Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][OH:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([CH3:27])[CH:29]=2)[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: Cc1cccc(CO)c1
Product: Cc1cccc(COc2cc(F)ccc2-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-methylbenzyl alcohol (99 mg; 0.789 mmol), example 83 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Na+:1].[NH:2]1[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O-:11])=[O:10])=[N:3]1.[F:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1.[N-]=C=O.O>CN(C=O)C>[Na+:1].[F:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([N:2]2[CH:6]=[CH:5][C:4]([C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([O-:11])=[O:10])=[N:3]2)=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: O=C([O-])c1cccnc1-c1cc[nH]n1
Agent: [N-]=C=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])c1cccnc1-c1ccn(C(=O)Nc2cc(F)cc(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.95 g (4.5 mM) of 2-(pyrazol-3-yl)-nicotinic acid sodium salt are stirred in 20 ml of DMF and 0.7 g (4.5 mM) of 3,5-difluorophenyl isocyanate added. After stirring for 1 hr at RT, a further 0.21 g of isocyanate in DMF are added. The DMF is stripped-off on a Kugelrohr and the resulting solid stirred with 4 ml water and filtered. The filtrate is chromatographed on a reverse phase column with 100 ml of water followed by 100 ml water-methanol. The product containing fraction was lypholized to yield the title product m.p. 165°-170° C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.[K+].[Br-]>CCCCCC>[C:22]([C:19]1[CH:20]=[CH:21][C:13]2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16](=[O:17])[N:15]([CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([Cl:26])[CH:28]=3)[C:14]=2[CH:18]=1)([O:24][CH3:25])=[O:23]
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(c1)N(Cc1cccc(Cl)c1)C(=O)C(CCO)O2

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-6-carbomethoxy-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, in 70% overall yield as a white solid, after trituration with hexane, IR (KBr) 3468, 2952, 1688, 1452, 1285, 1260, 765 cm-1 ; 1H NMR (CDCl3) δ1.61 (br s, 1H plus HDO), 2.17-2.39 (m, 2H), 3.86 (s, 3H), 3.93 (t, J=5.7 Hz, 2H), 4.94 (dd, J=7.6, 5.5 Hz, 1H), 5.16 (s, 2H), 7.04 (d, J=8.4, 1H), 7.15-7.33 (m, 4H), 7.59 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.4, 1.8 Hz, 1H); MH+ at m/z=376; Anal. Calc'd for C19 H18ClNO5.0.1H2O: C, 60.44; H, 4.86; N, 3.71. Found: C, 60.26; H, 4.60; N, 3.58.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI.Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)cc(Cl)cc1Br
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Cl)cc(Cl)cc1Br
Temperature: 0 °C
Yield: 113.1 %

Procedure:
2-Bromo-4,6-dichlorophenol (Preparation 24, 4.6 g, 19 mmol), potassium carbonate (4.5 g, 32.3 mmol) and methyl iodide (1.8 ml, 20.5 mmol) were combined in 46 ml acetone and heated to reflux for 18 hours. The reaction was cooled to 0° C., 1N HCl (aqueous) was added to give pH 3, and the reaction was extracted into 50 ml ethyl acetate. The organic layer was washed with brine (2×20 ml), dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown solid (5.5 g).
Reaction SMILES: OC(C)CC(OCC)=O.[C:10]([CH2:12][CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:11]>>[C:10]([CH2:12][C@@H:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:11]
Reactant: CCOC(=O)CC(O)CC#N
Agent: CCOC(=O)CC(C)O
Product: CCOC(=O)C[C@H](O)CC#N
Yield: 99 %

Procedure:
Instead of ethyl 3-hydroxybutyrate used in Example 1, ethyl 4-cyano-3-hydroxybutyrate (1%, w/v) was used as a reactant and novozyme 435 lipase was used as a biocatalyst. After reaction for 3 hours, ethyl (R)-4-cyano-3-hydroxybutyrate (99% e.e) was obtained at 57.3% conversion.
Reaction SMILES: [N:1]1([CH:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.O>[Br:29][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)[CH2:2][CH2:3]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(Br)ccc32)C1
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A solution of compound 2 (4.15 g, 14.390 mmol) in dry DMF (30 mL) was treated with NBS (2.56 g, 14.390 mmol) in dry DMF (20 mL) at 0° C. and resulting solution was stirred at same temperature for 3 h. The reaction was diluted with water (150 mL) and product was extracted into ethyl acetate (3×30 mL). The combined ethyl acetate layer was washed with water (2×25 mL), brine (25 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (ethyl acetate:hexanes, 1:4) to obtain compound 3 (5.12 g, 97%) as a syrup. 1H NMR (CDCl3) δ 7.18-7.07 (m, 2H), 6.33 (d, 1H, J=8.7 Hz), 4.13-3.99 (m, 1H), 3.68-3.26 (m, 6H), 2.94 (t, 2H, J=8.1 Hz), 2.17-1.99 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %): 390 (MNa+, 6), 368 (MH+, 3), 313, 311(100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.Br[CH2:20][C:21]#N.C(N(CC)C(C)C)(C)C.CN(C)C=O>[I-].[Na+]>[CH2:20]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]1)[CH3:21]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Reactant: N#CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CC(=O)N(C)c2cc([N+](=O)[O-])c(OC)cc2C1
Yield: 91.3 %

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), Sodium iodide (0.0148 g, 0.0000987 mol), Bromoacetonitrile (0.276 mL, 0.00396 mol) and N,N-Diisopropylethylamine (1.04 mL, 0.00597 mol) in N,N-Dimethylformamide (6 mL, 0.08 mol) was reacted in an analogous manner to example 736-E to give 4-Ethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (0.51 g, 88%). Mp 129-131° C.; LCMS (m/e) 291 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.96 (s, 1H), 7.51 (s, 1H), 3.93-92 (s, 3H), 3.86 (s, 2H), 3.82 (s, 2H), 3.27 (s, 3H), 3.16 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=2)[O:29][CH:30]=1.[I-].[K+]>CC(=O)CC>[CH3:1][C:2]1[CH:3]=[C:4]([O:17][CH2:25][C:26]2[N:27]=[C:28]([CH:31]=[CH:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=3)[O:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: Cc1cc(O)ccc1COCCn1ccnn1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: Cc1cc(OCc2coc(C=Cc3ccc(OC(F)(F)F)cc3)n2)ccc1COCCn1ccnn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 201 mg (0.86 mmol) 3-methyl-4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol and 169 mg (0.52 mmol) cesium carbonate in 10 ml 2-butanone was stirred at 60° C. for 30 minutes, then 261 mg (0.86 mmol) 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole and 143 mg (0.86 mmol) potassium iodide were added and stirring was continued overnight. After evaporation, the residue was mixed with aqueous NaOH (1N) and extracted with ethyl acetate. The combined extracts were dried, evaporated and the product purified on silica (ethyl acetate) to yield 208 mg (49%) of the title as a white solid melting at 84-85° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7]([NH2:9])=[O:8].[CH2:15]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[N:4][N:5]([CH2:10][CH3:11])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:21])[CH3:16]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCCc1nn(CC)c(C(N)=O)c1N
Product: CCCc1nn(CC)c(C(N)=O)c1NC(=O)c1ccccc1OCC

Procedure:
The title amide was prepared from 4-amino-1-ethyl-3-n-propylpyrazole-5-carboxamide and 2-ethoxybenzoyl chloride, following the procedure described in Example 6, and was obtained as a colourless solid (73%), m.p. 139°-141° C. Found: C,63.03; H,7.15; N,16.50. C18H24N4O3 requires C,62.77; H,7.02; N,16.27%.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].N12CCCN=C1CCCCC2.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 110 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
Methyl (2R)-2-(2,3,4-trifluoroanilino)propionate (100 mg, 38% ee) was dissolved in toluene (2 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 71.8 mg) was added thereto at room temperature. Then the liquid reaction mixture was stirred at 110° C. for 16 hours. After adding hydrochloric acid (1 mol/l; 1 ml) to the liquid reaction mixture, the aqueous layer was extracted with toluene. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to thereby give the title compound (86.8 mg) as colorless crystals. The optical purity of this product was 0% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 5.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([O:16]C)=O)=[N:4][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:6][C:7]=1[OH:8].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.Cl>CN(C=O)C>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:14]([C:3]2[C:2]([OH:1])=[C:7]([OH:8])[N:6]=[C:5]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[N:4]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(-c2cccs2)nc(O)c1O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1nc(-c2cccs2)nc(O)c1O
Reaction time: 8 h

Procedure:
Methyl 5,6-dihydroxy-2-thien-2-ylpyrimidine-4-carboxylate (A-2) was dissolved in DMF and 2.0 eq. of 4-fluorobenzylamine were added to the stirred solution. Reaction mixture was left overnight at 90° C. After cooling to room temperature 1 N HCl was added and a solid precipitated from the mixture. This solid was collected by filtration, washed with ethyl ether and dried under vacuum to afford the compound (A-3).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)CCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 8-bromooctanoic acid (2.5 g, 11.2 mmol, commercially available e.g. from Aldrich) in toluene (50 ml) was added thionyl chloride (2 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was co-evaporated with dichloromethane (2×25 ml) to give a brown oil which solidified on standing (found to be starting acid by NMR). This material was redissolved in toluene (25 ml), thionyl chloride (2 ml) was added, and the mixture was stirred at room temperature for 8 hours and then left standing overnight. The reaction mixture was evaporated to dryness and the residue was co-evaporated with dichloromethane (2×30 ml) to give the title compound as a brown oil (2.4 g), as a 3:2 mixture of product: starting acid (by NMR). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.37 (4H, m), 1.45 (2H, m), 1.67 (2H, m), 1.86 (2H, m), 2.90 (2H, t, J=7 Hz), 3.42 (2H, t, J=7 Hz).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:33][C:34]1[C:42]2[C:41]([CH2:43]O)=[CH:40][S:39][C:38]=2[CH:37]=[CH:36][CH:35]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:43][C:41]2[C:42]3[C:34]([CH3:33])=[CH:35][CH:36]=[CH:37][C:38]=3[S:39][CH:40]=2)[C:5]1=[O:13])([CH3:3])=[CH2:2]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2scc(CO)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
To a solution of 1-isopropenylbenzimidazolone (500 mg, 2.8 mmol) in dry THF (40 mL) are added triphenylphosphine (902 mg, 3.4 mmol) and (4-Methyl-benzo[b]thiophen-3-yl)-methanol (563 mg, 3.2 mmol). Then diisopropyl azodicarboxylate (0.70 mL, 3.4 mmol) is added drop wise into the above solution after it is cooled down to 0° C. The mixture is then stirred at room temperature for 5 hr and then the solvent is removed under vacuum and the residue is purified by flash column chromatography using gradient EtOAc/Hexane from 0% to 20% to give 630 mg (66%) of 1-isopropenyl-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(N)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: Cl
Product: CCOC(=O)C1(NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)CC1
Yield: 87 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and ethyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 87%, colorless liquid. MS 350 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[O:11][CH2:10][CH2:9]2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C2OCCc3cc(Cl)c(Cl)cc32)cc1

Procedure:
19.1 g (100 mM) of 2-(3,4-dichlorophenyl)-ethanol [G. J. Park et al.: J. Org. Chem. 22, 93 (1957)] and 15.1 g (100 mM) of 4-nitrobenzaldehyde were dissolved in 300 ml of anhydrous benzene, then 13.6 g (100 mM) of anhydrous zinc chloride were added and dry hydrochloric acid gas was led into the stirred suspension for 4 hours. Then the process described under Examples 1-7, Step a) was applied. The crude product was recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[C:11]([N+:20]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Zn].O>[NH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Yield: 86 %

Procedure:
A mixture of 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (11.94 g 39.6 mmol), ammonium chloride (13.48 g, 250 mmol), zinc powder (65.39 g, 1000 mmol), ethyl alcohol (720 ml) and water (70 ml) was refluxed until completion (5 hours). The mixture was filtered through celite and washed with hot ethyl alcohol. The filtrate was evaporated in vacuum. The residue was taken up in the mixture of chloroform (200 ml), water (200 ml) and the pH of this mixture was set to 8 by adding sodium hydroxide solution. The two layers were separated, the aqueous layer was extracted with chloroform (2×50 ml). The organic layers were combined, washed with water and over Na2SO4, and concentrated to give 9.25 product [α]. Yield 86%.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O>[CH3:12][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4][C:3]([OH:13])=[O:2]
Reactant: CCCCCN(C)CCC(=O)OC
Solvent: O
Product: CCCCCN(C)CCC(=O)O

Procedure:
68.8 g (367.4 mmol) N-methyl-N-pentyl-β-alanine methyl ester was hydrolyzed by refluxing with 138 ml water. Water was distilled off and 300 ml diethyl carbonate were added, followed by azeotropic distillation of diethyl carbonate/water (30 ml) to remove residual water. About 290 ml of a diethyl carbonate solution containing 63 g N-methyl-N-pentyl-β-alanine was obtained which could directly be used for the subsequent bisphosphorylation step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.Cl.[CH2:16](O)[CH2:17][CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:6]2
Reactant: CCCO
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: Cl
Product: CCCOC(=O)c1cc2cc(OC)ccc2[nH]1
Yield: 88 %

Procedure:
To a suspension of 300 (670 mg, 3.50 mmol) in anhydrous n-PrOH (20 mL) was added HCl (4 N in dioxane, 2.5 mL). The reaction mixture was heated at reflux for 36 h. Upon completion, volatiles were evaporated in vacuo and the resulting oil was purified by chromatography (0% to 20% EtOAc/hexanes) to produce a white powder (721 mg, 88%): mp 104-107° C. TLC Rf 0.51 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.82 (s, 1H), 7.32-7.31 (d, 1H, J=8.94 Hz), 7.15 (m, 1H), 7.08 (d, 1H, J=2.4 Hz), 7.01-6.99 (dd, 1H, J1=8.94 Hz, J2=2.46 Hz), 4.32-4.29 (t, 2H, J=6.72 Hz), 3.85 (s, 3H), 1.84-1.78 (sex, 2H, J=7.38 Hz), 1.05-1.03 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, CDCl3) δ 162.0, 154.7, 132.1, 127.88, 127.85, 117.0, 112.7, 108.2, 102.5, 66.5, 55.7, 22.2, 10.5. Elemental analysis calculated for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.87; H, 6.44; N; 6.00.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:31])[C:14]=2[C:18](=[O:30])[NH:19][CH2:20][C:21]2([OH:29])[CH2:28][CH2:27][C:24]3([CH2:26][CH2:25]3)[CH2:23][CH2:22]2)[C:9]1=[O:32])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[Cl:31][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:32])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:19][CH2:20][C:21]1([OH:29])[CH2:22][CH2:23][C:24]2([CH2:25][CH2:26]2)[CH2:27][CH2:28]1)=[O:30]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(C(=O)NCC3(O)CCC4(CC3)CC4)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](CO)n1ccc2c(C(=O)NCC3(O)CCC4(CC3)CC4)c(Cl)ccc2c1=O

Procedure:
(2R)-2-(6-Chloro-5-((6-hydroxyspiro[2.5]octan-6-yl)methylcarbamoyl)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (130 mg, 0.00029 mol) and potassium carbonate (140 mg, 0.0010 mol) were stirred in methanol (6 mL, 0.1 mol) at room temperature for 1 hour, concentrated, and purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=1.[C:29](=[O:31])=[O:30]>C1COCC1>[Br:21][C:22]1[CH:27]=[C:26]([C:25]([Br:28])=[CH:24][N:23]=1)[C:29]([OH:31])=[O:30]
Reactant: O=C=O
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)ncc1Br
Temperature: -30 °C

Procedure:
A 20-L 4-necked round-bottom flask purged and maintained under a N2 atmosphere was charged with a solution of diisopropylamine (582 g, 5.76 mol, 1.05 equiv) in THF (4.2 L), followed by the dropwise addition over 30 min of n-BuLi (2.4 M, 2.4 L, 1.05 equiv) with stirring at −30° C. The resulting solution was stirred at −30° C. for 30 min then cooled to −80° C. To the LDA solution was added dropwise over 1 h with stirring a solution of 2,5-dibromopyridine (1.3 Kg, 5.49 mol, 1.00 equiv) in THF (5.2 L). The resulting solution was stirred at −70° C. for 30 min. To the mixture was added CO2 (dry ice) (1267 g, 28.80 mol, 5.00 equiv) in several batches at −70° C. The resulting solution was stirred at −70° C. for 30 min, quenched by the addition of 5 L of water at −70° C., concentrated in vacuo and extracted with 3×4 L of EtOAc. The pH value of the aqueous layer was adjusted to 3-4 with HCl (12 mol/L). The precipitate was collected by filtration to afford 2,5-dibromoisonicotinic acid (A-2) white solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]3[C:21]([CH2:23][O:24][CH3:25])([CH3:22])[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[CH:26]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:25][O:24][CH2:23][C:21]1([CH3:22])[CH2:20][CH2:19][CH2:18][S:17][C:16]2[CH:26]=[C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]1=2
Reactant: COCC1(C)CCCSc2cc(C#Cc3ccc(C(=O)OC)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCC1(C)CCCSc2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reaction time: 18 h
Yield: 92.7 %

Procedure:
316 mg (0.83 mmol) of 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid methyl ester was dissolved in 8 ml of THF/EtOH (1/1) and treated with 1.38 ml of 3N NaOH (5 eq.). The reaction flask was kept in the dark and stirring continued for 18 h at room temperature. The mixture was then poured onto crushed ice/ HCl, extracted twice with diethylether, the organic phase was washed with brine, dried over magnesium sulfate, filtrated and evaporated to dryness. Crystallization of the residue from hexane/ethylacetate yielded 282 mg of the title product as white crystals of m.p. 182-183° C.