Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-])=O.[F:15][C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[C:23]([N+:26]([O-])=O)[CH:22]=[CH:21][CH:20]=2.O.O.[Sn](Cl)Cl>C(OCC)(=O)C.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:12].[F:15][C:16]1[CH:17]=[N:18][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([NH2:26])[C:24]=2[CH:25]=1
Reactant: O=[N+]([O-])c1cccc2ncc(F)cc12
Reactant: O=[N+]([O-])c1cccc2cc(F)cnc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc2cc(F)cnc12
Product: Nc1cccc2ncc(F)cc12
Temperature: 25 °C
Yield: 11 %
Yield: 37 %

Procedure:
3-Fluoro-8-nitroquinoline, 3-fluoro-5-nitroquinoline, and tin(II)chloride-dihydrate (68.23 g, 302 mmol) in ethyl acetate (200 ml) was placed into a preheated oil bath at 60° C. After heating for 4 h, the solution was cooled to ambient temperature, diluted with 3 N aq. NaOH, and filtered through a pad of celite. The filtrate was extracted with ethyl acetate, the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 19:1, 9:1, 17:3, 4:1, 3:1, 7:3, and 3:2 hexane:ethyl acetate as the eluant to afford 2.14 g (11% yield over two steps) 3-fluoroquinolin-8-amine and 7.02 g (37% yield over two steps) of 3-fluoroquinolin-5-amine. Method [6] retention time 1.57 and 4.02 min by HPLC (M+ 163) and (M+ 163).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([C:36]3[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=3)=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:42])=[CH:20][N:19]=1>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:18]3[N:23]=[C:22]([NH:24][C:25]4[C:26]([C:27](=[O:28])[NH:29][CH3:30])=[CH:31][C:32]([C:36]5[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=5)=[CH:33][C:34]=4[F:35])[C:21]([Cl:42])=[CH:20][N:19]=3)=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COC(=O)N1CCCOc2cc(N)ccc21
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a yellow solid (128 mg, 58%). m.p.=175-181° C.; LCMS (m/e) 581 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.39 (bs, 1H), 9.27 (s, 1H), 8.64-8.54 (m, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.79-7.65 (m, 2H), 7.31 (s, 1H), 7.19-7.08 (m, 1H), 6.93 (d, 1H, J=8.7 Hz), 3.94-3.79 (m, 2H), 3.89 (s, 3H), 3.74-3.37 (m, 5H), 2.76 (d, 3H, J=4.3 Hz), 1.88-1.76 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:7])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>O.CO.[Cl-].[Na+].O.CCOC(C)=O>[CH3:7][C:2]([NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)NC(=O)c1cnccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1cnccn1)C(=O)O

Procedure:
A solution of methyl 2-methyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoate (9.8 mmol) and 1 M NaOH in water (19.6 mL) was stirred in methanol for 6 hours. The reaction was diluted with brine and EtOAc and the layers were separated. The aqueous layer was acidified with 1 M HCl in water (28 mL) to an approximate pH˜2. The aqueous was extracted with EtOAc (3×). These three combined extracts were dried (Na2SO4), filtered and concentrated to obtain 1.96 g (96% over two steps) of the title compound. 1H NMR (300 MHz, CD3OD) δ 9.16 (d, J=1.3 Hz, 1H); 8.75 (d, J=2.4 Hz, 1H); 8.65 (dd, J=1.5, 2.4 Hz, 1H); 1.63 (s, 6H). LC/MS: Rt, =1.27 min, ES+210 (Formic Acid Method).
Reaction SMILES: [Cl:1][Si](C)(C)C.C([O:10][C:11](=[O:33])[C@@H:12]([NH:25]C(OC(C)(C)C)=O)[CH2:13][CH:14]([S:19][S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][N:16]=[N+:17]=[N-:18])(C)(C)C>FC(F)(F)CO>[ClH:1].[NH2:25][C@@H:12]([CH2:13][CH:14]([S:19][S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][N:16]=[N+:17]=[N-:18])[C:11]([OH:33])=[O:10]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)OC(C)(C)C
Solvent: OCC(F)(F)F
Product: CC(C)(C)SSC(CN=[N+]=[N-])C[C@H](N)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Chlorotrimethylsilane (467 μl, 2.344 mmol) was added to a solution of (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid tert-butyl ester (Compound 39) (160 mg, 0.368 mmol) in 2,2,2-trifluoroethanol (3.2 ml), and the mixture was stirred at room temperature for 2 hours. Chlorotrimethylsilane (467 μl, 2.344 mmol) was further added, and the reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of hexane/ethyl acetate/dichloromethane (3:1:0.1) to afford (S)-2-amino-5-azido-4-tert-butyldisulfanyl-pentanoic acid hydrochloride (Compound 40) (113 mg, 97%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:36])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:36])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(N2CCNCC2)c1
Temperature: 27 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To a solution of tert-butyl 4-(3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy propylcarbamoyl)phenyl)piperazine-1-carboxylate (140 mg, 0.28 mmol) in DCM (2 mL) was added TFA (2 mL). The resulting solution was stirred at 27° C. for 4 h. The solution was concentrated and the residue was purified by prep-HPLC to give the title product (64.0 mg, Yield 57%). 1H NMR (CD3OD, 400 MHz): δ 7.47-7.38 (s, 1H), 7.31-7.21 (m, 2H), 7.19-7.08 (m, 4H), 7.08-7.01 (m, 1H), 4.13 (quin, J=6.0 Hz, 1H), 3.77 (s, 2H), 3.62-3.52 (m, 1H), 3.51-3.43 (m, 1H), 3.31-3.19 (m, 4H), 3.15-3.00 (m, 4H), 2.98-2.83 (m, 4H), 2.75-2.62 (m, 2H). LCMS (m/z): 395.2 (M+1).
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=2)=O)[CH:6]=[CH:7][CH:8]=1.C[Sn](C)(C)C1[S:39][CH:40]=[CH:41][N:42]=1.[O:45]1CC[CH2:47][CH2:46]1>CCOCC.Cl[Pd]Cl>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][N:12]([C:10]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:4][C:3]3[S:39][CH:40]=[CH:41][N:42]=3)[CH:9]=2)[C:46](=[O:45])[CH3:47])=[CH:20][CH:19]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: C[Sn](C)(C)c1nccs1
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCOc1ccc(CCNC(=O)Cc2cccc(CBr)c2)cc1
Agent: Cl[Pd]Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CCN(C(C)=O)c2cccc(Cc3nccs3)c2)cc1

Procedure:
A mixture of 1.3 g of N-[3-(bromomethyl)phenyl-N-[2-[4-(tetradecyloxy)phenyl]ethyl]acetamide, 787.04 mg of 2-(trimethylstannyl)thiazole and 83.77 mg of PdCl2 (PO3)2 in 30 ml of tetrahydrofuran is stirred at reflux for 14 hours. The mixture is diluted with ether and filtered through a pad of silica gel. The filtrate is washed with 1N sodium hydroxide, dried and filtered through a pad of alumina. The solvent is evaporated and the residue chromatographed on silica gel using 1:1 ethyl acetate:hexane to give 0.7 g of the desired product as an oil which crystallized to an off-white solid, m.p. 46°-50° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:32])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][CH:25]3[CH2:29][O:28]C(C)(C)[O:26]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(O)(C(F)(F)F)=O>C1COCC1.O>[NH2:32][C:14]1[N:15]=[CH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][CH:25]([OH:26])[CH2:29][OH:28])[CH:23]=2)=[CH:18][C:13]=1[O:12][CH:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: CC(Oc1cc(-c2cnn(CC3COC(C)(C)O3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1cc(-c2cnn(CC(O)CO)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a stirred solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine (150 mg, 0.31 mmol) in THF (3 mL) and H2O (2 mL) was added TFA (2 mL) at 0° C., the mixture was stirred and warmed to room temperature, then heated at 50° C. for 5 hours, LCMS checked that the reaction was completed, remove THF, the residue was purified by prep-HPLC to leave 3-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propane-1,2-diol (102 mg), yield 74.2%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[S:27][C:26]([CH2:28]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:28][C:26]3[S:27][C:23]([Br:22])=[CH:24][CH:25]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Br)s1
Reactant: Oc1ccc(Oc2cccc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(Oc2ccc(OCc3ccc(Br)s3)cc2)n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
3.5 g of 4-(6-chloro-2-pyridinyloxy)-phenol and 3.2 g of potassium carbonate are stirred for one hour at 60° C. in 100 ml of anhydrous dimethylformamide. Subsequently, 5.5 g of 5-bromo-2-chloromethylthiophene in 30 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 6 hours at 80° C. and overnight at room temperature (about 20° C.). The mixture is then poured into 200 ml of ice water. The crude product which precipitates out is filtered off and recrystallized from n-hexane/ethyl acetate (4/1). There is obtained 3.1 g of 2-[4-(6-chloro-2-pyridinyloxy)-phenoxymethyl]-5-bromothiophene of m.p.: 78°-80° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][CH:29]1[CH:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][CH:29]1[CH:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1CNCC1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1NC(=O)OC(C)(C)C
Yield: 39.1 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-t-butoxycarbonylamino-4-methylpyrrolidine (0.53 g) and DBU (0.27 g) was refluxed for an hour. After cooling in a refrigerator, the resulting precipitate was collected by filtration and washed with acetonitrile and ether successively to give the title compound (0.32 g) as pale yellow powder, mp 230°-231° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:6]([N:5]([CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[F:1])[C:21](=[O:22])[CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)[CH3:7]
Reactant: CCNCc1ccccc1F
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1F)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
N-(2-Fluorobenzyl)ethanamine (0.554 g, 3.615 mmol) was dissolved in DMF (10 ml). 3-(4-hydroxyphenyl)propanoic acid (0.546 g, 3.286 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)-methylene]-N-methylmethanaminium tetrafluoroborate (1.161 g, 3.615 mmol) and N-ethyl-N,N-diisopropylamine (0.892 g, 6.901 mmol) was added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (starting with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product-containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and then solvent was removed by evaporation to give 0.803 g of N-ethyl-N-(2-fluorobenzyl)-3-(4-hydroxyphenyl)propanamide (yield 81.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:32])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-(2-hydroxyethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=468.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].N1C=[CH:16][N:15]=[N:14]1.[OH-].[Na+].[CH3:20][N:21](C)C=O>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:15]1[CH:16]=[N:21][CH:20]=[N:14]1
Reactant: CN(C)C=O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]nn1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
10 g (44.8 mmol) of 2,2′,4′-trichloroacetophenone were added portionwise at room temperature to a solution of 9.3 g (134 mmol) of triazole in 50 ml of dimethylformamide and stirred at 80° C. for 16 hours. The reaction mixture was added to 100 ml of 2N sodium hydroxide solution and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulphate and concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (ethyl acetate/methanol 100:5). 2.8 g (25%) of 1-(2,4-dichlorophenyl)-2-[1,2,4]triazol-1-yl-ethanone were obtained as a yellow-brown solid.
Reaction SMILES: [CH3:1][CH2:2][C@:3]1([C@H:31]2[O:35][C@H:34]([C@H:36]3[O:41][C@@:40]([OH:44])([CH2:42][OH:43])[C@H:39]([CH3:45])[CH2:38][C@@H:37]3[CH3:46])[CH2:33][C@H:32]2[CH3:47])[O:7][C@@H:6]([C@:8]2([CH3:30])[O:12][C@:11]3([O:17][C@H:16]([C@@H:18]([C@H:20]([O:26][CH3:27])[C@H:21]([C:23]([O-:25])=[O:24])[CH3:22])[CH3:19])[C@H:15]([CH3:28])[C@@H:14]([OH:29])[CH2:13]3)[CH2:10][CH2:9]2)[CH2:5][CH2:4]1.[Na+].O>C(O)C>[CH3:1][CH2:2][C@:3]1([C@@H:31]2[O:35][C@@H:34]([C@H:36]3[O:41][C@@:40]([OH:44])([CH2:42][OH:43])[C@H:39]([CH3:45])[CH2:38][C@@H:37]3[CH3:46])[CH2:33][C@@H:32]2[CH3:47])[O:7][C@@H:6]([C@@:8]2([CH3:30])[O:12][C@:11]3([O:17][C@H:16]([C@H:18]([C@@H:20]([O:26][CH3:27])[C@@H:21]([C:23]([OH:25])=[O:24])[CH3:22])[CH3:19])[C@H:15]([CH3:28])[C@@H:14]([OH:29])[CH2:13]3)[CH2:10][CH2:9]2)[CH2:5][CH2:4]1
Reactant: CC[C@@]1([C@H]2O[C@H]([C@H]3O[C@@](O)(CO)[C@H](C)C[C@@H]3C)C[C@H]2C)CC[C@H]([C@@]2(C)CC[C@]3(C[C@H](O)[C@@H](C)[C@@H]([C@H](C)[C@H](OC)[C@@H](C)C(=O)[O-])O3)O2)O1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC[C@@]1([C@@H]2O[C@@H]([C@H]3O[C@@](O)(CO)[C@H](C)C[C@@H]3C)C[C@@H]2C)CC[C@H]([C@]2(C)CC[C@]3(C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(=O)O)O3)O2)O1
Yield: 48 %

Procedure:
Treatments were: 1) C; 2) HS; 3) HS plus 10 ppm AQ; 4) HS plus 5 ppm RUMENSIN® (Elanco, Greenfield, Ind.) and 5) HS plus 10 ppm AQ. Fermentations supplemented with RUMENSIN® were prepared by first dissolving the RUMENSIN® in 96% ethanol and then adding the same volume of deionized water, yielding a concentration of monensin (in 48% ethanol) that would result in 5 ppm in the rumen fluid-buffer mix when 0.25 ml of the solution was added to 29.5 ml of the rumen fluid-buffer solution; finally, 0.25 ml of deionized water was added to yield a final volume of 30 ml. Each of the other treatment conditions (including the control fermentations) were modified by adding the same amount of ethanol to each as was present in the RUMENSIN® fermentation. This was done by doubling the concentration of the stock solutions, adding 0.25 ml of the stock solution (or deionized water for the controls) and 0.25 ml of 46% ethanol.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH2:3]1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=3)[CH2:3]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(N)C2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Br)cc1)C2

Procedure:
3.4 g of methyl 6-(2-aminoindan-5-yl)-6-(3-pyridyl)hex-5-enoate is placed in 40 ml of chloroform together with 3.3 g of 4-bromobenzenesulphonic acid chloride and 1.8 g of triethylamine are added in batches at ambient temperature. After 30 minutes the solution is washed with water, dried and rotary evaporated. The yellow oil is then chromatographed over a silica gel column using cyclohexane/ethyl acetate (1:2).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[O:16]
Reactant: COC(=O)C1CCCCO1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)O)CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
A solution of N,N-diisopropylamine (909 mg, 1.25 mL, 9 mmol) in tetrahydrofuran (4 mL) was stirred at −78° C. under nitrogen. n-Butyllithium (3.6 mL, 9 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. A solution of tetrahydro-pyran-2-carboxylic acid methyl ester (864 mg, 6 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was stirred at −78° C. for 20 minutes. Acetaldehyde (792 mg, 1.0 mL, 18 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 1:1 to 0:1 to afford the title compound (1.28 g) as an oil and as a 2:1 mixture of diastereoisomers. LCMS (m/z) 189.3 [M+H], Tr=1.23 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](O)[C:5]2[C:10]([C:12]3[C:17]([C:18](=[O:19])[C:4]=2[C:3]=1O)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11].[C:21](OC(=O)C)(=[O:23])[CH3:22].CN(C1C=CC=CN=1)C.[C:37](OCC)(=[O:39])[CH3:38]>C(Cl)Cl>[C:21]([C:6]1[C:5]2[C:10](=[O:11])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:19])[C:4]=2[C:3]([C:37](=[O:39])[CH3:38])=[C:2]([CH3:1])[C:7]=1[CH3:8])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c(O)c2c(c1O)C(=O)c1ccccc1C2=O
Reactant: CCOC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=O)c1c(C)c(C)c(C(C)=O)c2c1C(=O)c1ccccc1C2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a stirred suspension of 2,3-dimethylquinizarin (5.00 g, 18.637 mmol) in dry CH2Cl2 (250 ml) was added acetic anhydride (40 ml) pyridine (40 ml) and dimethylaminopyridine (DMAP, 1.7 g) at room temperature under argon. After two hours, the reaction mixture was poured into a mixture of ethyl acetate and ice (1:1, 800 ml), extracted with CH2Cl2, and the combined organic layers were dryed over MgSO4. Flash chromatography with toluene and ethylacetate; (95.5%) gave 2.517 g of pure compound (38% yield). (MP: 222°-224° C.). 1H NMR (CDCl3) δ:2.27 (s, 6H, CH3, 2.53 (s, 6H, COCH3), 7.72 (m, 2H, ArH), 8.15 (m, 2H, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])C=1.C.C[N:24]1C(=O)CCC1>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:18]1[CH:19]=[CH:14][N:24]=[C:16]([S:20][CH3:21])[N:17]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: CN1CCCC1=O
Reactant: CSc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CSc1nccc(-n2ccc3c(Br)cccc32)n1
Reaction time: 2 h

Procedure:
4-Bromoindole (20 g, 102 mmol) was dissolved in 70 mL of NMP and the solution was stirred under ice bath. Sodium hydride (6 g, 60% in mineral oil, 150 mmol) was added in small portions over 30 minutes. The mixture was stirred at room temperature for 40 minutes and then cooled under ice bath. A solution of 4-chloro-2-methylsulfanylpyridine (19.7 g, 122 mmol) in 10 mL of NMP was added through a dropping funnel over 10 minutes. The mixture was stirred at room temperature overnight. Water (150 mL) was added with stirring. The solid material was filtered and washed with water, air dried. This material was suspended in hot ethyl acetate (200 mL) and dichloromethane (200 mL) was added to give a clear solution. Charcoal (5 g) was added and the mixture was stirred for 10 minutes, filtered through Celite. The resulting solution was gently evaporated to remove dichloromethane until crystalline material appeared. The mixture was kept at room temperature for 2 hrs and crystals were filtered, rinsed with cold ethyl acetate (90 mL), air dried, to give 4-bromo-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indole as an off white solid (21.5 g, 65%). LC-MS calcd for C13H10BrN3S (m/e) 318.98, obsd 320.0 (M+H).