Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.C(O)(C)C>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[O:21][N:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of 129b (280 mg, 0.49 mmol) in THF (4 mL), i-propanol (4 mL), and water (2 mL) was added lithium hydroxide (24 mg, 0.98 mmol). The reaction mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 129 as a white solid (85 mg, 33%). MS-ESI: [M+H]+ 531.3. 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.58 (d, J=5.0 Hz, 1H), 8.54 (d, J=3.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.91 (d, J=1.0 Hz, 1H), 7.78 (dd, J=1.0, 13.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 6.26 (s, 1H), 4.92 (s, 1H), 4.43 (d, J=6.0 Hz, 2H), 3.61 (s, 3H), 2.32 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][Si:3](Cl)(Cl)Cl.[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O[CH2:18][CH3:19])(=O)C>CCOCC>[Cl:1][CH2:2][Si:3]([C:19]1[CH:18]=[CH:9][CH:8]=[CH:7][CH:12]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]c1ccccc1
Reactant: ClC[Si](Cl)(Cl)Cl
Reactant: CCOC(C)=O
Solvent: CCOCC
Product: ClC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.6 ml (18.4 g, 0.10 mol) of (chloromethyl)trichlorosilane in 150 ml of dry ether was stirred under nitrogen and chilled in ice while 162 ml (0.30 mol) of 1.85 molar phenyllithium in cyclohexane-ether 70:30 was added dropwise at a rate that held the mixture below 15° C. The resulting slurry was stirred overnight at room temperature, treated carefully with 10 ml of ethyl acetate to quench any remaining phenyllithium, washed with water and brine, dried over magnesium sulfate, and evaporated to leave 33 g of sticky solid. Recrystallization from 30 ml of cyclohexane provided 15.8 g (51%) of the title compound as an off white solid: m.p. 112°-115° C.; ir (Nujol®) 1420, 1110, 735, 730, 705, 695 cm-1 ; nmr (CDCl3) 3.5 (2H, s), 7.0-7.8 (15H, m).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=3)[C:9]([S:21][CH3:22])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=3)[C:9]([S:21]([CH3:22])=[O:34])=[C:8]2[CH3:23])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(SC)c(C)n2Cc1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)c(S(C)=O)c(C)n2Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
A 300 mg portion of ethyl 1-(4-fluorobenzyl)-2-methyl-3-(methylthio)-1H-indole-5-carboxylate was dissolved in 3 ml of chloroform, and 203 mg of 3-chloroperbenzoic acid was added under ice-cooling, followed by stirring at the same temperature for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol:hexane=1:0:1 to 1:0:0 to 100:1:0 to 50:1:0 to 30:1:0) to obtain 279 mg of ethyl 1-(4-fluorobenzyl)-2-methyl-3-(methylsulfinyl)-1H-indole-5-carboxylate as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]#[N:27])=[CH:22][N:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:19]=4[N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-:34].[K+].O>C(O)(C)(C)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]([NH2:27])=[O:34])=[CH:22][N:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:19]=4[N:20]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C#N)cn(-c5ccccc5)c4n3)cc2)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C(N)=O)cn(-c5ccccc5)c4n3)cc2)CC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (Example 13F, 9 mg) in 1 mL of t-butanol was added potassium hydroxide (ground, 5 mg). The mixture was stirred at 85° C. for 1 hour. After cooling to rt, water was added and the precipitates were extracted into EtOAc. The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum to leave 2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide as a yellow solid (7.2 mg, 79%). 1H NMR (300 MHz, CDCl3) δ (ppm): 10.64 (br, 1H), 10.30 (s, 1H), 9.17 (s, 1H), 7.71 (m, 3H), 7.53 (br, 1H), 7.43 (m, 2H), 6.94 (br, 2H), 6.35 (br, 2H), 5.06 (br, 1H), 3.12 (m, 4H), 2.59 (m, 4H), 2.37 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H25N7O2: 456.51 (M+H), Found: 456.6.
Reaction SMILES: C(=O)([O-])[O-:2].[Na+:5].[Na+].[O-:7][Si:8]([O-:10])=[O:9].[Na+].[Na+]>>[Si:8]([O-:2])([O-:10])([O-:7])[O-:9].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O=[Si]([O-])[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
A crystalline alkali metal phyllosilicate, as described on page 2, was prepared by dissolving 810 g of anhydrous sodium carbonate in 60 kg of water glass having a percentage composition Na2O/SiO2/H2O=15.3/29.7/55. The solution was spray-dried in a laboratory spray drier (spray tower) from Anhydro to give an amorphous sodium silicate having an active substance content of 82%. 15 kg of the amorphous sodium silicate were heat-treated at 720° C. for 90 min in a muffle furnace (Nabertherm, model W1000/H). This was repeated once more. The cooled silicate powder (about 24 kg) was pulverized with a jaw crusher and a disk mill. 2.55 kg of the silicate powder were mixed with of Arbocell FIC 200 in a tumble mixer. The mixture was compacted in accordance with the general procedures “Roll compaction” at a pressure of 20 kN, and processed in accordance with the general procedure “Production of particle size fractions” to give a particle size fraction of from 500 to 1000 μm.
Reaction SMILES: C=O.[C:3](B)#N.[Na].C(#N)C.[F:10][C:11]1[CH:12]=[C:13]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH3:24])[CH2:19][CH2:18]1>CO>[CH3:24][N:23]([CH3:3])[CH:20]1[CH2:19][CH2:18][N:17]([C:16]2[CH:15]=[CH:14][C:13]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:12][C:11]=2[F:10])[CH2:22][CH2:21]1
Reactant: BC#N
Reactant: CNC1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Agent: C=O
Agent: [Na]
Solvent: CC#N
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
Formaldehyde (37% aq. sol., 0.4 ml) and sodium cyanoboron hydride (138 mg) were successively added to an acetonitrile suspension (3 ml) of 400 mg of the (S)-N-{3-[3-fluoro-4-(4-methylamino-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 70) which was synthesized in Example 18, and the mixture was stirred at room temperature for 48 h. Methanol was added and the mixture was stirred for 10 min. Thereafter, alumina (5 g) was added and the residue was evaporated under vacuum. The residue was purified by alumina column chromatography (solvent: chloroform/methanol=100/1) to afford the title compound (363 mg) in a yield of 87%.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)C.[Li]CCCC.C1COCC1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]#[N:26].ClC1C=CC=CC=1CSC#N>C1(C)C=CC=CC=1.O>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([C:1]#[N:4])[C:25]#[N:26]
Reactant: CC(C)NC(C)C
Reactant: N#CCc1ccccn1
Agent: N#CSCc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(C#N)c1ccccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To diisopropylamine (15.3 mL, 109 mmol) in toluene (500 mL), at 0-5° C., under nitrogen, was added drop wise over ˜½ hour 1.6M″ BuLi/THF (68.5 mL, 109 mmol). The reaction mixture was stirred for a further 15 minutes before the drop wise addition of 2-pyridylacetonitrile (5.55 mL, 49.6 mmol) over 1 hour. 2-Chlorobenzylthiocyanate (20.0 g, 109 mmol), described in the literature by Schlesinger J. Am. Chem. Soc. 1954, 76, 585, was then added in solution in toluene (100 mL) over a period of 1 hour. The reaction mixture was stirred for an additional 2 hours. Water was added and the layers were separated. The organic phase was extracted twice with 200 mL 2N NaOH. The combined aqueous phases were cooled down to 0° C and acidified to ˜pH 1. The precipitate obtained was filtered and dried to give the title compound as a pale tan solid (4.50 g, 63% yield). δH (DMSO-d6) 6.79 (1H, t), 7.09 (1H, d), 7.73 (1H, t), 7.79 (1H, dd), 12.95 (1H, br s).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH:8]([CH3:10])[O:7][CH:6]([CH3:11])[CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>>[Cl:32][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]([CH3:10])[O:7][CH:6]([CH3:11])[CH2:5]1
Reactant: CC1CN(CCO)CC(C)O1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1CN(CCCl)CC(C)O1
Temperature: 0 °C
Yield: 43 %

Procedure:
To a flask was added 5.0 g. (0.03 mole) of 4-(2-hydroxyethyl)-2,6-dimethylmorpholine in 50 ml. of carbon tetrachloride followed by 10.2 g. (0.04 mole) of triphenylphosphine. The mixture was stirred at reflux for three hours, then the reaction was cooled to 0° C., the triphenylphosphine oxide was filtered and the solvent stripped. The residue was dissolved in 10% aqueous hydrochloric acid and the by-products were extracted into ethyl acetate. The acid layer was then basified with ammonium hydroxide and extracted into ethyl acetate. The ethyl acetate solution was dried with magnesium sulfate, filtered, and concentrated. The crude product was further purified by flash chromatography to give 2.31 g. (43% yield) of 4-(2-chloroethyl)-2,6-dimethylmorpholine as a colorless liquid.
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([C:13]([NH:15][CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1)=[O:14])[CH:9]([CH3:12])[CH2:10][CH3:11])(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:7][CH:8]([CH:9]([CH3:12])[CH2:10][CH3:11])[C:13]([NH:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:14]
Reactant: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)C(N)C(=O)NCc1nc2ccccc2[nH]1

Procedure:
The title compound is prepared by the procedure of Example 2 using 0.588 g of product from Example 11 in 6 ml of methylene chloride and 1.3 g of trifluoroacetic acid (TFA). The resulting desired intermediate is used as is in the next reaction. The 1HNMR indicates the correct product with associated TFA molecules.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:37][C:36]=2[O:46]COC)=[CH:31][CH:30]=1>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:26])([F:27])[F:25])[CH:5]=[CH:4][C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][C:36]=2[OH:46])=[CH:33][CH:34]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COCOc1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3O)cc2)ccc(C(F)(F)F)c1O

Procedure:
According to a method similar to Example (40-2), Example (51-2), Example (33-5) and Example (17-4), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (1.66 g, 3.93 mmol) obtained in Example (28-5) and methyl [4′-hydroxy-2-(methoxymethoxy)-1,1′-biphenyl-4-yl]acetate (990 mg, 3.28 mmol), the title compound was obtained as a colorless amorphous compound (111 mg, yield: 7%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]1[CH:42]=[C:43]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]=[CH:45][CH:46]=1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:40][C:41]1[CH:42]=[C:43]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]=[CH:45][CH:46]=1)[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]
Reactant: NCCCN1CCCC1=O
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCBr)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCCN3CCCC3=O)Cc3cccc(CC(=O)OC)c3)c2n1

Procedure:
Using the compound obtained in Example 2-13 step (i) (400 mg), 1-(3-aminopropyl)pyrrolidin-2-on (1 ml), potassium carbonate (175 mg) and methyl [3-(bromomethyl)phenyl]acetate (175 mg), the same manner to Example 2-29 was conducted to give the titled compound as a white solid. Yield: 200 mg (48%); mp 115-116° C., MS APCI+ve 582 (M+H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C=O.C1N2CN3CN(C2)CN1C3.C1([OH:43])C=CC=CC=1>>[CH2:1]=[O:2].[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:18]1[CH:23]=[CH:22][C:21]([OH:43])=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: CCCCCCCCCc1ccccc1O
Agent: C1N2CN3CN1CN(C2)C3
Agent: C=O
Agent: Oc1cccc(O)c1
Product: CCCCCCCCCc1ccc(O)cc1

Procedure:
Resorcinol and nonyl phenol are reacted with formaldehyde in the presence of a catalytic amount of hexamethylenetetramine at a total phenol:formaldehyde molar ratio of 1.7:1 to afford a novolak cocondensate resin (97 mole % resorcinol/3 mole % nonylphenol). The solid resin is washed to remove formaldehyde odor. The wet resin is dried under vacuum. The dry resin is dispersed in water with sodium caseinate at 40% N.V. to afford Emulsion A.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:6]=[C:7]([N:9]([CH3:11])[CH3:10])[CH:8]=1.[BH4-].[Na+]>C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:9]([CH3:11])[CH3:10])[CH:8]=1)[CH:12]([OH:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CN(C)c1cc(C(=O)CS(C)(=O)=O)cc(N(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1

Procedure:
A suspension of 7.4 g. of 3',5'-bis(dimethylamino)-2-methylsulfonylacetophenone and 3.8 g. of sodium borohydride in 100 ml. of ethanol was stirred for 20 hours at 25° C. After the addition of 50 ml. of water, the alcohol was removed in vacuo and the remaining aqueous suspension extracted with 400 ml. of ethyl acetate. The ethyl acetate phases were washed with 50 ml. of water, dried over magnesium sulfate and evaporated to dryness in vacuo. Recrystallization of the residue from ethanol gave 3,5-bis(dimethylamino)-α-[(methylsulfonyl)-methyl]benzyl alcohol, having a melting point of 142°-143° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=O)=[C:10]([CH3:20])[N:9]=1.O=S(Cl)[Cl:23]>C1COCC1.C(Cl)Cl>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][Cl:23])=[C:10]([CH3:20])[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(Cl)c2ccccc2c1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nc(Cl)c2ccccc2c1CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
LAH (3.6 ml of 1M in THF, 3.62 mmol) is added to a solution of 1-chloro-3-methyl-isoquinoline-4-carbaldehyde (744 mg, 3.62 mmol) in THF (10 ml) at 0° C. After stirring for 30 min at ambient temperature, the mixture is quenched with small amounts of saturated sodium sulfate and filtered through a pad of celite. The filtrate is concentrated in vacuo to give the crude alcohol. SOCl2 (13 ml of 2M in DCM, 25 mmol) is added to a solution of the crude alcohol in DCM (5 ml). After stirring for 1 h at room temperature, the mixture is concentrated in vacuo and the residue is chromatographed on silica gel to give 737 mg of 1-chloro-4-chloromethyl-3-methyl-isoquinoline. 1H NMR (CDCl3) 8.44 (d, 1H), 8.18 (d, 1H), 8.02 (t, 1H), 7.82 (t, 1H), 5.03 (s, 2H), 3.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[NH2:15][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[NH2:15][C:16]1[C:17]([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:19])=[CH:21][CH:22]=[CH:23][N:24]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Nc1ncccc1C(=O)O
Product: Nc1ncccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-aminonicotinic acid to produce 2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide. MS (Q1) 325.2 (M)+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.Cl.Cl.[NH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].CN(C)C=O>O>[CH3:26][N:17]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][NH:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:4][N:5]=1)=[CH:16]2
Reactant: CCOC(=O)CCCN
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (424 mg), triethylamine (693 μL), ethyl 4-aminobutanoate dihydrochloride (335 mg) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 4-{[(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methyl]amino}butanoate as a crude product from a fraction eluted with ethyl acetate. A mixture of this product, methanol (2 ml), 1N aqueous sodium hydroxide solution (4 ml) and tetrahydrofuran (4 ml) was stirred at 45° C. for 20 hr. The mixture was neutralized with 1N aqueous hydrochloric acid solution, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (49 mg, yield 10%) as colorless crystals from a fraction eluted with ethyl acetate. MS 473 (M+1).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:23])([CH3:22])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:16]2[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]2)[N:14]=1)([CH3:6])([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.[CH:33]1[CH:38]=[C:37]([CH2:39][O:40][C:41](Cl)=[O:42])[C:36]([Cl:44])=[CH:35][CH:34]=1>C(Cl)Cl.O>[Cl:44][C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[CH2:39][O:40][C:41](=[O:42])[NH:21][C:19]1[CH:18]=[N:17][N:16]([CH2:15][C:13]2[N:14]=[C:10]([C:9]([CH3:23])([CH3:22])[O:8][SiH2:7][C:3]([CH3:6])([CH3:4])[CH3:5])[O:11][CH:12]=2)[CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2cc(N)cn2)co1
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)co1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl]-1H-pyrazol-4-ylamine (347 mg, 1.12 mmol) in CH2Cl2 (5.0 mL) was treated with DIPEA (0.31 mL, 1.78 mmol) followed by 2-chlorobenzylchloroformate (0.23 mL, 1.45 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and water (5.0 mL) was added. The layers were separated and the aq. layer extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (9:1 to 1:1 hept-EA) gave the title compound as an orange oil. TLC: rf (1:1 hept-EA)=0.27. LC-MS-conditions 02: tR=1.13 min; [M+H]+=476.95.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[N:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][NH:8]1.[OH-:14].[K+]>O>[CH3:1][S:2]([O:4][C:9]1[CH:10]=[CH:11][C:12](=[O:13])[NH:7][N:8]=1)(=[O:14])=[O:3]
Reactant: [OH-]
Reactant: CS(=O)(=O)Cl
Reactant: OC1=CC=CNN1O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)Oc1ccc(=O)[nH]n1
Temperature: -10 °C
Yield: 50.8 %

Procedure:
102.9 g (0.9 mole) of methanesulfonic acid chloride were added dropwise at 0° C. to a solution of 100.8 g (0.9 mole) of 1,6-dihydroxypyridazine and 50.4 g (0.9 mole) of potassium hydroxide in 500 ml of water. The mixture was allowed to react for a further hour at 20° C. and was then cooled to -10° C., and the precipitate formed was filtered off. After recrystallization from acetonitrile, 87 g (51% of theory) of 1,6-dihydro-3-methylsulfonyloxy-6-oxopyridazine were obtained in the form of colorless crystals of melting point 148° C. ##STR194##