Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:50]6[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]6)[CH:41]=5)[C:36]([CH3:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (0.033 g, 0.05 mmol), and piperazine (0.043 g, 0.5 mmol) were combined in CH2Cl2 (2 mL) and stirred for 30 min. Sodium triacetoxyborohydride (0.0318 g, 0.15 mmol) was added and the mixture stirred for 30 h. Aqueous workup was followed using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 1 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a white solid. LC-MS m/z 729.4 (M+H)+, 1.31 min (ret time); mp 135-138° C. Analytical HPLC shows 98.4% purity, (ret time 10.019 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH3:26].CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:12]=[C:13]([NH2:26])[C:14]([CH3:16])=[N:15]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: N
Reactant: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)NC1=S
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)N=C1N
Temperature: 100 °C
Yield: 30 %

Procedure:
6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione (Example 49 Step 2), directly from the previous step was dissolved in dry DMF (4 mL) in a microwave vial. Ammonia, 7M in MeOH (18 mL, 126 mmol) was added. The vial was sealed and the reaction was heated at 100° C. for 60 min in a microwave reactor (fixed hold time). The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 18 mL, 126 mmol) and heated at 120° C. for 30 min in a microwave reactor. This cycle was repeated three more times. After evaporation of the solvent, the remaining product was subjected to flash chromatography (0-7% of MeOH(NH3) in DCM) to give the title compound as a mixture of isomers (1.29 g, 30% yield over two steps): MS (ES+) m/z 406 [M+H]+.
Reaction SMILES: [Br:1][C:2]1(O)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[C:9](=O)([O-])[O-:10].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:10][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: OC1(Br)C=CC=CN1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccnc1Br
Temperature: 70 °C
Yield: 76.7 %

Procedure:
2-Bromo-2-pyridinol (15 g, 86 mmol) in acetone (500 ml) was treated with potassium carbonate (23.8 g, 172 mmol) and iodomethane (8.1 ml, 130 mmol) and the suspension was refluxed at 70° C. for 16 hours. Once cooled, the mixture was filtered and the filtrate concentrated in vacuo. The residue was then purified by silica wet flash chromatography to give the product as yellow crystals (12.4 g, 66 mmol, 77% yield).
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[NH2:10][CH:11]1[C:37](=[O:38])[N:13]2[C:14]([C:21]([O:23][CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]12
Reactant: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
6.4 (12.2 mmol) of benzhydryl 7-phenylacetamido-3-[(Z)-propen-1-yl]-3-cephem-4-carboxylate (Example 9) are dissolved in 64 ml of methylene chloride, the solution is cooled to -40° C. with a dry ice bath and 2.47 ml (30.5 mmol) of pyridine and 2.54 g (12.2 mmol) of phosphorus pentachloride are added in succession. After 5 minutes, the mixture is allowed to warm to -20° C., after which the temperature should rise to -10° C. in the course of 20 minutes and then rise to +10° C. The solution is now stirred at +10° C. to +15° C. for 1 hour. The mixture is subsequently cooled to -40° C., 100 ml of methanol (-30° C.) are added and the mixture is stirred at +10° C. for a further 30 minutes. The reaction solution is concentrated gently, the oil obtained is dissolved in 600 ml of methylene chloride, the solution is stirred into 800 ml of sodium bicarbonate solution and the mixture is stirred for 10 minutes. The methylene chloride phase is separated off, washed once with water and dried over sodium sulphate. The methylene chloride filtrate is chromatographed on 400 ml of silica gel (0.04-0.063 mm), elution being carried out first with methylene chloride and then with methylene chloride with the addition of methanol (gradient up to 10%). The eluate is investigated by means of analytical HPLC and TLC (thin layer chromatography) (methylene chloride/methanol=100:1).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH2:24][CH3:25])[C:22]([CH3:26])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>S(Cl)(Cl)=O.CO>[CH2:24]([N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([S:2](=[O:5])(=[O:3])[NH:30][CH2:29][CH2:27][OH:28])=[CH:9][CH:8]=3)[N:18]=2)=[CH:20][N:21]=[C:22]1[CH3:26])[CH3:25]
Reactant: NCCO
Reactant: O=S(=O)(O)Cl
Reactant: CCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCO)cc3)n2)cnc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
Chlorosulphonic acid (150 μL, 2.16 mmol) was added dropwise to solution of 2-anilino-4-(1-ethyl-2-methylimidazol-5-yl)pyrimidine (Example 28; 150 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled at 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of ethanolamine (494 mg, 8.1 mmol) in MeOH (3 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. Water (20 ml) was added and the precipitated solid was collected by filtration, washed with water (2×10 ml) and ether (2×10 ml) and and dried under vacuum at 60° C. to yield the title compound (177 mg, 81%) as a beige solid. NMR 1.22 (t, 3H), 2.41 (s, 3H), 2.80 (s, 2H), 3.38 (q, 2H), 4.63 (m, 3H), 7.20 (d, 1H), 7.36 (s, 1H), 7.77 (s, 1H), 7.82 (d, 2H), 7.91 (d, 2H), 8.34 (d, 1H), 9.85, (s, 1H); m/z 403.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([O-])(=O)[CH:8]=[CH2:9].CC(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)(C1C=C[C:18]([O:21]CC(O)COC(C=C)=O)=CC=1)C>>[C:18]1(=[O:21])[O:6][C:1](=[O:5])[C:2]2=[CH:4][CH:7]=[CH:8][CH:9]=[C:3]12
Reactant: C=CC(=O)[O-]
Reactant: C=C(C)C(=O)[O-]
Reactant: C=CC(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C=C)cc2)cc1
Product: O=C1OC(=O)c2ccccc21

Procedure:
As the compound having a boiling point of 100° C. or higher at atmospheric pressure and at least one kind of ethylenic unsaturated group (component (1)) which is used in the photopolymerizable composition of this invention, there are exemplified, for example, compounds obtained by adding α, β-unsaturated carboxylic acids to polyhydric alcohols, such as tetraethylene glycol di(meth)acrylate (the term "di(meth)acrylate" means methacrylate or acrylate; hereinafter the same applied), polyethlene glycol di(meth)acrylate (having 2 to 14 ) ethylene groups), trimethylolpropane di(meth)acrylate, trimethylolpropane tri(meth)acrylate, tetramethylolmethane tri(meth)acrylate, tetramethylolmethane tetra(meth)acrylate, polypropylene glycol di(meth)acrylate (having 2 to 14 propylene groups), dipentaerythritol penta(meth)acrylate, dipentaerythritol hexa(meth)acrylate, and the like; compounds obtained by adding α, β-unsaturated carboxylic acids to glycidyl group containing compounds, such as trimethylolpropane triglycidyl ether triacrylate, bisphenol A diglycidyl ether diacrylate, and the like; esterified products obtained from carboxylic acids having two or more hydroxyl groups, e.g., phthalic anhydride and substances having a hydroxyl group and an ethylenic unsaturated group, e.g., β-hydroxyethyl (meth)acrylate; and alkyl ethers of acrylic acid or methacrylic acid, such as methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, and the like.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[CH3:25].C(N(C(C)C)CC)(C)C.[CH2:35]([NH:37][C:38]1([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:36]>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:8][N:7]3[C:2]([N:41]4[CH2:40][CH2:39][C:38]([NH:37][CH2:35][CH3:36])([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]4)=[C:3]([CH3:25])[CH:4]=[N:5][C:6]=23)=[CH:12][CH:13]=1
Reactant: Cc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1Cl
Reactant: CCNC1(C(N)=O)CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(N)=O)CCN(c2c(C)cnc3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidine (I-3A-1d; 31.3 mg, 0.0806 mmol) and diisopropylethylamine (0.025 ml, 0.14 mmol) in THF (1 ml) was added 4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1g; 18.5 mg, 0.108 mmol). The mixture was stirred at 50° C. for 20 hours. After cooling to room temperature, the reaction was extracted from saturated aqueous NaHCO3 with ethyl acetate, the combined organic layers were dried (MgSO4), concentrated and purified on a Biotage™ Flash 12S column using 0–5% methanol in methylene chloride as eluant to afford, after trituration from hexanes/methylene chloride, product 3A-1 as a solid (29 mg, 69%): +ESI MS (M+1) 523.4; 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.48–7.34 (m, 6H), 7.21 (d, J=8.7 Hz, 2H), 3.82–3.74 (m, 2H), 3.66–3.58 (m, 2H), 2.51 (q, J=7.1 Hz, 2H), 2.39 (s, 3H), 2.28–2.20 (m, 2H), 1.88–1.80 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl-].[CH3:13][O:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:35]1[C:40]([C:41]([C:43]([F:46])([F:45])[F:44])=O)=[CH:39][CH:38]=[C:37]([C:47]([F:50])([F:49])[F:48])[CH:36]=1.CCCCCC>C1COCC1>[CH3:13][O:14][CH:15]=[C:41]([C:40]1[CH:39]=[CH:38][C:37]([C:47]([F:50])([F:49])[F:48])=[CH:36][CH:35]=1)[C:43]([F:46])([F:45])[F:44]
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=C(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 25.0 ml of n-butyllithium/hexane solution (1.2M solution) was added to a solution of 12.7 g of methoxymethyltriphenylphosphonium chloride in 100 ml of dry THF at -60° C. The reaction solution was stirred at -60° C. for 30 minutes and at -20° C. for 30 minutes. A solution of 6.0 of 4-trifluoromethyl-α,α,α-trifluoroacetophenone in 10 ml of dry THF was slowly added to the reaction solution at -60° C. The reaction solution was stirred at -60° C. for 1 hour and at room temperature for 14 hours. Thereafter, 150 ml of n-hexane was added to the reaction mixture and insoluble materials were filtered out. The filtrate was washed with dilute HCl-ice water and saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and 6.1 g of the crude product (E/Z=ca. 1/1) was obtained.
Reaction SMILES: [S:1]1[CH2:7][CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:8][NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:31][CH2:32][C:33](Cl)=[O:34]>CCOCC.O>[Cl:31][CH2:32][C:33]([N:9]([CH2:8][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][CH2:7][S:1]1)[C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19])=[O:34]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(CC)c1NCC1SCCCCS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCc1cccc(CC)c1N(CC1SCCCCS1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dithiepan-2-ylmethyl)-2,6-diethylaniline (15 grams), sodium bicarbonate (10 grams), dioxane (30 ml) and water (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0°C and chloroacetyl chloride (7 grams) is added, with stirring, over a period of about 15 minutes. After the addition is completed stirring is continued for a period of about 1 hour. After this time ether (100 ml) is added to the mixture and the resulting solution is washed with water. The washed solution is then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue is recrystallized to yield the desired product N-α-chloroacetyl-N-(1,3-dithiepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]([C@H:17]([CH3:34])[C@:18]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])([OH:25])[CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:11]3)=[CH:4][CH:3]=1.[CH:37](N(C(C)C)CC)(C)[CH3:38].BrCC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]([CH2:37][CH3:38])[C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]([C@H:17]([CH3:34])[C@:18]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])([OH:25])[CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:11]3)=[CH:4][CH:3]=1
Reactant: C[C@@H](N1Cc2cc(NCc3ccc(Cl)cc3)ccc2N1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCBr
Product: CCN(Cc1ccc(Cl)cc1)c1ccc2c(c1)CN([C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F)N2
Reaction time: 0.5 h

Procedure:
To a solution of (2R,3R)-3-(5-(4-chlorobenzylamino)-1H-indazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (0.043 g, 0.08 mmol), prepared in Example 244, in N,N′-dimethylformamide (0.5 ml) was added diisopropylethylamine (0.015 ml, 0.08 mmol), followed by stirring for 30 min. The reaction solution was further stirred at 80° C. for 18 hours after the addition of bromoethane (0.019 ml, 0.17 mmol) thereto. The reaction product was diluted with ethyl acetate (10 ml) and washed with saturated ammonium chloride solution (10 ml), and then with brine (10 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][OH:25]>CN(C=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[O:15][CH2:23][CH2:24][OH:25])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2Cc2ccccc21
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of anthrone (5.0 g, 25.7 mmole) in 34 mL anhydrous DMF under an inert atmosphere was added potassium carbonate (7.47 g, 54.1 mmole). To the resulting reaction mixture was added 2-bromoethanol (2.0 mL, 28.3 mmole). The resulting reaction mixture was stirred for 1 hr at room temperature, then 3 hrs at 80° C. The reaction was then cooled to room temperature and quenched with saturated NaHCO3. Ethyl acetate was added and the organic layer was collected and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified via flash chromatography.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCC(O)CC2)cc1
Reaction time: 18 h
Yield: 482.9 %

Procedure:
1.15 g (0.00114 mol) of 4-hydroxypiperidine were dissolved in 15 ml of dimethylformamide and cooled to 0°. 1.92 g (0.001037 mol) of 4-methylbenzyl bromide and 1.59 ml (0.0114 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 18 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (9:1) as the eluent. 1.028 g (48%) of 1-(4-methyl-benzyl)-piperidin-4-ol were obtained as beige crystals; m.p. 72°-74°.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CO.[Cu]>[Br:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(Br)cccc2s1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: Brc1cccc2sccc12
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
Copper powder (49.8 g) is added to a stirred mixture of 4-bromo-benzo[b]thiophene-2-carboxylic acid (995.5 g, 3.87 mol) and quinoline (1.99 L) and the resultant mixture is heated to and maintained at 15 to 195° C. for 5 h. The mixture is allowed to cool to room temperature and the reaction is quenched by the addition of a mixture of ice (5.81 Kg) and concentrated hydrochloric acid (2.48 L). TBME (9 L) is added and the mixture is stirred vigorously for 10 min and filtered. The clarified layers are separated and the aqueous layer is extracted with TBME (1.0 L). The combined extracts are washed with hydrochloric acid (1 M, 2×5.00 L) and water (4.0 L), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product (640 g) as a brown oil which solidifies on standing overnight. The residue is slurried in methanol (500 mL, 0.5 vol) at −10 to 0° C. for 1.5 h, the observed solid material is collected by filtration and pulled dry on the filter. The methanolic mother liquors are concentrated by rotary evaporation. The residue is combined with the isolated solid material, slurried in TBME (2.0 L) and the collected solids are washed with TBME (660 L). The combined liquors and washes are washed with hydrochloric acid (1 M, 660 mL), saturated aqueous sodium hydrogen carbonate. (2×1.0 L) and water (4.0 L), dried over magnesium sulfate, filtered and concentrated by rotary evaporation at 40° C. to afford the crude product. The residue is slurried in methanol (1.10 L) at −10 to 0° C. for 1 h. The observed solid is collected by filtration and dried under vacuum at 20° C. to afford 4-bromo-benzo[b]thiophene as an off-white solid (315 g, 37%). 1H NMR (CDCl3): δ 7.81 (d, 1H, J=8.0 Hz), 7.57-7.48 (m, 3H), 7.21 (t, 1H, J=7.7 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=[O:21].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20]([NH:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4])=[O:21]
Reactant: N[C@@H](CO)c1ccc2ccccc2c1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1F)N[C@@H](CO)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.5 %

Procedure:
A mixture of (R)-2-amino-2-naphthalen-2-yl-ethanol (0.2 mmol), 2-fluorocinnamic acid (0.2 mmol), EDC HCl (0.4 mmol), DMAP (0.2 mmol), triethyl amine (0.6 mmol) in dichloromethane (4 mL) was stirred at room temperature for 14 h. The reaction mixture was purified by flash chromatography with 50% ethyl acetate in hexanes to provide the desired product (56 mg) as a solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1(OB(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1>[C:7]1([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1nccs1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nccs2)cc1
Yield: 67.2 %

Procedure:
2-Bromothiazole (1.2 mmol, 0.11 mL) and phenylboric acid (1.2 mmol, 0.146 g) were added to a solution of potassium carbonate (2M, 1.2 mL) and ethanol (0.6 mL) in deoxygenated toluene (12 mL). The resulting mixture was degassed for 30 minutes, then tetrakistriphenylphosphine palladium (0.036 mmol, 0.042 g) was added and the solution heated at reflux for 48 hours. The solids were removed by filtration and the solution extracted with toluene (5x), dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (hexane followed with 5% ethyl acetate/hexane and then 10% ethyl acetate/hexane) to afford 0.13 g (69%) of 2-phenylthiazole.