Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C@@H:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:16])=[CH:10][CH:11]=1)=[O:13]
Reactant: CC[C@H](C)COC(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@H](C)COC(=O)c1ccc(CBr)cc1

Procedure:
20.63 g (0.1 mole) of the 4-methylbenzoic acid[(S)-2-methylbutyl]ester obtained in Step A-1, 17.80 g (0.1 mole) of N-bromosuccinimide, and 1.32 g (0.005 moles) of benzoyl peroxide were dissolved in 120 ml of dry carbon tetrachloride and allowed to react under reflux for three hours. On completion of the reaction, the reaction mixture was filtered while hot to remove the succinimide, which is a by-product of the reaction, and 27.70 g of a crude form of the objective 4-((S)-2-methyl butoxycarbonyl)benzylbromide was obtained from the filtrate by evaporating off the carbon tetrachloride.
Reaction SMILES: N([O-])=O.[Na+].Cl.C(O)(=O)C.[CH:10]([C@@H:14]1[N:19]([CH3:20])[CH2:18][CH2:17][N:16]([C:21]([C:23]2[N:28]=[N:27][C:26]([C:29]([NH:31]N)=[O:30])=[C:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH:24]=2)=[O:22])[CH2:15]1)([CH2:12][CH3:13])[CH3:11].C(=O)(O)[O-].[Na+].N[C@H:43]([CH2:47][OH:48])[CH:44]([CH3:46])[CH3:45]>O>[OH:48][CH2:47][C@@H:43]([NH:31][C:29]([C:26]1[N:27]=[N:28][C:23]([C:21]([N:16]2[CH2:17][CH2:18][N:19]([CH3:20])[C@@H:14]([CH:10]([CH2:12][CH3:13])[CH3:11])[CH2:15]2)=[O:22])=[CH:24][C:25]=1[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH:44]([CH3:46])[CH3:45]
Reactant: CCC(C)[C@H]1CN(C(=O)c2cc(CC(C)C)c(C(=O)NN)nn2)CCN1C
Reactant: CC(C)[C@H](N)CO
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)[C@H]1CN(C(=O)c2cc(CC(C)C)c(C(=O)N[C@H](CO)C(C)C)nn2)CCN1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
A 7 mL glass vial was charged with 500 μL water and cooled to 0° C. Sodium nitrite (1.8 mg, 0.026 mmol, 180 μL of 10 mg/mL aqueous solution), 1M hydrochloric acid (52 μL, 0.052 mmol) and acetic acid (0.039 mmol, 2.3 mg, 230 μL of 10 mg/mL aqueous solution) were added sequentially and stirred for ca. five minutes. A solution of acyl hydrazide 14 (5 mg in 500 μL THF:200 μL H2O, 0.013 mmol) was added slowly and the reaction mixture was stirred at 0° C. for 10 minutes. The acidic solution was neutralized with saturated sodium bicarbonate (2 mL) and extracted with cold diethyl ether (3×2 mL). The organic fractions were collected in a second 20 mL vial at 0° C., and 270 μL of a cold, ethereal solution of L-valinol (10 mg/mL, 0.026 mmol, 2.7 mg) was added slowly. The reaction was allowed to warm to room temperature, and stirred overnight. The solvent was evaporated, and the product was purified by silica gel chromatography (9.4:0.6:0.1% DCM:MeOH:Et3N, Rf=0.35) to give 5 mg (86% yield) of a colorless oil. MS: (ESI-TOF) MH+ expected: 448.3282, found: 448.3283.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][CH:11]3[C:6]=2[C:7]=1[CH2:8][N:9]([CH3:23])[CH2:10]3.[OH-].[C:27]1([N+](C)(C)C)C=CC=CC=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:25][O:24][C:3]1[C:2]([O:1][CH3:27])=[C:7]2[CH2:8][N:9]([CH3:23])[CH2:10][CH:11]3[CH2:12][C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[C:5](=[C:6]23)[CH:4]=1
Reactant: COc1cc2c(cc1OC)-c1cc(OC)c(O)c3c1C(C2)CN(C)C3
Reactant: C[N+](C)(C)c1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)-c1cc(OC)c(OC)c3c1C(C2)CN(C)C3

Procedure:
9.1 g. (±)-5,6,6a,7-Tetrahydro-3-hydroxy-2,9,10-trimethoxy-5-methyl-4H-dibenz(de,g)isoquinoline (see Example 2) are reacted with phenyltrimethylammonium hydroxide in toluene/dimethylformamide in a manner analogous to that described in Example 7. When the methylation is finished, the reaction mixture is worked up in the manner described in Example 7. By chromatography of the crude product on silica gel (elution with chloroform +1% triethylamine) and crystallisation from chloroform-diethyl ether, there is obtained (±)-5,6,6a,7-tetrahydro-2,3,9,10-tetramethoxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of beige crystals; m.p. 170°-177° C.
Reaction SMILES: C(OC(C1NC=CC=1)=O)C.FC1C=CC(CBr)=CC=1.[F:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][N:26]2[CH:30]=[CH:29][CH:28]=[C:27]2[C:31]([OH:33])=[O:32])=[CH:23][CH:22]=1.[NH2:36][C:37]1[S:38][CH:39]=[CH:40][N:41]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[CH:30]=[CH:29][CH:28]=[C:27]2[C:31]([OH:33])=[O:32])=[CH:34][CH:35]=1.[S:38]1[CH:39]=[CH:40][N:41]=[C:37]1[NH:36][C:31]([C:27]1[N:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=1)=[O:33]
Reactant: Nc1nccs1
Agent: CCOC(=O)c1ccc[nH]1
Agent: Fc1ccc(CBr)cc1
Agent: O=C(O)c1cccn1Cc1ccc(F)cc1
Product: O=C(Nc1nccs1)c1cccn1Cc1ccc(F)cc1

Procedure:
1-(4-Fluorobenzyl)-pyrrole-2-carboxylic acid (1.18 g) was prepared from ethyl-pyrrole-2-carboxylate (1.39 g, 10.0 mmol) and 4-fluorobenzyl bromide (1.38 mL, 11.0 mmol) following the general procedures A and B. 1-(4-Fluorobenzyl)-pyrrole-2-carboxylic acid thiazol-2-ylamide (45 mg) was prepared from 1-(4-fluorobenzyl)-pyrrole-2-carboxylic acid (55 mg, 0.25 mmol) and 2-aminothiazole (25 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: I[Si](C)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:23][CH2:22][CH2:21][C@@H:20]3[N:15]2[C:16](=[O:24])[CH2:17][CH2:18][CH2:19]3)=[CH:10][CH:9]=1.CN(C)CCN(C)C.[I:33]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[I:33][CH:17]1[C:16](=[O:24])[N:15]2[C@@H:20]([CH2:21][CH2:22][CH2:23][C@@H:14]2[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)[CH2:19][CH2:18]1
Reactant: II
Reactant: COc1ccc([C@H]2CCC[C@H]3CCCC(=O)N32)cc1
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc([C@H]2CCC[C@H]3CCC(I)C(=O)N32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Iodotrimethylsilane (0.02 mL) was added to a solution of (6R*,9aS*)-6-(4-methoxyphenyl)octahydroquinolizin-4-one (23 mg) and N,N,N′,N′-tetramethylethylenediamine (0.05 mL) in methylene chloride (3 mL) at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes. Iodine (34 mg) was added to the reaction solution, which was then stirred at 0° C. for one hour. Ethyl acetate and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 34 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:13](OCC)[O:14]CC)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:13]=[O:14])=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12])=[O:4]
Reactant: CCOC(OCC)c1cc(C(C)C)c(C(=O)OC)s1
Solvent: O=CO
Solvent: C1COCCO1
Product: COC(=O)c1sc(C=O)cc1C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 118.4 %

Procedure:
A solution of 5-Diethoxymethyl-3-isopropyl-thiophene-2-carboxylic acid methyl ester (0.58 g, 2.03 mmol) in dioxane (5 ml) was cooled to 0° C. (ice bath). 88% formic acid (6 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 60 min. The reaction mixture was quenched by pouring into EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (0.51 g, 99% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]([NH2:15])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]#[N:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N=NC(C#N)=C2NC(C)(C)Cc3ccccc32)cc1

Procedure:
2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetamide (Asinex Corp., Russia), thionyl chloride and DMF are mixed and stirred slowly. An excess of thionyl chloride is removed from the mixed solvent by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][NH:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:28]3[CH:29]=[C:24]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:21][CH3:20])=[O:23])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CNC(=O)c1cccc(-c2cccn3nc(Nc4ccccc4OC)nc23)c1

Procedure:
3-[2-(2-Methoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-N-methyl-benzamide was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and 3-methylaminocarbonylbenzeneboronic acid (31.0 mg, 0.173 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2c and was isolated as a yellow solid (0.048 g, 82%). MP=199-202° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48-8.44 (m, 2H), 8.40 (dd, J=7.9, 1.3 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.65-7.57 (m, 3H), 7.07-6.99 (m, 4H), 6.30 (br s, 1H), 3.92 (s, 3H), 3.07 (d, J=4.9 Hz, 3H). MS=374 (MH)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[NH:8][C:7]=1[CH3:14])=[O:5])C.[OH-].[K+].O>CO>[CH:12]([C:9]1[NH:8][C:7]([CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 8 °C
Yield: 93.5 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (806 g), potassium hydroxide (548 g), water (2400 mL) and methanol (300 mL) were refluxed for two hours with stirring and then cooled to 8° C. The mixture was extracted twice with dichloromethane. The aqueous layer was adjusted to pH 4 with 1000 mL of 10 N hydrochloric acid keeping the temperature under 15° C. Water was added to facilitate stirring. The solid was collected by vacuum filtration, washed three times with water and dried under vacuum at 50° C. to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic (645 g, 93.5% yield) acid as a yellow solid. NMR (DMSO-d6) δ 2.40, 2.43 (2×s, 2×3H, 2×CH3), 9.57 (s, 1H, CHO), 12.07 (br s, 2H, NH+COOH). MS m/z 168 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>O1CCCC1>[NH:1]([C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][N:12]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:13]3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[C:26]([CH3:27])=[O:28]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1
Reaction time: 8 h

Procedure:
80.2 g (0.24 mole) of 3-(4-aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane (cf. European Pat. No. 62,199) were dissolved in 500 ml anhydrous tetrahydrofuran and cooled with ice. 23.5 g (0.3 mole) of acetyl chloride, dissolved in 50 ml of tetrahydrofuran, were added dropwise, followed by 48.6 g (0.48 mole) of triethylamine at room temperature. The entire mixture was stirred overnight and then evaporated down under reduced pressure. The residue was taken up in water and the solution was extracted 3 times with methylene chloride. The combined organic phases were washed with water, dried and evaporated down under reduced pressure. Yield: 78.1 g, mp.: 208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH3:35])[CH2:30]1.C([O-])([O-])=O.[Cs+].[Cs+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:28][CH:29]5[CH2:34][CH2:33][CH2:32][N:31]([CH3:35])[CH2:30]5)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCCC(CCl)C1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1CCCN(C)C1
Temperature: 25 °C

Procedure:
A solution containing 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (77 mg, 0.20 mmol, the preparation of which may be found in Example K1) and 3-(chloromethyl)-1-methylpiperidine (74 mg) was mixed with Cs2CO3 (261 mg, 0.80 mmol) and the resultant mixture was heated at 85° C. for 3 hours. The mixture was then cooled to room temperature, diluted with dichlormethane, washed with a saturated solution of NaHCO3 and brine, dried (MgSO4), and concentrated under reduced pressure. The resultant residue was purified by column chromatography to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1>>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:34]=[CH:35][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cnc(-c2cnc3c(Cl)ccnc3n2)c(C(F)(F)F)c1
Reactant: Nc1cnc2ccccc2n1
Product: NC(=O)c1cnc(-c2cnc3c(Nc4cnc5ccccc5n4)ccnc3n2)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 6-(8-chloropyrido[2,3-b]pyrazin-3-yl)-5-(trifluoromethyl)nicotinamide (70.6 mg, 0.2 mmol) and 2-aminoquinoxaline (85.8 mg, 0.6 mmol) in a screw cap vial at 140° C. for 20 hours under N2 atmosphere. Purify the reaction mixture by column chromatography using 1-2% MeOH/EtOAc as eluent to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.017 (s, 1H), 9.461 (s, 2H), 9.335 (d, 1H, J=1.1 Hz), 9.307 (s, 1H), 9.129 (d, 1H, J=1.3 Hz), 8.836 (s, 1H), 8.557(s, 1H), 7.975 (m, 3H), 7.789 (t, 1H), 7.647(t, 1H). MS=463.12 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([S:22]([CH2:25][C:26]2[C:31]([C:32]([OH:34])=[O:33])=[C:30]([OH:35])[C:29]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)=[CH:28][CH:27]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:41](O)([CH3:44])([CH3:43])[CH3:42]>C1COCC1.CN(C)C1C=CN=CC=1>[C:16]1([S:22]([CH2:25][C:26]2[C:31]([C:32]([O:34][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:33])=[C:30]([OH:35])[C:29]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)=[CH:28][CH:27]=2)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)O
Reactant: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O

Procedure:
A solution of dicyclohexylcarbodiimide (0.124 g) in THF (1 ml) was added dropwise to a mixture of 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoic acid (Intermediate 114, 0.358 g) and 4-dimethylaminopyridine (0.0032 g) and t-butanol (3 ml) in THF (1 ml). The resultant mixture was stirred at room temperature for 4 hours. The solid was removed by filtration and the filtrate was washed with citric acid (5% aqueous solution), sodium bicarbonate (saturated aqueous solution) and brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (20%) to give t-butyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (0.19 g) as a waxy white solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C:5]([CH:18]=[CH2:19])(O)[C:4]=2[CH:3]=1.[NH2:20][C:21]([NH2:23])=[S:22].C(O)(C(F)(F)F)=O>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C:5]3([CH2:18][CH2:19][S:22][C:21]([NH2:23])=[N:20]3)[C:4]=2[CH:3]=1
Reactant: NC(N)=S
Reactant: C=CC1(O)c2cc(Br)ccc2Oc2ccc(I)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: NC1=NC2(CCS1)c1cc(Br)ccc1Oc1ccc(I)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol (0.50 g, 1.16 mmol) and thiourea (0.18 g, 2.33 mmol) in acetic acid (2.00 mL) was added TFA (4.00 mL). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc, followed by a solvent mixture of CHCl3: i-PrOH (3:1). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (10%-100% EtOAc/hexane) to provide 0.36 g of 2′-bromo-7′-iodo-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as a light yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[S:17][CH:16]=[CH:15][C:11]=2[N:12]([CH3:14])[N:13]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[S:17][CH:16]=[CH:15][C:11]=2[N:12]([CH3:14])[N:13]=1
Reactant: COc1ccccc1-c1nn(C)c2ccsc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2O)c2sccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 3-(2-methoxyphenyl)-1-methyl-1H-thieno[3,2-c]pyrazole (4.2 g) in 30 ml of dichloromethane was added dropwise 24 ml of a stock solution of BBr3 in dichloromethane. The mixture warmed up spontaneously and a precipitate begain to deposit. After stirring at ambient temperature for 2 hours, the reaction mixture was quenched with 50 ml of 1H hydrochloric acid. Stirring was continued overnight whereupon the mixture became almost clear. The organic layer was diluted with ether, the phases were separated, and the aqueous layer was basified with concentrated NH3 and extracted three times with 200 ml total of ether. The combined organic solution was washed with water, dried (over anhydrous magnesium sulfate) and concentrated to a solid. Purification of the crude product was effected by passing it through a column of silica gel packed in dichloromethane, which afforded 3.48 g of crystals. They were further purified by recrystallization from ether/hexane, m.p. 112°-113° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:21][C@@H:22]([CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]>C(Cl)Cl>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:21][C@@H:22]([CH2:31][N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)[C@H:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:24])=[O:20])([OH:19])=[O:18]
Reactant: O=C1CCCCCCCCC(=O)O1
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCCCCCCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 5 h
Yield: 30.4 %

Procedure:
Methylene chloride (10 ml), triethylamine (190 μl, 1.37 mmol) and sebacic anhydride (292.4 mg, 1.59 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (316.2 mg, 1.34 mmol), followed by stirring for 5 hours. Then, the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:methanol=20:1 and chloroform:methanol=9:1) to obtain the title compound (171.1 mg, yield 30.4%) as colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([OH:30])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:27])([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:29])(=[O:3])[CH3:2].N1C=CN=C1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([O:30][Si:38]([CH3:40])([CH3:39])[CH3:37])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:27])([C@@H:22]([O:26][Si:38]([CH3:40])([CH3:39])[CH3:37])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)[C@@]1(O[Si](C)(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.9 %

Procedure:
To a solution of (11β,16β)-9-fluoro-11,17-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-21-yl acetate (18.79 g, 43.25 mmol) and imidazole (58.89 g, 864.9 mmol) in 200 mL of dry N,N-dimethylformamide was added neat trimethylsilyl chloride (55.0 mL, 433 mmol) dropwise during 15 min. The resulting pale yellow solution was stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed successively with water, sat. NH4Cl, water, sat. NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered and evaporated in vacuo to yield 26 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.[OH-].[Ba+2].[OH-].COCCOC>O>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: OB(O)c1ccccn1
Reactant: Nc1ncc(Br)cn1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2ccccn2)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 2-amino-5-bromopyrimidine (0.299 g, 1.72 mmol), 2-pyridylboronic acid (1.57 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME (8 mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenylphosphine) palladium(0) (99.0 mg, 0.086 inmol) is added, and the resultant solution is stirred at 80° C. for 4 hours. The solvents are evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc. The organic extracts are combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.