Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][C@@H:16]1[C@@:36]2([CH3:37])[C:20](=[CH:21][CH2:22][C@@H:23]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:31])[CH2:29][OH:30])[CH2:19][C@@H:18]([O:39][C:40](=[O:42])[CH3:41])[CH2:17]1)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:15][C@@H:16]1[C@@:36]2([CH3:37])[C:20](=[CH:21][CH2:22][C@@H:23]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:31])[CH2:29][O:30][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:19][C@@H:18]([O:39][C:40](=[O:42])[CH3:41])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
A solution of 55.1 mg of p-toluenesulphonyl chloride in 0.2 ml. of dry pyridine was added at 0° C. to a solution of 100 mg of (20S)-1α,3β-diacetoxy-21-hydroxy-20-methyl-pregn-5-ene in 0.5 ml. of dry pyridine. After standing at 0° C. for 6 hours, the mixture was poured on to ice-water and extracted with ether. The extract was washed successively with 2-N hydrochloric acid, water, saturated sodium bicarbonate solution and water. The residue obtained after drying over sodium sulphate and concentration was chromatographed on 3.5 g of silica gel using hexane/ether (4:1) for the elution, there being obtained 100 mg of uniform (20S)-1α,3β-diacetoxy-20-methyl-21-(p-toluene-sulphonyloxy)-pregn-5-ene. After recrystallisation from ether, the product melted at 168°-170° C.; [α]D =-20.8° (c=0.5 in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([CH2:13]S(OC)(=O)=O)[C@H:8]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:7][CH2:6]2.C([N:46]1[CH:50]=[C:49]([CH3:51])[N:48]=[CH:47]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([CH2:13][N:48]1[C:49]([CH3:51])=[CH:50][N:46]=[CH:47]1)[C@H:8]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH2:7][CH2:6]2
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1ccc([C@@H]2CCc3cc(OC)ccc3[C@@H]2CS(=O)(=O)OC)cc1
Solvent: CC#N
Product: COc1ccc([C@@H]2CCc3cc(OC)ccc3[C@@H]2Cn2cncc2C)cc1

Procedure:
A mixture of methyl (1R*,2R*)-1,2,3,4-tetrahydro-6-methoxy-2-(4-methoxyphenyl)-1-naphthylmethanesulphonate (0.2 g) and 1-trityl-4-methylimidazole (0.172 g) in acetonitrile (10 ml) was stirred and heated under reflux for 72 h. The acetonitrile was evaporated under reduced pressure, and the residue was dissolved in 90% by volume aqueous acetic acid (20 ml). This acetic acid solution was heated under reflux for 24 h, and then evaporated to dryness under reduced pressure, and the residue was dissolved in a mixture of ethylacetate (25 ml) and water (25 ml). The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (40 ml). The combined ethyl acetate solutions were dried and evaporated to dryness, and the residue was purified by flash column chromatography on silica (K60), using methanol/dichloromethane, 2:98 by volume, then methanol/dichloromethane, 5:95 by volume, as the eluting solvent, to give (1R*,2R*)-1,2,3,4-tetrahydro-6-methoxy-2-(4-methoxyphenyl)-1-(5-methylimidazol-1 -ylmethyl)naphthalene as a colourless gum. Nmr in CDCl3 : δ 7.25(2H, d); 6.95(3H, m); 6.7(2H, m); 6.5(1H, dd); 5.95(1H, d); 3.85(3H, s); 3.8(3H, s); 3.65(2H, m); 3.3(1H, m); 3.05(3H, m); 2.15(2H, m); 1.65 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([NH2:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[C:26]12([CH2:36][C:37](Cl)=[O:38])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>O1CCOCC1>[C:26]12([CH2:36][C:37]([NH:18][C:12]3[C:11]4[CH2:10][CH2:9][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[O:38])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccnc2c1CCN(Cc1ccccc1)C2
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccnc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 3.9 %

Procedure:
7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-4-ylamine (48 mg, 0.202 mmol) in 6 ml of dioxane was treated with NMM (22 μl, 0.202 mmol) followed by adamantan-1-yl-acetyl chloride (0.043 g, 0.202 mmol) and stirred at rt under argon. The reaction was monitored by TLC and LCMS. Excess acid chloride was added and the reaction was stirred. The contents were concentrated and purified by HPLC to afford the desired product (3.3 mg, 4%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cnccn3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[O:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:24]2[CH:25]=[CH:26][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (0.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.9 g) and triphenylphosphine (2.3 g) in dry tetrahydrofuran (20 mL) under a nitrogen atmosphere was cooled to 0° C. Di-isopropylazodicarboxylate (1.8 mL) was added drop-wise and the mixture was stirred at room temperature for 72 hours. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was extracted with pentane and the pentane phase was decanted and concentrated to give compound 51 as an oil. This was used without further purification.
Reaction SMILES: [NH2:1][C:2]1S[C:4]2[CH:10]=CC=C[C:5]=2[N:6]=1.[N-:11]=[C:12]=[O:13]>C(Cl)(Cl)Cl>[NH:6]1[CH:5]=[CH:4][CH:10]=[N:1][CH:2]1[C:12]([NH2:11])=[O:13]
Reactant: [N-]=C=O
Reactant: Nc1nc2ccccc2s1
Solvent: ClC(Cl)Cl
Product: NC(=O)C1N=CC=CN1
Yield: 40 %

Procedure:
After cooling the reactant, the residue obtained under reduced pressure was dissolved into chloroform, and insolubles were removed. The filtrate was concentrated to about 30 ml. 2-Aminobenzothiazole (3.35 g, 22.3 mmol) was added into the obtained filtrate which contained an isocyanate derivative, and the mixture was refluxed for one hour. After cooling, crystals were filtered. The obtained crystals were washed with methanol and vacuum-dried. 5-Fluoro-3,4-dihydro-2,4-dioxo-N-{6-[3-(benzothiazole-2-yl)ureido]hexyl}-1(2H-pyrimidinecarboxamide (4.04 g, 9.02 mmol) was obtained.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:24])(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCC(=O)N1CCOCC1
Temperature: -13 °C

Procedure:
To the solution of 1.79 g of 3-acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline and 0.51 g of triethylamine in 20 ml of anhydrous methylene chloride, 0.68 g of isobutyl chloroformate is added dropwise while stirring at -13° C. and stirred additional 10 minutes at the same temperature. To the solution 0.44 g of morpholine in 5 ml of methylene chloride is added dropwise.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9](O)=O)[CH:5]=[CH:4][N:3]=1.CS(Cl)(=O)=O.[NH3:17]>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]#[N:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(C(=O)O)ccnc1Cl
Reactant: N
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(C#N)ccnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Chloro-3-methyl-4-pyridinecarboxylic acid (30 g; 174 mmol) was dissolved in pyridine (250 ml) and cooled to 0° C. Methanesulfonyl chloride (13.6 ml) was then added dropwise and the reaction mixture was stirred at 0° C. for 1 hour. NH3 (gas) was added under pressure and the reaction mixture was stirred at room temperature for 1 h. After the reaction had reached completion, the excess NH3 was removed in vacuo. The reaction mixture was then cooled to 0° C., methanesulfonyl chloride (140 ml) was added and the reaction mixture stirred at room temperature overnight. The mixture was then poured into 0.1 M HCl (200 ml) at 0° C. (with care), and adjusted to pH=7 with 1 M NaOH. The reaction mixture was extracted with EtOAc (2×100 ml), washed with brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (Biotage flash purification system; gradient: EtOAc/heptane from 15/85 to 30/70). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 12.6 g of D1.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:19]=2)[CH:4]=1.C(N(CC)CC)C.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44]>C(Cl)Cl>[CH2:43]([NH:45][C:46](=[O:47])[NH:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:20][CH:19]=2)[CH:4]=1)[CH3:44]
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(OCC(=O)OCC)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a mixture of 200 mg of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 40.5 mg of triethylamine and 5 ml of methylene chloride was added 30 mg of ethyl isocyanate followed by stirring at room temperature overnight. The reaction mixture was treated in a manner similar to Example 68 to obtain 130 mg of ethyl 4-(3-ethylureido)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](N)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:25])=O.CN(C)C=O>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([Cl:25])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 89 %

Procedure:
Heat 40 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide together with 290 ml of thionyl chloride and 1 ml of dimethylformamide for 16 hours at boiling point. Cool the resulting solution, draw off the formed precipitate and wash it with thionyl chloride and with carbon tetrachloride to obtain an 89% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride [m.p. 208° to 210° C (from dioxane)].
Reaction SMILES: Br.[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2.[OH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=O.Cl>>[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][OH:25])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1CCC(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: O=CCCCCO
Agent: Br
Agent: Cl
Product: CC1CCC(C)c2cc(-c3csc(C4CCN(CCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 100 mg (0.25 mmol) of 4-[4-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide and 50 mg (0.49 mmol) of 5-hydroxypentanal. The product is in the form of the hydrochloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[CH:8]2)=O.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>O1CCCC1>[C:17]([O:16][C:14]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([CH2:3][OH:2])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1ccc2cc(CO)ccc21
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of N-tert-butoxycarbonylindole-5-carboxylic acid methyl ester (23.6 g, 85.7 mmol) in dry tetrahydrofuran (225 mL) at −78° C. was added 1.5 M DIBALH in toluene (171 mL, 257 mmol). After 2 h, the reaction mixture was quenched by the slow addition of methanol (45 mL), water (60 mL), and saturated aqueous NH4Cl (30 mL). The cold bath was removed and after stirring for an additional 1 h, the reaction mixture was filtered over Celite. The Celite cake was washed with tetrahydrofuran and the filtrate was concentrated to remove the more volatile tetrahydrofuran. The biphasic mixture was extracted with ethyl acetate. The combined organic layers were washed with water and the aqueous layer back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to afford N-tert-butoxycarbonylindol-5-yl methanol (21.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:19]([NH2:23])=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=1)[CH2:9][CH2:8]2.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[NH:23][S:26]([N:25]([CH3:30])[CH3:24])(=[O:28])=[O:27])[N:14]=1)[CH2:9][CH2:8]2
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cccc2c1C(Nc1ccc3c(N)cccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3c(NS(=O)(=O)N(C)C)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=413.4 (M+H+), was prepared in accordance with the general method of example 17 from N2-(7-methoxy-indan-1-yl)-quinoline-2,5-diamine and dimethyl sulfamoyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:25]=[NH:26])[C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15](C1C=CC=CC=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:25][NH:26][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2c([nH]c3cccc(-c4ccccc4)c32)c(C=N)n1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc2c([nH]c3ccccc32)c(CNc2ccccc2)n1
Reaction time: 0.67 h
Yield: 119.3 %

Procedure:
5-phenyl-iminomethyl-beta-carboline-3-carboxylic acid ethyl ester (0.25 g) is hydrogenated in 100 ml of ethanol with addition of Raney nickel at normal pressure and a temperature of 25° C. Taking up of 1 mol of hydrogen takes about 40 minutes. The residue remaining after filtering of the catalyst and evaporation of the filtrate is chromatographed on silica gel with a mixture of 10 parts of dichloromethane and one part of ethanol. Thus, 0.15 g of phenylaminomethyl-beta-carboline-3-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cl
Reactant: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(=O)OCC
Yield: 80 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.10 gm, 0.3 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (0.7 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 90 mg (80%) of 2-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl-7-fluorobenzofuran, mp. 85°-88° C.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[O:6][C:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[OH:22].[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32])([CH3:25])[CH3:24].N1CCCCC1>ClCCl>[OH:22][C:3]1[CH2:4][C:5]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7](=[O:8])[C:2]=1[S:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)c1ccccc1S
Reactant: O=C(O)CCCCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1ccccc1SC1=C(O)CC(CCCCC(=O)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.1 mmol of 5-[5-bromo-3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl]pentanoic acid (prepared in example DDD), 1.3 mmol of 2-isopropylbenzenethiol, and 1.3 mmol of piperidine in 20 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with 5% methanol in chloroform and then with 9:1:0.5 chloroform:methanol:acetic acid, to give the title compound, (m.p. 145°-146° C.). 1H NMR (DMSO-d6) δ 1.07-1.19 (t plus m, 7 H), 1.25 (m, 1 H), 1.43 (m, 2 H), 1.91 (m, 2 H), 2.15 (t, 2 H), 3.19 (m, 1 H), 3.41 (2 H+H2O), 5.81 (d, 1 H), 6.54 (t, 1 H), 6.93 (t, 1 H), 7.12 (d, 1 H), 7.29-7.44 (m, 5 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19].O1CCCC1>CC(=O)CC>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6])[CH3:19]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)O)ccc1I
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 3-hydroxy-4-iodo-benzoic acid (4 g, 15.15 mmol) in 2-butanone (100 mL) were added potassium carbonate (20 g, finely ground) and ethyl iodide (4.85 mL). The mixture was stirred at reflux overnight. Upon cooling to room temperature, the solids were filtered off, and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with 10% sodium carbonate solution, brine, and concentrated. The residue reconstituted in methanol. 1.0 M sodium hydroxide was added giving a cloudy solution. Tetrahydrofuran was added to clarity and the mixture stirred at room temperature for one hour. The volatiles were evaporated and the residue was dissolved in water. It was washed once with diethyl ether and then acidified with 37% hydrochloric acid to precipitate a white solid. The solid was filtered, washed with water and dried in a vacuum oven to give 3-ethoxy-4-iodo-benzoic acid (2.73 g, 62%). LC-MS: 293 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NC(=O)Nc1ccc(Br)cn1
Reaction time: 12 h

Procedure:
To a solution of 2-amino-5-bromo-pyridine (1.05 eq.) in TBF (0.2M) was added DBU (1.0 eq.) followed by iso-propyl-isocyanate (1.0 eq.). The mixture was stirred for 12 h, diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated. Crystallization from acetone afforded the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].CC1C=CC(S([CH2:19][N+:20]#[C-:21])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH:21]=[N:20][CH:19]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2cnco2)nc1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of picolinaldehyde (2.3 g, 42.6 mmol), TosMIC (4.4 g, 45.2 mmol) and K2CO3 (3.4 g, 48.8 mmol) in methanol (70 mL) was reflux for 2 h. The reaction was cooled to room temperature, then the mixture was concentrated and purified by silica gel column chromatography to give the desired product (3.05 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2.[CH2:13]([B-](F)(F)F)[CH2:14][CH2:15][CH3:16].[K+]>>[CH2:13]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2)[CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1cc2cc(Br)ccc2[nH]1
Reactant: CCCC[B-](F)(F)F
Agent: [K+]
Product: CCCCc1ccc2[nH]c(C=O)cc2c1
Yield: 27.8 %

Procedure:
5-Butyl-1H-indole-2-carbaldehyde was synthesized as in Example 3.1 using 5-bromo-1H-indole-2-carbaldehyde (300 mg, 1.34 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (352 mg, 2.21 mmol) in place of hexylboronic acid to give 5-butyl-1H-indole-2-carbaldehyde (75 mg, 28%). Used without further characterization.