Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17]C#N)[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:25](=[O:28])(O)[O-:26].[Na+]>O.C(O)(=O)C>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:25]([OH:26])=[O:28])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccc2nc(-c3ccccc3)ccc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1

Procedure:
A mixture of 10 g of 2-phenyl-6-quinolineacetonitrile, 19 ml of water, 19 ml of concentrated sulphuric acid and 19 ml of glacial acetic acid is kept under reflux for 2 hours. Thereafter, ice and water are added and the pH is adjusted to 5-6 with solid sodium bicarbonate. The crystals which thereupon precipitate are filtered off and rinsed with water. Recrystallisation from methanol-ether-petroleum ether yields 2-phenyl-6-quinolineacetic acid of melting point 176°-179°C. 2-(p-Chlorophenyl)-6-quinoline-acetic acid and 2-(p-fluorophenyl)-6-quinolineacetic acid are obtained analogously.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH2:1]([NH:8][C:9]1[C:10]([NH2:19])=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(NCc2ccccc2)c(N)c1
Yield: 94.2 %

Procedure:
A stirred solution of benzyl-(4-methanesulfonyl-2-nitro-phenyl)-amine (0.300 g, Reference Example 66) and tin chloride (1.86 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140° C. for 10 minutes. The reaction mixture was basified using saturated sodium hydrogen carbonate solution to pH 8 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give N*1*-benzyl-4-methanesulfonyl-benzene-1,2-diamine (0.255 g) as a pale brown solid. LC-MS (METHOD B): RT=2.74 minutes, 275.20 (M−H)−.
Reaction SMILES: [NH3:1].[CH:2]([S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH3:20])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5])=[CH2:3]>C(#N)C>[NH2:1][CH2:3][CH2:2][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH3:20])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: N
Reactant: C=CS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OCCC)c1OCCC
Solvent: CC#N
Product: CCCOc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(S(=O)(=O)CCN)c1OCCC
Temperature: 65 °C

Procedure:
Ammonia was bubbled into a solution of trans-2-(3-vinylsulfonyl-4,5-dipropoxyphenyl)-5-(3,4,5-trimethoxy-phenyl)tetrahydrofuran (30 mg, 0.06 mmol) at 0.5° C. for 3 min in acetonitrile (3 mL). The solution was then heated at 65° C. in a pressure bottle overnight, cooled, and evaporated to dryness. Purification by preparative TLC (CHCl3 -MeOH; 95:5, v/v) gave the title compound MS, m/z 538 (M+1)+. ; Rf 0.27; NMR (CDCl3) δ 1.05 & 1.09 (2 t J=7.5 Hz, 2 CH2CH2CH3), 3.58 (bt, SO2CH2CH2), 4.02 & 4.14 (2 t, J=6.5 Hz, 2 CH2CH2CH3), 5.16-5.28 (m, H-2 & H-5), 6.63 (s, 2 H, C5ArH), 7.27 & 7.48 (2 d, J=1.5 Hz, 2 H, C2ArH).
Reaction SMILES: [CH:1](=[C:8]1/[CH2:9][N:10]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:12][C:13]/1=[O:14])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[BH4-].[Na+].[Cl-].[NH4+]>ClCCl>[CH:1](=[C:8]1/[CH2:9][N:10]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][CH:13]/1[OH:14])/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of (E)-3-benzylidene-1-(triphenylmethyl)piperidin-4-one (3.91 g) in a mixed solvent of ethanol (30 ml) and dichloromethane (30 ml) was added sodium borohydride (0.34 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7) as the eluent to afford the title compound (2.61 g, yield: 66%) as a colourless amorphous solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (78.0 mL of a 0.91M stock solution, 70.98 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid (5.76 g, 33.8 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (84 mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (7.45 g, 35.49 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). This solution was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (6.76 g, 79.1%) as a yellow solid: mp 82–84° C.: EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0906.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:45][CH2:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52]>C(Cl)Cl.CCOC(C)=O>[C:51]([O:50][C:49](=[O:55])[NH:48][CH2:47][CH2:46][NH:45][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Formylphenoxyacetic acid (0.306 g, 1.70 mmol) was dissolved in DCM (5 mL). DIEA (0.524 g, 4 mmol) and TBTU (0.550 g, 1.70 mmol) were added followed by tert-butyl N-(2-aminoethyl)carbamate (0.250 g, 1.56 mmol). The mixture was stirred 2 h at room temperature, dissolved in EtOAc and washed sequentially with 5% aqueous K2CO3, KHSO4, water and brine. The extract was dried (MgSO4) and concentrated under reduced pressure to give a yellow solid (0.350 9).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([N+:18]([O-])=O)[C:5]=1[CH:21]=[CH:22][C:23]([O:25]C)=O)(=[O:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]2[C:5]=1[CH2:21][CH2:22][C:23](=[O:25])[NH:18]2)(=[O:3])[CH3:2]
Reactant: COC(=O)C=Cc1c(C(C)=O)cc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1CCC(=O)N2
Reaction time: 2 h

Procedure:
A suspension of methyl 3-(2-acetyl-4-benzyloxy-6-nitrophenyl)-acrylate (5.0 g, 14.07 mmol) in ethanol (100 mL) is hydrogenated with Raney nickel (3 g) at ambient temperature and 4 bar hydrogen pressure. After 6 hours more Raney nickel (2 g) is added and the mixture is hydrogenated for a further 2 hours. The catalyst is separated off and the filtrate is combined with 2 M aqueous hydrochloric acid (15 mL). The product that crystallises out is filtered off and dried.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C@H:15]([CH2:16][C:17](=[O:25])[CH:18]=[CH:19]1)[CH2:14][CH2:13]3>C(OCC)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C@H:15]([CH2:16][C:17](=[O:25])[C@@H:18]2[CH2:3][C@@H:19]21)[CH2:14][CH2:13]3
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Ethereal diazomethane (40 ml. generated from 3 g. of N-methyl-N'-nitro-N-nitrosoguinidine) is added to a mixture of 17β-methoxy-5α-androst-1-en-3-one (IV, Example 23, 1.0 g.) and palladium diacetate (10 mg.) in diethyl ether (20 ml.). After a few hours the organic diluents are removed by reduced pressure and the residue is column chromatographed thru silica gel (100 g.) eluting by gradient between ethyl acetate:SSB (5:95, 5 l.) and ethyl acetate:SSB (20:80, 5 l.). The appropriate fractions (TLC) are pooled and concentrated to give the title compound, m.p. 114°-118°; MS (m/e) 316, 301, 269, and 243; NMR (CDCl3) 0.77, 0.97, 3.23 and 3.34 δ; CMR (CDCl3) 9.66 δ.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([SH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[C@H:28]1[CH2:32][N:31]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[O:34])[C@H:30]([C:46]([O:48][CH3:49])=[O:47])[CH2:29]1)(=O)=O.Cl>CN(C)C=O.C(OCC)(=O)C>[C:3]1([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:22][C@@H:28]2[CH2:32][N:31]([C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[C@H:30]([C:46]([O:48][CH3:49])=[O:47])[CH2:29]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
To a suspension of sodium hydride (1.26 g) (60% dispersion in oil) in dimethylformamide (50 ml) under ice cooling is added triphenylmethylmercaptan (10.9 g) in small portions and stirred for 5 minutes at room temperature. A solution of crude (2S,4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2:10.6 g) in dimethylformamide (80 ml) is added to this mixture, and the whole mixture is stirred in an oil bath at 50° C. overnight. The reaction mixture is diluted with ethyl acetate and mixed with ice water containing 1N-hydrochloric acid (35 ml). The organic layer is taken, washed with water and satd. brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography (toluene-ethyl acetate) to give (2S ,4S)-4-triphenylmethylthio-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (3:9.12 g) an orange foam (Yield: 52% from hydroxyproline) and the starting compound (2:3.11 g: Yield: 29%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[CH2:18][CH2:17][C:16]4[C:22]([C:26]([NH:28][C:29]5[C:34]([CH2:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=5[CH2:37][CH3:38])=[O:27])=[N:23][N:24]([CH3:25])[C:15]=4[C:14]=3[N:13]=2)[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:39][NH2:40]>O1CCCC1.ClCCl.CO.[OH-].[NH4+]>[CH2:37]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][CH3:36])[C:29]=1[NH:28][C:26]([C:22]1[C:16]2[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][C:12]([NH:11][CH:8]4[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH2:3][NH:40][CH3:39])[CH2:10][CH2:9]4)=[N:13][C:14]=3[C:15]=2[N:24]([CH3:25])[N:23]=1)=[O:27])[CH3:38]
Reactant: C=CC(=O)N1CCC(Nc2ncc3c(n2)-c2c(c(C(=O)Nc4c(CC)cccc4CC)nn2C)CC3)CC1
Reactant: CN
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)CCNC)CC3)nc1-2
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution 8-[(1-acryloylpiperidin-4-yl)amino]-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (30 mg, 0.058 mmol) in tetrahydrofurane (1 mL) in a sealed tube, methylamine (2M in tetrahydrofurane) (0.3 mL) was added. The mixture was then heated at 60° C. for 2 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol/30% ammonium hydroxide: 8/2/0.2) to 27 mg of the title compound (77% yield).
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(C(O)=O)=C(I)C=1.N1C=CN=N1>>[F:16][C:3]1[CH:2]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:4]=1
Reactant: O=C(O)c1ccc(F)cc1I
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: c1c[nH]nn1
Product: O=C(O)c1ccc(F)cc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 4-fluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 208.2 [M+1]+.
Reaction SMILES: C1N=C2N([C@@H]3[O:14][C@H](COP(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@@H](O)C3)C=NC2=C(N)N=1.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[CH:90]1[C:96](=[O:97])[NH:95][C:93](=[O:94])[N:92]([C@@H:98]2[O:102][C@H:101]([CH2:103][O:104]P(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@@H:100]([OH:117])[CH2:99]2)[CH:91]=1.C1(O)C=CC=CC=1>>[C@@H:98]1([N:92]2[CH:91]=[CH:90][C:96](=[O:97])[NH:95][C:93]2=[O:94])[O:102][C@H:101]([CH2:103][OH:104])[C@@H:100]([OH:117])[C@H:99]1[OH:14]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Agent: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Solvent: Oc1ccccc1
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1

Procedure:
The subtracter-amplicon was diluted to 10 μg/ml, and four PCR reactions were set up on ice to generate subtracter U-DNA for the control set. Each 50 μl reaction contained 2 μl diluted ligation, 1 μl 4 μg/μl S-hpa-24mer oligo, 2 μl dNTPs (10 mM dATP, 10 mM dCTP, 10 mM dGTP, and 30 mM dUTP), 5 μl 10× PCR buffer, 1 μl 3.5 U/μl Taq DNA polymerase and ddH2O. The S-hpa-12mer was melted away (5 min, 72° C.), and ends filled in with Taq DNA polymerase (7 min, 72° C.). Twenty-one cycles of amplification were performed (1 min, 95° C.; 3 min, 72° C.), and the products were phenol-extracted, isopropanol-precipitated and resuspended in 20 μl 10 mM Tris-buffer each (Sambrook et. al., "Molecular Cloning, 2nd Edition", p10.49 (1989)). The S-adaptors were then removed with Hpa2-restriction, and the restricted products (subtracters) were phenol-extracted, isopropanol-precipitated, combined and resuspended in a total 16 μl EEx3 buffer (30 mM EPPS, pH 8.0 at 20° C.; 3mM EDTA). 6 μl (9 μg) subtracters were measured on a 2.5% TBE-agarose gel.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]([O:16]CC)=O.[CH3:19][O:20][C:21]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:22]=1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N#N.CCO>CCCCCCC>[CH3:19][O:20][C:21]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:22]=1[CH2:23][N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]([C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:16]
Reactant: COc1ccc(CNc2ccccc2)c(OC)c1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(C)c1=O
Agent: N#N
Solvent: CCO
Solvent: CCCCCCC
Product: COc1ccc(CN(C(=O)c2c(O)c3ccccc3n(C)c2=O)c2ccccc2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate (9.25 g, 37.4 mmol) and N-(2,4-dimethoxybenzyl)-aniline (9.10 g, 37.4 mmol) in heptane (200 mL) was stirred at 110° C. under a flow of N2 for 6 h letting the EtOH evaporate from the reaction mixture. The product started to precipitate and some extra heptane was added. The reaction mixture was then stirred at 100° C. overnight, still under a gentle flow of N2. The product (12.21 g, 73%) crystallized from the reaction mixture and was collected by filtration while still warm (ca 50° C.).
Reaction SMILES: Br[C:2]1[C:3](=[O:33])[N:4]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:5]2[C:10]([C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])=[CH:9][CH:8]=[CH:7][CH:6]=2>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][O:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:3](=[O:33])[CH:2]=1
Reactant: COC(=O)c1ccc(Cn2c(=O)c(Br)c(OCc3ccc(F)cc3F)c3ccccc32)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)c1ccc(Cn2c(=O)cc(OCc3ccc(F)cc3F)c3ccccc32)cc1
Reaction time: 12 h
Yield: 51.3 %

Procedure:
In a 25 mL round bottom flask was added, at room temperature, a solution of methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxoquinolin-1(2H)-yl]methyl}benzoate (step 2) (120 mg, 0.233 mmol) in MeOH (3.0 mL). Next, a combination of Pd on carbon (10% Pd, weight by weight 50% water, 100 mg, 0.047 mmol) and Pd(OAc)2 (15 mg, 0.067 mmol) was added to the reaction vessel that purged with argon and then fitted with a septum. The vessel was then equipped with a 2.0 L hydrogen balloon (c.a. 20 psi). The resulting suspension was allowed to stir of 12.0 hours and was then directly applied to SiO2 chromatography using ethyl acetate/hexanes (3:7) to furnish the desired title compound as a solid (52 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 8.05-7.98 (m, 3H), 7.55 (app q, J=8.3 Hz, 1H), 7.48 (app t, J=7.5 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (app q, J=8.5, 2H), 7.05-6.90 (m, 2H), 6.28 (s, 1H), 5.60 (s, 2H), 5.26 (s, 2H), 3.91 (s, 3H); LC/MS C-18 column, tr=3.71 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 436 (M+H). ES-HRMS m/z 436.1371 (M+H calcd for C25H20BrF2NO4 requires 436.1355).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-])=[O:7])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12].[Na+].[Na+].Cl[C:17]1C=CC(C([O-])=O)=CC=1S(O)=O.CI.CN(C)[CH:33]=[O:34]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:34][CH3:33])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:17])(=[O:13])=[O:12]
Reactant: CN(C)C=O
Reactant: O=C([O-])c1ccc(Cl)c(S(=O)O)c1
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
250 g of disodium 4-chloro-3-hydroxysulfinylbenzoate were suspended in 500 ml of abs. dimethylformamide at RT, 218 ml of methyl iodide (3.5 mol) were added and the reaction mixture was heated to 60° C. It was subsequently stirred at this temperature for 4 hours, then allowed to stand at RT overnight. The mixture became solid on cooling. It was warmed to 70° C., diluted with 250 ml of abs. dimethylformamide and subsequently stirred at 70° C. for a further 3 hours. The solvent was distilled off, the residue was taken up in 1000 ml of water, stirred for 30 minutes in an ice bath, filtered off with suction and washed 3 times with about 200 ml of water each time, sucked dry and dried in vacuo (50° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O-:22].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:22][CH3:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Reactant: C[O-]
Agent: [Na+]
Product: COc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
1 mmol of 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester [example 4.9(a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 10 ml of methanol). The mixture was heated overnight to 70°, concentrated and the product purified by chromatography (SiO2; dichloromethane/methanol 99:1) to yield the title compound as a colorless foam. MS (m/e): 295.3 (MH+, 100%)
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCCc1ccccc1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCCCCCCOCCCCc1ccccc1
Yield: 48 %

Procedure:
NaH (46% dispersion in oil; 6.5 g) was added portionwise to a solution of 4-phenyl-1-butanol (15.0 g) and 1,6-dibromohexane (48.8 g) in THF (200 ml) under nitrogen. The resulting suspension was refluxed for 27h and treated with H2O (80 ml). The mixture was extracted with ER (2×200 ml) and the dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (800 ml) [A] to give a yellow oil which on distillation gave the title compound as a colourless oil (15.0 g) b.p. 90°-95°/0.1 mmHg.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[C:8](=[O:24])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:23])[NH:21][OH:22])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:31](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:22]1[CH:31]=[N:23][C:20]([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])=[O:24])=[N:21]1
Reactant: COC(OC)OC
Reactant: COC(CN(C(=O)CCOCCc1cccc(C(=N)NO)c1)C1CCCCC1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2ncon2)c1)C1CCCCC1)OC
Temperature: 100 °C

Procedure:
To N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(N-hydroxycarbamimidoyl)phenethoxy)propanamide [Example 11, Step i)] (530 mg) in a 10 mL microwave vial was added trimethyl orthoformate (1 mL), sealed and heated at 100° C. for 20 min. The vial was then heated to 120° C. for 3 h before the addition of p-toluenesulfonic acid (3 mg) and then heated to 120° C. for a further 60 min. Ethanol was added (30 mL) and the solvent was evaporated to afford the sub-titled compound (500 mg). MS [M+H-MeOH]+=400 (MultiMode+)