocarbonyloxy-3,5-dimethoxybenzene of m.p. 77°-78°. This product is rearranged, by heating for half an hour at 270°, to give 1-dimethylaminocarbonylmercapto-3,5-dimethoxybenzene, which, in the crude state, by leaving to stand for 3 days with ethanolic KOH, is saponified to give 3,5-dimethoxythiophenol of b.p. 103°-109°/0.25 mm. Reaction with glutaconic acid dimethyl ester gives 3-(3,5-dimethoxyphenylmercapto)-glutaric acid dimethyl ester, which is converted, at 80° by means of polyphosphoric acid, into 5,7-dimethoxy-thiochroman-4-one-2-acetic acid methyl ester of m.p. 98°-99°. The corresponding free acid (m.p. 180°-182°) is converted, via the chloride and the amide (m.p. 199°-202°), into the corresponding nitrile (m.p. 123°-124°), which is split, by means of BBr3, into 5-hydroxy-7-methoxy-thiochroman-4-one-2-acetonitrile (m.p. 97°-98°). Analogously to Example 1, there are obtained therefrom 5-hydroxy-7-methoxy-thiochroman-4-one-2-acetaldehyde (m.p. 112°-115°), 2-phenyl-4-[2-(5-hydroxy-7-methoxy-thiochroman-4-on-2-yl)-ethylidene]-2-thiazolin-5-one (m.p. 97°-99°), 4-thiobenzamido-1,4,4a,5,5a,6,11,12-octahydro-3,10,12-trihydroxy-8-methoxy-1,11-dioxo-6-thianaphthacene-2-carboxamide (mixture of stereo-isomers), 4-de-dimethylamino-4-thiobenzamido-8-methoxy-12a-dehydroxy-6-thiatetracycline (m.p. 212°-215°) and, finally, by hydroxylation
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:20](=[O:22])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 52.5 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-methoxy-benzoic acid (1.50 g, 8.97 mmol) in anhydrous acetonitrile (15 mL) at 50-55° C. were simultaneously added pyridine (1.42 g, 17.9 mmol) and a solution of triphosgene (0.870 g, 2.96 mmol) in anhydrous dichloromethane (20 mL) over 20 minute span, and the reaction was stirred at 50-55° C. for 2 hours. The solvent was removed and the residue was mixed with water (100 mL), the solid was filtered and rinsed with cold water (30 mL) and dried. The crude product was further washed with ether (20 mL) to give 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione. Yield: 1.40 g (81%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH2:9](Br)[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:9][CH2:10][CH3:11])[N:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1ncc(C#N)c1N
Temperature: 80 °C

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Acros, 3.24 g, 30.0 mmol), propylbromide (Acros, 4.43 g, 36 mmol) and anhydrous potassium carbonate (Fisher, 5.0 g, 36 mmol) were suspended in 20 mL anhydrous DMF and heated at 80° C. in a sealed tube under argon overnight. The reaction was permitted to cool and the DMF was removed on a rotary evaporator. Water was added (100 mL) and the organics were extracted with dichloromethane (3×100 mL). The combined dichloromethane fractions were washed with water (50 mL) and brine (50 mL) and were dried (magnesium sulfate). Concentration of the organics afforded an oil which was subjected to flash chromatography on silica gel (1-3% methanol/dichloromethane). Two white crystals were obtained: compound 101 (1.88 g, 42%) elutes first and compound 102 (711 mg, 16%) elutes second. Compound 101: mp 85-90° C.; MS (ES+ calculated: 150.18; found: 151.15 M+H). HPLC (99%) purity, retention time 5.8 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 5.52 (s, 2H), 3.82 (t, J=7, 2H), 1.70 (m, 2H), 0.79 (t, J=7, 3H). Compound 102: mp 162-164° C.; MS (ES+ calculated: 150.18; found: 151.18 M+H). HPLC (95%) purity, retention time 6.4 minutes—Method A); 1H 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 6.53 (s, 2H), 3.82 (t, J=7, 2H), 2.95 (m, 2H), 0.81 (t, J=7, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(C(C)C)CC)(C)C.[CH:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:28][C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:31]3)[CH2:17][CH2:18]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCC(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)piperidine-4-carboxamide hydrochloride (1.55 g) in dichloromethane (100 mL) was added di-iso-propylethylamine (1.3 mL). The solution was stirred for 15 minutes after which tert-butyl (3R)-3-formylpiperidine-1-carboxylate (1.17 g) and sodium triacetoxyborohydride (1.59 g) was added. The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and water and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to give the title compound as a white foam (2.34 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: OCCN1CCOCC1
Solvent: Cc1ccccc1
Product: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 117 °C
Reaction time: 2 h

Procedure:
7g (0.02 moles) of (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and toluene (25ml) are warmed gently to form a solution. A slight excess (1.05 molar equivalents) of 2-morpholinoethanol (3 g, 0.021 moles) and toluene (25 ml) are added. The reaction mixture is stirred for half an hour and then heated to reflux at an initial pot temperature of 117° C. (which increases a few degrees during reflux) under a Dean-Stark trap for 80 hours. The reaction mixture is cooled, washed with water (2×15ml), 10% aqueous sodium bicarbonate (2×15ml) and finally with water (15 ml). The toluene layer is stripped to a volume of about 20 ml in vacuo, n-hexane (30 ml) is added and the resulting slurry is aged at room temperature for 2 hours. The product is filtered, washed with n-hexane (ca. 10 ml) and dried in vacuo at 60° C. to yield 2-(morpholin-4-yl)ethyl (E)-6- (1,3-dihydro-4-amino-6-methoxy-7-methyl -3-oxoisobenzofuran- 5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(N2CCN(c3ccc(N/C=C4\C(=O)NC(=O)c5ccc(I)cc54)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), 1-methyl-piperidin-4-one (0.318 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 45 mg (78%) of the title compound as a yellow solid. MS (ESI) m/z 572.2 (M+H)+1.
Reaction SMILES: C[Li].C1(C)C=CC(S(NN=[C:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([C@H:31]([N:33]([CH3:35])[CH3:34])[CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C@H:23]([CH2:24][C@H:25]([OH:39])[C@@H:26]([O:36][CH2:37][CH3:38])[CH2:27]2)[CH2:22][CH2:21]4)(=O)=O)=CC=1>CCOCC.O1CCCC1>[CH3:34][N:33]([C@@H:31]1[CH2:32][C@@:15]2([CH3:16])[C@@H:17]([CH2:18][CH:19]=[CH:14]2)[C@H:20]2[C@H:30]1[C@:28]1([CH3:29])[C@@H:23]([CH2:22][CH2:21]2)[CH2:24][C@H:25]([OH:39])[C@@H:26]([O:36][CH2:37][CH3:38])[CH2:27]1)[CH3:35]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)C(=NNS(=O)(=O)c4ccc(C)cc4)CC[C@@H]32)C[C@@H]1O
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)C=CC[C@@H]32)C[C@@H]1O
Reaction time: 72 h

Procedure:
A 1.5 M solution of methyl lithium in ether (20 ml) was added to a cooled solution of 11α-N,N-dimethylamino-2β-ethoxy-3α-hydroxy-5α-androstan-17-one 17-p-toluenesulphonylhydrazone (1.2 g) in dry tetrahydrofuran (100 ml). The mixture was kept at room temperature for three days and then most of the solvent was evaporated in vacuo. The residue was acidified with 2 N-hydrochloric acid, washed with ether, and the aqueous layer was then basified with 2 N-sodium hydroxide and extracted into ether. The washed and dried (Na2SO4) extract was evaporated in vacuo and the residue was purified by chromatography over silica (ethyl acetate-petroleum ether 1:1) and crystallization from aqueous methanol to give the title compound m.p. 51°-54°, [α]D -23.8°.
Reaction SMILES: [C:1](OC)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](=O)[CH3:20])=[CH:14][CH:13]=1.C[O-].[Na+].[NH2:25][NH2:26]>C(O)(=O)C.C(O)C.C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:26][N:25]=[C:1]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[CH:20]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccncc1
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: NN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A 22 liter, three-neck, round bottom flask equipped with a mechanical stirrer, thermocouple, and reflux condenser with N2 inlet adapter was charged with THF (6.0 L), methyl isonicotinate (259.1 g, 1.89 mol), and 4-fluorophenylacetone (287.5 g, 1.89 mol). Sodium methoxide (204.3 g, 3.78 mol) was added in several portions. The addition of sodium methoxide is slightly exothermic. The reaction mixture turned orange and was heated to reflux for 2 hours. After 2 hours, the absence of methyl isonicotinate and the formation of the β-diketone were verified by LC-MS. After the addition of ethanol (6 L) and acetic acid (380 mL), the temperature of the reaction mixture decreased to 45° C. The reflux condenser was then replaced with an addition funnel and hydrazine (387 g, 6.0 mol) was added drop-wise. During the addition the temperature of the reaction rose to 60° C. The reaction mixture was then stirred overnight slowly cooling to room temperature. The majority of the solvents were removed by rotary evaporation. The reaction mixture was partitioned between water (4.5 L) and ethyl acetate (4.5 L). The layers were separated and the aqueous layer extracted with ethyl acetate (4.5 L). The combined organic layers were then washed with dilute NaHCO3, brine, dried (Na2SO4), filtered and concentrated. The resulting solid was triturated with ether (2 L) and the solid isolated by filtration. The solid was washed with ether (1.5 L) until the filtrate was colorless. This process gave 190 g (40%) of the title compound. Additional material (5 g) was then isolated by column chromatography using 5% methanol:95% methylene chloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 13.10 (s, 1 H), 8.44-8.60 (m, 2 H), 7.68 (d, 2 H), 7.30 (t, 2 H), 7.13 (t, 2 H), 6.62 (s, 1 H), 4.00 (s, 2 H); m/z (APCI+) for C15H12N3F 254.2 (M+H)+.
Reaction SMILES: [C:1]([C@@:4]12[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([OH:14])[CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:3])[CH3:2].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl.C(N(CC)CC)C>C1COCC1>[C:1]([C@@:4]12[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:3])[CH3:2]
Reactant: CC(=O)[C@]12CCCC[C@@]1(O)CCCC2
Reactant: COCCOCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOCO[C@]12CCCC[C@@]1(C(C)=O)CCCC2

Procedure:
A mixture of 100 mmol of 4a-acetyl-8a-hydroxy-cis-decalin, 110 mmol of 2-methoxyethoxymethyl chloride, 110 mmol of triethylamine, and 200 ml of THF was refluxed for 3 hours. The resulting reaction mixture was subjected to column chromatography on a silica gel to yield 4a-acetyl-8a-(2-methoxyethoxymethoxy)-cis-decalin represented by the following formula (yield: 90.3%). The conversion rate from 4a-acetyl-8a-hydroxy-cis-decalin was 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[CH:24]=[C:23]([C:25]#[N:26])[C:18]([C:19](OC)=[O:20])=[C:17]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH3:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:17]2[C:18]3[C:19](=[O:20])[NH:26][CH2:25][C:23]=3[CH:24]=[C:15]([NH:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[N:16]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:35])=[O:36]
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1Nc1cc2c(c(Nc3cccc(S(C)(=O)=O)c3)n1)C(=O)NC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
A mixture of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclopentylamino)-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (141.1 mg, 0.266 mmol) and palladium hydroxide on carbon (43.2 mg, 0.308 mmol) in MeOH (10 mL) and HOAc (10 mL) was stirred at RT for 12 h under a hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (20 mL) and MeOH (20 mL). The mixture was stirred at RT for 6 h and then concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (30 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (DM1020, EtOAc) to give the desired product (46.5 mg). The product was washed with IPE/EtOAc to give the title compound as a pale brown solid (34.7 mg, 26%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>CCO.CC(O)=O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][N:19]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][NH2:1])=[CH:14][CH:13]=1
Reactant: NCC(=O)c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NCC(=NNc1ccc(Cl)cc1)c1ccccc1
Yield: 84 %

Procedure:
A mixture of 10.43 g 2-aminoacetophenone and 11.0 g 4-chlorophenylhydrazine in 30 ml EtOH and 10 ml HOAc was refluxed for one hour. The cooled reaction mixture was diluted with water and the precipitate was collected, washed with water, and dried to give 16.83 g solid. Recrystallization from methanol gave 3.48 g solid, m.p. 109°-112° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[S:31][CH:32]=[CH:33][N:34]=4)=[O:28])=[C:22]([F:35])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:36]#[N:37])C1C=CC=CC=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[C:36]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[O:28])=[C:22]([F:35])[CH:21]=1)#[N:37]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
The N-(4-(7-benzyloxy-6-cyanoquinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea (5.53 g) synthesized in Example 141 was dissolved in TFA (55 ml), and then thioanisole (5.5 ml) was added and the mixture was heated and stirred at 70° C. for 6 hours. After cooling the reaction solution and concentrating it under reduced pressure, sodium bicarnobate water and methanol were added and the precipitated crystals were filtered. These were washed with diethyl ether to obtain 3.63 g of the title compound (80% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(N(CCCCCCBr)CCc1ccccc1)C(F)(F)F
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(CCCCCCN(CCc2ccccc2)C(=O)C(F)(F)F)C(=O)C(F)(F)F)cc1N
Reaction time: 4 h
Yield: 55.2 %

Procedure:
N-[2-[3-Amino-4-methoxyphenyl]ethyl]-2,2,2-trifluoro acetamide (2.62 g, 0.01 moles) in dry dimethylformamide (50 ml) was added dropwise with stirring to sodium hydride (0.3 g., 80% oil dispersion, 0.01 moles) in dry dimethylformamide (50 ml) under nitrogen. The solution was warmed at 60° for 30 min then cooled and N-(6-bromohexyl)-2,2,2-trifluoro-N-(2-phenylethyl)acetamide (3.80 g., 0.01 mole) was added. The solution was stirred for 4 hours then quenched with water and extracted with ethyl acetate. The extracts were washed with water dried and evaporated to give crude N-[2-(3-amino-4-methoxyphenyl)ethyl]-N'-(2-phenylethyl)-1,6-hexanediylbis (2,2,2-trifluoroacetamide) (3.1 g) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1.[F:21][C:22]1[CH:23]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](=[O:43])(=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:25]=[CH:26][C:27]=1[CH2:28]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36](=[O:42])(=[O:43])[NH:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[CH:23][C:22]=2[F:21])[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)[nH]1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 93 %

Procedure:
The alkylation of 2-(2-bromo-5-nitrophenyl)-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 75, Step A) with [3-fluoro-2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Step B) was carried out according to the procedure of Example 13, Step A, to give a 93% yield of the title compound as a brownish, stiff foam, mp 137°-139° C., homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 666, 668 (M+Li)+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:26](=O)[CH3:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+]>CO.C(#N)C>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([CH:26]([NH2:35])[CH3:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloroquinolin-7-yl]ethanone (275 mg, 0.656 mmol) and ammonium acetate (506 mg, 6.56 mmol) in methanol (3.7 mL) and acetonitrile (3.7 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (82.5 mg, 1.31 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C22H35ClN3OSi (M+H)+: m/z=421.2; Found: 421.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N+:31]([O-])=O)[CH:22]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O-])=O.[H][H]>[Pd].COCCO>[NH2:31][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=1)[O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:34]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:36]=[C:4]([NH2:1])[CH:5]=3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cc(Oc2ccc(-c3ccc(Oc4cc([N+](=O)[O-])cc(C(F)(F)F)c4)cc3)cc2)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: Nc1cc(Oc2ccc(-c3ccc(Oc4cc(N)cc(C(F)(F)F)c4)cc3)cc2)cc(C(F)(F)F)c1
Yield: 96 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 33 g (0.0585 mol) of 4,4'-bis(3-nitro-5-trifluoromethylphenoxy)biphenyl, 100 ml of methyl cellosolve and 1.7 g of 5%-Pd/c having a moisture content of 50% were charged and reacted in a hydrogen atmosphere at 70°~80° C. for 4 hours. After finishing the reaction, the catalyst was filtered off. The filtrate was concentrated under reduced pressure to obtain 4,4'-bis(3-amino-5-trifluoromethylphenoxy)biphenyl as light yellow crystals.