Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>C(O)C>[OH:25][N:24]=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(C=O)c(Oc2ccccc2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C=NO)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 60.2 %

Procedure:
To a solution of 4-formyl-3-phenoxy-benzonitrile (2.21 g) in dry ethanol (45 ml) was added sodium acetate (0.894 g) and hydroxylamine hydrochloride (0.757 g). The mixture was stirred at rt for 4.5 h. The solvent was evaporated and the product was purified by flash chromatography (cyclohexane/EtOAc 8:2=>3:7) to give 4-(hydroxyimino-methyl)-3-phenoxy-benzonitrile (1.42 g). Light yellow solid. MS 238.1 ([M]+)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][CH2:20][C:21]([O:23]CC)=[O:22])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[OH-]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][CH2:20][C:21]([OH:23])=[O:22])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)CSCC1(c2ccc3c(c2)OCO3)OCC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC1(C)COC(CSCC(=O)O)(c2ccc3c(c2)OCO3)OC1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
Ethyl ({[2-(1,3-benzodioxol-5-yl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetate (Method 12) (14.2 g, 0.039 mol) was dissolved in THP (300 mL) and cooled to 0° C. LiOH (4.87 g, 0.12 mol) in water (100 mL) was added, and the mixture was given room temperature and stirred for 19 hours. The solvents were evaporated, the crude product was added water and extracted with diethyl ether. The aqueous layer was added 1M HCl until pH=3 and extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (Na2SO4) and concentrated under reduced pressure to afford the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:24][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: NCCc1ccccc1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccc(C=NCCc2ccccc2)cc1
Yield: 91.2 %

Procedure:
4-(3-Dimethylaminopropoxy)benzaldehyde (30.0 g) is reacted with 18 g of phenethylamine in 150 ml of toluene as described under Example 1 to give 41 g of an oil; boiling point 184°-189° C./0.1-0.2 mm of Hg.
Reaction SMILES: [NH2:1][C:2]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[CH:11][C:12]=2[Cl:14])[NH:7][C@@H:6]([C:16]([O:18]C)=[O:17])[CH2:5]1)=[O:3].[OH-].[Na+].Cl>CO.O>[NH2:1][C:2]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[CH:11][C:12]=2[Cl:14])[NH:7][C@@H:6]([C:16]([OH:18])=[O:17])[CH2:5]1)=[O:3]
Reactant: COC(=O)[C@H]1C[C@@H](C(N)=O)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)[C@@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.6 %

Procedure:
Cis-4-aminocarbonyl-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.12 g) was dissolved in 50% aqueous methanol (20 ml) and 1N sodium hydroxide solution (0.6 ml) was added. The reaction mixture was stirred at room temperature for 14 h then the solvents were evaporated in vacuo to leave a residue which was redissolved in water (20 ml) and acidified to pH 1 with concentrated hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3×40 ml), dried (Na2SO4), filtered and concentrated under vacuum to give an off white solid which was triturated with diethyl ether and collected by filtration to give the title compound (0.082 g, m.p. 220°-222° C.); δ (360 MHz, DMSO) 2.28 (2H, m, CHACHBHCCHD), 3.71 (1H, m, CHACHBHCCHD), 3.89 (1H, m, CHACHBHCCHD), 6.62 (1 H, d, J=2.1 Hz, 6-H or 8-H), 6.64 (1H, br, s, NH), 6.74 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.81 (1H, s, br, NH), 7.26 (1H, s, br, NH); m/e (FAB) 289 (M+1); Found: C, 44.84; H, 3.67; N, 8.95. C11H10Cl2N2O3.0.4H2O requires C, 44.59; H, 3.67; N, 9.45%.
Reaction SMILES: C(OC([C:6]1[N:7]([CH2:19][CH:20]([NH:22][C:23]([O:25]C(C)(C)C)=O)[CH3:21])[N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[CH3:21][CH:20]1[CH2:19][N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[C:6]2[C:23](=[O:25])[NH:22]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1

Procedure:
The compound was prepared from (rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester using the method described in the preceding example 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>CC(O)=O>[Br:15][C:11]1[CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][C:6]=1[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1Br
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of N-tert-butyl-4-nitroaniline (1 g, 5.1 mmol) in AcOH (5 mL) was added Br2 (0.86 g, 54 mmol) dropwise at 15° C. After addition, the mixture was stirred at 30° C. for 30 min and then filtered. The filter cake was basified to pH 8-9 with aqueous NaHCO3. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 43%). 1H-NMR (CDCl3, 400 MHz) δ 8.37 (dd, J=2.4 Hz, 1H), 8.07 (dd, J=2.4, 9.2 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 5.19 (brs, 1H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:12]([O-])=O.[NH:15]1[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:17][CH2:16]1>>[NH2:12][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:2]=1[N:15]1[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cnn(CC(F)(F)F)c1Br
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Product: Nc1cnn(CC(F)(F)F)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 53.6 %

Procedure:
Following the procedure for Intermediate 8 starting from 5-bromo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (150 mg, 0.55 mmol) and (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide (115 mg, 0.55 mmol) gave (R)—N-(1-(4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a colourless gum (110 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.11 (br s, 1H), 4.54 (q, J=8.5 Hz, 2H), 4.35-4.22 (m, 1H), 3.40-3.23 (m, 2H), 3.21-3.08 (m, 2H), 2.62 (br s, 2H), 2.17-2.08 (m, 1H), 2.06-1.91 (m, 1H), 1.92-1.71 (m, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@@H:9]3[CH2:20][C@@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[N:12]1[C:11]2[C@H:10]3[CH2:20][C@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[N:13]1
Reactant: CCOC(=O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Temperature: 23 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a suspension of (1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (106 g, 392 mmol) in MeOH (300 mL) and THF (300 mL) was added a 2.0 M aqueous solution of NaOH (235 mL, 471 mmol). The reaction was stirred at 23° C. for 20 h. The organic solvents were removed on rotovap. The remaining aqueous solution was diluted to −1.5 L with H2O then acidified to pH ˜2 with 6 M HCl (ca. 95 mL). The resulting fine precipitate was collected by filtration, rinsed with water, and dried to give the title compound (95 g) as a white solid. LCMS m/z=243.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.43 (td, J=4.6, 3.2 Hz, 1H), 1.26 (td, J=8.0, 4.4 Hz, 1H), 2.27-2.33 (m, 1H), 2.71-2.75 (m, 1H), 2.76 (d, J=16.8 Hz, 1H), 2.89 (dd, J=16.4, 6.4 Hz, 1H), 8.61 (dd, J=2.7, 1.5 Hz, 1H), 8.67 (d, J=2.5 Hz, 1H), 9.17 (d, J=1.5 Hz, 1H), 13.02 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:6]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:5][N:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(Cl)Cl.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:25]([O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]2[C:6]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[CH:5][N:4]=[C:3]([NH2:2])[N:8]=2)=[CH:11][CH:12]=1)(=[O:27])[CH3:26]
Reactant: Nc1ncc(Oc2ccc(Cl)cc2)c(Nc2ccc(O)cc2)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(Nc2nc(N)ncc2Oc2ccc(Cl)cc2)cc1
Reaction time: 120 h
Yield: 11 %

Procedure:
1.26 g (3.45 mmoles) of 2-amino-5-(4-chlorophenoxy)-4-(4-hydroxyanilino)pyrimidine hydrochloride (see Example 11) and 0.05 g of 4-dimethylaminopyridine were dissolved in 3.2 g of dry N,N-dimethylformamide. 5.3 g of acetic anhydride was added, and the container was sealed. After 5 days at 24° C., 100 mL of CH2Cl2 were added to the reaction mixture and stirred with 150 mL of cold saturated aqueous NaHCO3. The organic layer was then washed twice with 250 mL of water, then with 200 mL of brine and dried over Na2SO4. After filtering off the salt, the filtrate was applied to a Silica Gel 60 column (2.5×7.5 cm) which had been preequalibrated with hexanes. The column was eluted with 200 mL hexanes, a mixture of 100 mL hexanes and 200 mL CH2Cl2, and 500 mL CH2Cl2. Fractions with product which was pure by TLC (EtOAc; Rf 0.6) were pooled and spin evaporated to a waxy solid. This solid was removed from the flask with the aid of hot hexanes. After cooling, solids were collected by filtration and washed with hexanes. After drying in vacuo at 89° C. for 16 hours, the product, a cream colored powder, 0.14 g (11% yield), was obtained, mp 132-133° C.
Reaction SMILES: BrC1C=CC=CC=1CCO.BrC1C=CC=C2C=1CCOC2CC(OCC)=O.BrC1C=CC=C2C=1CCOC2CC(O)=O.CON1CCN(C2C=CC=CC=2)CC1.[CH3:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:70][CH2:69][N:68]([C:71](=O)[CH2:72][CH:73]3[C:82]4[C:77](=[C:78]([Br:83])[CH:79]=[CH:80][CH:81]=4)[CH2:76][CH2:75][O:74]3)[CH2:67][CH2:66]2)=[CH:61][CH:60]=1>>[CH3:57][O:58][C:59]1[CH:60]=[CH:61][C:62]([N:65]2[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH:73]3[C:82]4[C:77](=[C:78]([Br:83])[CH:79]=[CH:80][CH:81]=4)[CH2:76][CH2:75][O:74]3)[CH2:67][CH2:66]2)=[CH:63][CH:64]=1
Reactant: COc1ccc(N2CCN(C(=O)CC3OCCc4c(Br)cccc43)CC2)cc1
Agent: CCOC(=O)CC1OCCc2c(Br)cccc21
Agent: CON1CCN(c2ccccc2)CC1
Agent: O=C(O)CC1OCCc2c(Br)cccc21
Product: COc1ccc(N2CCN(CCC3OCCc4c(Br)cccc43)CC2)cc1

Procedure:
Following the general procedure of EXAMPLE 45 (step 1) and making non-critical variations 2-(o-bromophenyl)-1-ethanol (XLIX, 3.3 g) is converted to ethyl 2-(5-bromoisochroman-1-yl)acetate (LXXI). Following the general procedure of EXAMPLE 45 (Step 2) and making non-critical variations ethyl 2-(5-bromoisochroman-1-yl)acetate (LXXI, 1.0 g) is hydrolyzed to the corresponding acid, 2-(5-bromoisochroman-1-yl)acetic acid (LXXII). The acid (LXXII, 740 mg) is coupled with p-methoxyphenylpiperazine (V) and the resulting amide, 1-(4-methoxyphenyl)-4-[2-(5-bromoisochroman-1-yl)]acetyl piperazine (LXXIII, 1.10 g) is reduced according to the general procedure described in EXAMPLE 50 (making non-critical variations) to give the title compound, mp 105-106°.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:3]=2[CH2:2]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>CO.O>[N:8]1[C:3]2[CH2:2][CH2:1][CH2:11][C:9](=[N:13][OH:14])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2ncccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1CCCc2ncccc21
Temperature: 25 °C

Procedure:
A mixture of 1.0 eq of 5,6,7,8-tetrahydroquinolinone-5 (93) (Tyger Scientific, Ti 1850), 3.0 eq of hydroxylamine hydrochloride (Aldrich, 37,992-1), and 3.0 eq of sodium acetate in 50 mL of MeOH and 15 mL of H2O was refluxed for 4 hrs. The mixture was allowed to cool to rt. After rotary evaporation of the MeOH, 100 mL of H2O was added. The solid formed was collected by vacuum filtration. The solid collected was triturated with hexanes and dried under vacuum to give 94.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Si:23]([O:40][CH2:41][CH2:42][CH2:43]/[C:44](=[CH:54]\[S:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)/[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Si:23]([O:40][CH2:41][CH2:42][CH2:43]/[C:44](=[CH:54]\[S:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)/[C:45](=[S:10])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:36]([CH3:38])([CH3:37])[CH3:39])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=S)Nc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Lawesson reagent was added to tetrahydrofuran solution including 2.81 g of (E)-5-(tert-butyldiphenylsilyloxy)-N-phenyl-2-(phenylthiomethylene)pentanamide. The resulting solution was heated under reflux for one night and cooled to room temperature, followed by adding saturated sodium bicarbonate water to extract. The water layer was extracted with ethyl acetate, and the organic layer was mixed and dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.17 g of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[O:33][C:34]([CH3:37])=[CH:35][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[O:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3ccc(C)o3)c(C)sc2n1
Temperature: 120 °C
Yield: 45 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (90 mg, 0.208 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 4,4,5,5-Tetramethyl-2-(5-methyl-2-furanyl)-1,3,2-dioxaborolane (0.064 mL, 0.313 mmol), tetrakis(triphenylphosphine)palladium(0) (24.09 mg, 0.021 mmol) and potassium carbonate (86 mg, 0.625 mmol) were added and the mixture heated in a microwave at 120° C. for 10 min. Ethyl acetate (10 mL) was then added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and further triturated with MeOH, to give the title compound (40.5 mg). LCMS (A) m/z: 433 [M+1]+, Rt 1.50 min (acidic).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](Cl)[N:17]=1)[CH3:12].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.[OH-].[Na+]>[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([O:3][CH:4]2[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)[N:17]=1)[CH3:12]
Reactant: CCOC(=O)Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCC(O)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 1.64 g, 41 mmol) is added to a solution of 4-hydroxy-1-methylpiperidine (4.72 g, 41 mmol) in THF (82 mL) at room temperature. The mixture is stirred for a period of 30 minutes. A solution of (6-chloro-3-nitro-pyridin-2-yl)-acetic acid ethyl ester (5.0 g, 20.5 mmol) in THF (10 mL) is then added. The resulting purple mixture is stirred at room temperature for a period of 70 minutes. An additional portion of NaH (410 mg, 10.3 mmol) is added. The resulting mixture is stirred for a period of 70 minutes at room temperature and a saturated solution of NaHCO3 (30 mL) is then added slowly. The mixture is diluted with EtOAc (100 mL) and 1 N NaOH (aq, 10 mL). The layers are partititioned and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic extracts are washed with H2O (50 mL) and brine (50 mL) and dried over Na2SO4. The mixture is filtered to remove the solids, concentrated, and purified by flash chromatography on silica (gradient elution: 50% EtOAc in hexanes to 2% MeOH/CHCl3 with 0.1% NH4OH to 4% MeOH/CHCl3, with 0.1% NH4OH) to give the title compound as a dark brown oil: 1H NMR (400 MHz, CDCl3) δ 8.34 (d, 1H, J=9.1 Hz), 6.73 (d, 1H, J=9.1 Hz), 4.18 (q, 2H, J=7.1 Hz), 4.17 (s, 2H), 2.70-2.65 (m, 2H), 2.35-2.27 (m, 2H), 2.30 (s, 3H), 2.07-2.00 (m, 2H), 1.89-1.80 (m, 2H), 1.25 (t, 3H, J=7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 169.5, 164.6, 150.6, 139.5, 136.5, 111.3, 72.5, 61.4, 53.0, 46.3, 44.0, 30.9, 14.4; MS (CI) m/z 324.2 (M+1).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:27][C@@H:24]([O:25][CH3:26])[C@H:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:22]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:21]1[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH2:29]([O:28][C@@H:23]1[C@@H:22]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:21]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:20]([CH2:19][OH:18])[O:27][C@H:24]1[O:25][CH3:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a stirred solution of methyl 6-O-tert-butyldiphenylsilyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside (2.81 g, 3.98 mmol) in dry THF (40 ml, 0.1 M) at room temperature was added tetrabutyl ammonium fluoride (4.37 ml, 4.37 mmol, 1 M solution in THF). After stirring for 3 hours, the reaction solution was diluted with ethyl acetate (300 ml) and washed with water (1×100 ml) and saturated aqueous NaCl (1×100 ml), and dried with magnesium sulfate. Concentration and flash chromatography (silica, 50% ether in petroleum ether) provided pure target compound (1.62 g, 88%) as a white solid.
Reaction SMILES: [OH-].[Na+].C([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)(=O)C1C=CC=CC=1.[Cl-].[NH4+]>CO>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[O:18][C:15]1[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=1
Reactant: COc1cc2ncnc(Oc3ccc(OC(=O)c4ccccc4)cc3)c2cc1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(O)cc3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Methanol (5 ml) and sodium hydroxide (0.2 g) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl benzoate (500 mg), and the mixture was stirred at 0° C. for 30 min. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by filtration and was washed to give the title compound (350 mg, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)[CH3:5].[CH3:18][C:19]1([CH3:28])[CH2:24]C(O)[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1.[NH2-].[Li+].CO>CCCCCCC>[CH3:18][C:19]1([CH3:28])[CH2:24][CH:1]([O:2][C:3](=[O:17])[CH:4]([NH:6][CH:7]2[CH2:8][C:9]([CH3:16])([CH3:15])[NH:10][C:11]([CH3:14])([CH3:13])[CH2:12]2)[CH3:5])[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1
Reactant: COC(=O)C(C)NC1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCCC
Solvent: CO
Product: CC(NC1CC(C)(C)NC(C)(C)C1)C(=O)OC1CC(C)(C)NC(C)(C)C1
Yield: 76.2 %

Procedure:
To the same flask as used in Example 1 were added 24.4 g (0.1 mole) of N-(2,2,6,6-tetramethyl-4-piperidinyl)aminopropionic acid methyl ester, 17.3 g (0.11 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 28 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)aminopropionic acid (2,2,6,6-tetramethyl-4-piperidinyl)ester as a pale yellow liquid. Yield, 73.5% based on N-(2,2,6,6-tetramethyl-4-piperidinyl)aminopropionic acid methyl ester. A pale yellow oily product was obtained by the subsequent column chromatographic separation.
Reaction SMILES: [CH2:1]([NH:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13](Cl)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].[OH-].[Na+]>>[CH2:1]([N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC
Reactant: CC(C)CCCCCCCl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCN(C)CCCCCCC(C)C
Temperature: 190 °C
Yield: 83 %

Procedure:
A mixture of 300 moles of decylmethylamine, 300 moles of isononyl chloride and 350 moles of 50% caustic soda, contained in a 50 gallon reactor, was heated for 6 hours at a temperature of 190° C. The organic mixture was cooled, washed with water and further purified by fractional distillation. The amination process afforded a yield of 83% decylisononylmethylamine. When nonyl chloride is used instead of isononyl chloride, the product is decylnonylmethylamine.