Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](Br)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[CH:33]=[CH:32][S:31][C:30]=3[C:34]#[N:35])[CH:26]=[CH:27][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH3:8].[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:27]3[CH:28]=[CH:23][CH:24]=[C:25]([C:29]4[CH:33]=[CH:32][S:31][C:30]=4[C:34]#[N:35])[CH:26]=3)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccn2c(Br)cnc2c1
Reactant: CC1(C)OB(c2cccc(-c3ccsc3C#N)c2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccn2c(-c3cccc(-c4ccsc4C#N)c3)cnc2c1
Product: N
Temperature: 80 °C
Yield: 132.9 %

Procedure:
3-Bromoimidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (0.63 g, 2.47 mmol) and 3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]thiophene-2-carbonitrile (0.55 g, 1.76 mmol) were suspended in 1,2-dimethoxyethane (10 ml) and 2N sodium carbonate solution (5 ml) and degassed with nitrogen for 30 min before addition of tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol). The mixture was heated at 80° C. for 18 h then cooled to room temperature. The mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed with brine, dried over sodium sulfate and pre-adsorbed onto silica gel. Purification by silica gel chromatography eluting with dichloromethane/methanol/conc. ammonia (gradient 99:1:0.1 through to 97:2:0.2) gave the title compound (0.59 g, 94%) as pale brown needles. 1H NMR (400 MHz, CDCl3) δH 3.98 (3H, s), 7.35 (1H, d, J 5), 7.48 (1H, dd, J 7 and 2), 7.65-7.75 (3H, m), 7.93 (2H, m), 8.43 (1H, s), 8.54 (1H, dd, J 7 and 1); m/z (ES+) 360 (M++H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) was added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirring at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 601.7 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].[Cl:21][S:22](O)(=[O:24])=[O:23]>CC#N.O>[O:20]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[N:10]1[CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1C1Cc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of compound 747-C (0.72 g, 2.7 mmol) in MeCN (50 mL) was added chlorosulfonic acid (3.72 g, 32.4 mmol), drop-wise, and the reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with H2O, extracted with CH2Cl2, dried over Na2SO4, filtered, and dried to afford 0.976 g of compound 747-D as a brown solid. 1H-NMR (CDCl3) δ 3.26-3.43 (m, 2H), 3.60-3.78 (m, 2H), 5.26 (t, 1H), 7.46 (d, 1H), 7.68-7.79 (m, 2H), 7.79-7.93 (m, 4H); MS: m/z 384.1 (MNa+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]1=[O:16].CN(C)[CH:19]=[O:20].O.Cl>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([CH:19]=[O:20])[S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:3]1=[O:16]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C=O)sc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine (300 mg; WO98/54190) was dissolved in phosphorus oxychloride (4 ml) and dimethylformamide (2 ml) was added. The mixture was then heated to 100° C. with stirring under nitrogen for 1 hour. The mixture was allowed to cool to ambient temperature and then added dropwise to vigorously stirred hot water (˜50° C.), containing a small amount of 2M hydrochloric acid. The mixture formed was allowed to cool to ambient temperature and filtered to give the title compound as a brown solid (210 mg).
Reaction SMILES: [H-].[Na+].[C:3]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H][H].[CH2:25](Br)[CH:26]=[CH2:27]>C(OCC)(=O)C.O.O1CCCC1>[C:3]([N:13]([CH2:27][CH:26]=[CH2:25])[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: C=CCBr
Reactant: O=C(Nc1ccc2c(c1)CCC2)OCc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN(C(=O)OCc1ccccc1)c1ccc2c(c1)CCC2
Reaction time: 1 h

Procedure:
A sodium hydride/mineral oil dispersion (50%, 2.00 g) is carefully added to a solution of N-(carbobenzyloxy)-5-aminoindan (XVIA, EXAMPLE 41, 8.856 g) in freshly distilled tetrahydrofuran (about 350 ml) at 20° under argon. The reaction is mildly exothermic with evolution of hydrogen gas. Allyl bromide (3.4 ml, 4.8 g) is then added over 1 min. The mixture is stirred at 20°-25° for 1 hr forming a solid. The mixture is then heated at reflux for 3.5 hr then stirred at 20°-25° overnight. An aliquot is taken, poured into water and ethyl acetate, and the organic layer evaporated. NMR analysis indicates complete reaction. The mixture is poured into ethyl acetate (300 ml), and washed with water (2×250 ml). The combined aqueous layers are extracted with ethyl acetate (100 ml). The combined organic layers are washed with saline, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. The residue is purified by gravity filtration thru a silica gel column (2.5 cm×10 cm, 60-200 μ), eluting with hexane. The appropriate fractions are pooled and concentrated to give the title compound as an oil. An analytical sample is obtained by MPLC using ethyl acetate/hexane (10/90). NMR (CDCl3, 300 MHz) 7.30, 7.16, 7.06, 6.96, 5.91, 5.16, 5.13, 4.24, 2.88 and 2.07 δ; IR (CHCl3) 2944, 1694, 1400 and 1153 cm-1 ; MS(m/e) 307, 263, 248, 172, 144 and 91, exact mass calculated for C20H21NO2 =307.1572, found 307.1565.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=3)[NH:18]2)=[CH:13][C:12]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:7][S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[O:30])[CH:23]=3)[NH:18]2)=[CH:13][C:12]=1[N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (190 mg, 1.55 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (62 mg, 1.55 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.31 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h. Then the above suspension of cyclopropanesulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (38 mg, 25%) as a white solid: LC/MS m/e calcd for C25H30FN3O4S (M+H)+: 488.6, observed: 488.5.
Reaction SMILES: C(#N)C.[CH2:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[CH2:4]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1cccc(OCc2ccccc2)c1

Procedure:
In an acetonitrile (50 mL) solvent, benzyl bromide (4.6 mL, 38.68 mmol) was added to a solution including 3-hydroxybenzaldehyde (5.0 g, 40.94 mmol) and potassium carbonate (8.49 g, 61.43 mmol), and the reaction mixture was refluxed for 3 hours. After cooling, the reaction mixture was distributed between methylene chloride and water. An organic layer was dried by using MgSO4, and filtered. A filtrate was evaporated, and water was added to the resultant solid. The solid was filtered and washed with water to obtain Compound 107b.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[CH:38](F)OC1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:38][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH:34]([F:36])[F:35])=[CH:31][CH:32]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)F)cc1)CCC2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)F)cc2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(4-difluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 537.24 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 4-difluoromethoxy-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(4-difluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][C:11]=1[F:25]>O>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:1]#[N:2])=[C:11]([F:25])[CH:12]=1
Reactant: Fc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1F

Procedure:
To a solution of 0.6 gm. of sodium cyanide in 25 ml. of dimethyl sulfoxide preheated to 65°-70°C. is slowly added 2.5 gm. of 2-(4-bromomethyl-3-fluorophenyl)-benzoxazole. The reaction mixture is heated at 60°-70°C. for 1 hour, then cooled and poured into water. The resulting precipitate is filtered off and chromatographed on 300 gm. of silica gel. Elution with methylene chloride gives 4-(benzoxazol-2-yl)-2-fluorophenylacetonitrile.
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[CH:12][C:13](O)=[O:14])(=O)=O)=CC=1.ClC(N(C)C)=C(C)C.[F:25][C:26]1[CH:27]=[C:28]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:29]=[CH:30][C:31]=1/[CH:32]=[CH:33]/[CH2:34][OH:35].CN(C)C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[N+:11](=[CH:12][C:13]([O:35][CH2:34]/[CH:33]=[CH:32]/[C:31]1[CH:30]=[CH:29][C:28]([NH:36][C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])=[CH:27][C:26]=1[F:25])=[O:14])=[N-:10]
Reactant: Cc1ccc(S(=O)(=O)NN=CC(=O)O)cc1
Reactant: O=C(Nc1ccc(/C=C/CO)c(F)c1)OCc1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of glyoxylic acid p-toluenesulfonylhydrazone (24 g, 0.10 mol, prepared as described by C. J. Blankley, F. J. Sauter and H. O. House, Organic Syntheses, Coll. Vol. V, p. 258; John Wiley, New York (1973)) in CH2Cl2 (600 mL) at 23° C. was added commercially available 1-chloro-N,N,2-trimethyl-1-propenylamine (15 mL, 0.114 mol, 1.14 equiv.) over 5 min. The reaction mixture was stirred at the same temperature for 40 min. The reaction mixture was then cooled to 0° C. and benzyl 3-fluoro-4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (23 g, 0.077 mol) was added in one portion followed by the addition of N,N-dimethylaniline (12 mL, 0.095 mol). After 30 minutes, triethylamine (53 mL, 0.385 mol) was added and the mixture stirred for 30 minutes at 0° C. and 15 minutes at room temperature. The reaction mixture was then concentrated to a volume of about 100 mL and 500 mL of water added. The mixture was extracted with two portions of diethyl ether and the combined organic solutions washed with saturated NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by column chromatography (0-25% ethyl acetate-hexane) provided the title compound as a yellow solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([NH2:35])([CH3:34])[CH3:33]>>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([NH:35][C:15]([NH:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)=[O:16])([CH3:33])[CH3:34]
Reactant: NC1CN2CCC1CC2
Reactant: CC(C)(N)c1ccc2ccccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(NC(=O)NC1CN2CCC1CC2)c1ccc2ccccc2c1
Yield: 48.4 %

Procedure:
Using general procedure C, quinuclidin-3-amine (102 mg, 0.808 mmol), CDI (131 mg, 0.808 mmol) and 2-(naphthalen-2-yl)propan-2-amine (150 mg, 0.819 mmol) gave 1-(2-(naphthalen-2-yl)propan-2-yl)-3-(quinuclidin-3-yl)urea (132 mg, 49%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.94-7.78 (m, 4H), 7.69 (dd, J=2.0, 8.7 Hz, 1H), 7.53-7.46 (m, 2H), 4.84 (s, 1H), 4.23 (d, J=8.0 Hz, 1H), 3.68-3.54 (m, 1H), 3.07 (ddd, J=2.3, 9.3, 14.1 Hz, 1H), 2.61-2.51 (m, 2H), 2.42-2.32 (m, 1H), 1.95-1.83 (m, 2H), 1.75 (s, 3H), 1.74 (s, 3H), 1.58-1.54 (m, 1H), 1.46-1.40 (m, 2H), 1.03-0.91 (m, 1H), 0.72-0.60 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.5, 143.7, 133.4, 132.8, 129.3, 128.1, 127.8, 126.9, 126.7, 124.4, 124.0, 57.0, 55.0, 47.1, 47.1, 46.6, 30.5, 30.3, 26.0, 25.9, 20.0 ppm. Purity: >99.9% UPLCMS (210 nm); retention time 0.71 min; (M+1) 338.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11]S(C(C)(C)C)=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[ClH:18].O1CCOCC1>CO.C(OCC)C>[ClH:18].[Br:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH2:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccc(Br)nc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1ccc(Br)nc1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide (5.35 g, 16.8 mmol) in methanol (25 mL) was added a solution of 4 N HCl in dioxane (10.0 mL, 40.0 mmol). The mixture was monitored by TLC for the disappearance of starting material (ethyl acetate-hexanes 3:7). After 2 hours, the mixture was concentrated to near dryness to afford a white solid which was diluted with diethylether and collected by filtration to afford (S)-1-(6-bromo-pyridin-3-yl)-propylamine hydrochloride.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9].[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([OH:22])=[CH:16][C:15]=2[O:14]1.C(=O)([O-])[O-].[Ca+2]>CC(C)=O>[CH3:12][C:4]([CH2:5][CH2:6][C:7]([CH3:11])=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:22][C:17]1[CH:18]=[CH:19][C:20]2[O:21][CH2:13][O:14][C:15]=2[CH:16]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(=CCBr)CCC(C)=C(C)C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)=O
Product: CC(=CCOc1ccc2c(c1)OCO2)CCC(C)=C(C)C

Procedure:
26 g of 1-bromo-3,6,7-trimethyl-2,6-octadiene, 13 g of 3,4-methylenedioxy-phenol [sesamol] and 20.75 g of finely pulverized calcium carbonate were refluxed for 68 hours in 100 ml of acetone. After reflux the reaction mixture was filtered and the acetone solution was evaporated. By chromatography on Kieselgel with hexane-diethylether (4:1 parts by volume) and distillation under vacuum there was obtained pure 3,6,7-trimethyl-1-[3,4-(methylenedioxy)-phenoxy]-2,6-octadiene, b.p. 114°-117°C/0.002 mmHg; nD20 = 1.5352.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([O:8][C@@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[CH:2]=1.[Cl:20][C:21]1[CH:30]=[CH:29][N:28]=[C:27]2[C:22]=1[CH:23]=[C:24]([O:32][CH2:33][CH3:34])[C:25]([CH3:31])=[N:26]2>>[ClH:20].[O:8]([C:3]1[CH:2]=[CH:1][C:6]([NH:7][C:21]2[C:22]3[C:27](=[N:26][C:25]([CH3:31])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[CH:5][CH:4]=1)[C@@H:9]1[O:14][C@H:13]([CH2:15][OH:16])[C@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]1[OH:19]
Reactant: Nc1ccc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCOc1cc2c(Cl)ccnc2nc1C
Product: CCOc1cc2c(Nc3ccc(O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)cc3)ccnc2nc1C
Product: Cl

Procedure:
A solution of 4-aminophenyl-β-D-galactopyranoside (2.08 g) in IMS (50 ml) was added to a solution of 5-chloro-3-ethoxy-2-methyl-1,8-naphthyridine (1.7 g) in IMS (30 ml). The mixture was boiled under reflux for 18 hours. The mixture was cooled and filtered to give 4-(6-ethoxy-7-methyl-1,8-naphthyridin-4-ylamino)phenyl β-D-galactopyranoside hydrochloride, m.p. 223°-225° C. Active (1/1) at 30 mg/kg.
Reaction SMILES: [C:1]1([CH2:7][C:8]2([NH2:26])[CH2:17][CH2:16][CH2:15][C:14]3[N:13]=[C:12]([O:18]CC4C=CC=CC=4)[CH:11]=[CH:10][C:9]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(O)C.[ClH:31].[H][H]>C(O)C.[Pd]>[ClH:31].[NH2:26][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][C:12](=[O:18])[CH:11]=[CH:10][C:9]1=2
Reactant: [H][H]
Reactant: NC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: NC1(Cc2ccccc2)CCCc2[nH]c(=O)ccc21
Yield: 28 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-(phenylmethyl)-2-(phenylmethoxy)-5-quinolinamine (19.1 g) and 10% palladium-on-carbon (1.5 g) in ethanol (1 l) was acidified to about pH 2-3 with 2-propanol/hydrochloric acid solution. The mixture was shaken on Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst was removed by filtration, the filtrate was neutralized with 4-polyvinylpyridine and concentrated. The residue was triturated with a mixture of methanol and ethyl acetate. The precipitate was collected and recrystallized form water/methanol/ethyl acetate to afford 4.6 g (28%) of product, mp 235°-238° C. (dec), in two crops.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=O)[CH2:8][CH3:9].[C:11](=O)([O:13]CC)[NH2:12]>[Cl-].[Zn+2].[Cl-].O>[CH2:8]([C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[NH:1][C:11](=[O:13])[N:12]=1)[CH3:9]
Reactant: CCOC(N)=O
Reactant: CCC(=O)c1ccsc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CCc1nc(=O)[nH]c2sccc12
Temperature: 200 °C

Procedure:
A mixture of 4.0 g of 2-amino-3-propionylthiophene, 8.9 g of ethyl carbamate and 0.53 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the resulting material is treated with hot water and then filtered. The filtrate is extracted with chloroform and the insoluble matter is washed with hot chloroform. The chloroform extracts were combined and washed with water. After removing the chloroform by distillation under reduced pressure, the resulting residue is crystallized from ethanol to give 4-ethyl-1,2-dihydrothieno[2,3-d]pyrimidine-2-one. Recrystallized from a mixture of ethanol and chloroform, there are obtained crystals having a melting point of 217° - 220°C.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH:13]([C:26]([OH:28])=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[OH-:29].[Na+].[SH-].[Na+].Cl>O>[C:1]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]3[C:18]([NH:23][C:26](=[O:28])[CH:13]2[CH2:12]1)=[CH:19][CH:20]=[CH:21][CH:22]=3)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:29]
Reactant: [OH-]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [SH-]
Solvent: O
Product: O=C1Nc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC12
Reaction time: 2.5 h

Procedure:
To a solution of 13 g. of 4-carbobenzoxy-1-(o-nitrophenyl)piperazine-2-carboxylic acid and 11.0 g. of sodium hydroxide in 200 ml. of water is added a solution of 20 g. of sodium hydrosulfide in 200 ml. of H2O. The orange solution gradually turns colorless over a period of 2-3 hours. Dilute hydrochloric acid is added to bring the pH of the solution to about 3. A white precipitate forms. Stirring is continued for about 3-5 minutes, and the pH is raised to about 7 by the addition of 40% sodium hydroxide. Filtration gives 8.6 g. of product, m.p. 125°-140°. The analytical sample on recrystallization from ethyl acetate hexane gave a m.p. 167°-170°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.N(C([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=1)=O)=[N+]=[N-].C[N:27](C)[CH:28]=[O:29]>>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:28]([NH:27][C:19]2[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=2)=[O:29])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1cc(C(=O)N=[N+]=[N-])n(C)n1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Product: Cc1cc(NC(=O)Nc2ccc(Cl)c(S(N)(=O)=O)c2O)n(C)n1
Yield: 7.7 %

Procedure:
Under Ar, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (137 mg, 0.61 mmol) and 5-(azidocarbonyl)-1,3-dimethylpyrazole (203 mg, 1.23 mmol) in 2 mL of N,N-dimethyl-formamide was stirred at room temperature for 3 days. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (17 mg, 7.7%). LC-MS (m/z) 360.2 (M+).