Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:15]1[C:16]2[CH2:39][NH:38][CH2:37][CH2:36][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:15]1[C:16]2[CH2:39][N:38]([C:1](=[O:3])[CH3:2])[CH2:37][CH2:36][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C(C)=O)CC3)ccc1-n1cnc(C)c1
Reaction time: 1 h
Yield: 33.3 %

Procedure:
Acetic anhydride (0.039 mL, 0.41 mmol) was added to a solution of 4-benzyl-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (175 mg, 0.41 mmol, example 109) in THF (3 mL) and stirred for one hour. The solvent was evaporated under reduced pressure and the crude product purified on prepHPLC yielding 1-(4-benzyl-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (64.0 mg, 33.3%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC=CC=1>CCOCC>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 135 °C
Yield: 99 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (25 g), 10-campharsulfonic acid, ethylene glycol (40 mL), and toluene (400 mL) was heated under reflux with a Dean-Stark apparatus for 2.5 h (bath temp. 135° C.). The mixture was cooled down, and then was diluted with ether (200 mL). After the ethylene glycol layer was separated, the organic layer was washed with saturated aqueous sodium bicarbonate solution (2×) and brine (1×), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 2 as an oil (31.29 g, 99%): 1H NMR (CDCl3) δ 4.13 (2H, q, J=7.1 Hz), 3.95 (4H, s), 2.33 (1H, m), 1.93 (2H, m), 1.79 (4H, m), 1.56 (2H, m) 1.25 (3H, t, J=7.1 Hz); 13C NMR (CDCl3) δ 175.4, 108.3, 64.5, 60.5, 41.8, 33.9, 26.5, 14.4.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@@H:10]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@H:11]2[OH:20])[CH2:4][CH2:3]1.N.[Li].C(O)C>CCOCC.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@@H:10]2[CH2:19][C:18]3[CH2:17][CH:16]=[CH:15][CH2:14][C:13]=3[CH2:12][C@H:11]2[OH:20])[CH2:4][CH2:3]1
Reactant: CN1CCN(CC[C@@H]2Cc3ccccc3C[C@H]2O)CC1
Agent: N
Agent: [Li]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CN1CCN(CC[C@@H]2CC3=C(CC=CC3)C[C@H]2O)CC1
Reaction time: 0.5 h
Yield: 105.4 %

Procedure:
A solution of 25.4 g (92.7 mmol) of the amine of Example 1 in 100 ml ether is added to 1 liter liquid ammonia. Lithium (10.0 g) is added portionwise over a period of 10 minutes. After stirring 30 minutes, absolute ethanol is added dropwise until the color is discharged (140 ml added in 1 hour). More ether is added and the ammonia is boiled off. While cooling in an ice bath, the mixture is diluted with 1 liter water. The layers are separated and the aqueous is reextracted with ether. The combined organic layers are dried over K2CO3, filtered, and the solvent is removed in vacuo leaving 27 g of the title compound in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][S:11][CH3:12].O=P(Cl)(Cl)Cl.[CH2:18]([O:20]CC)C.[OH-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:10][S:11][CH3:12])[CH:18]=[O:20]
Reactant: COc1ccccc1C=CSC
Reactant: CCOCC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccccc1C(C=O)=CSC

Procedure:
A solution of 5.5 g of 1-methoxy-2-(2-methylsulphanyl-vinyl)-benzene in 15 ml of dimethylformamide is heated to 80° C. with 4.7 g of POCl3 for 2 hours with stirring. After cooling diethylether and water are carefully added and the mixture obtained is adjusted to pH 9 with aqueous NaOH solution (10%). The organic phase is separated off and after drying the solvent is eliminated in vacuo. Chromatography on silica gel (cyclohexane:ethyl acetate 70:30) yields 2.5 g of 2-(2-methoxyphenyl)-3-methylsulphanyl-propenal.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[Cl:25]N1C(=O)CCC1=O>C(OC(C)=O)(C)C.O>[Cl:25]/[C:3](=[N:2]\[OH:1])/[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:23][CH:24]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(/C=N/O)cc1)C1CCOCC1
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(/C(Cl)=N/O)cc1)C1CCOCC1
Temperature: 20 °C
Yield: 88.8 %

Procedure:
A suspension of (E)-tert-butyl 4-((hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4) (1662 g, 4.97 mol) in i-PrOAc (16.6 L) is stirred at 20° C. in a reactor. N-chlorosuccinimide (730 g, 5.47 mol) is added maintaining about 20° C. The suspension is stirred at about 20° C. to complete the reaction. The suspension is diluted with water (8.3 L) and stirred to dissolve the solid. The phases are separated and the organic phase is washed with water (8.3 L). The organic phase is concentrated then diluted with i-PrOAc (831 mL). Heptane (13.3 L; 8 V) is slowly added to induce crystallization. The thick suspension is then stirred for 1 h. The solid is collected by filtration; the filter-cake is washed with heptane (2×1.6 L; 2×1 V) and dried to afford (Z)-tert-butyl 4-(chloro(hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4-i) (1628 g; 89%, 98.0 area % purity by HPLC) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]([C:17](Cl)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:18])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: Cc1cc(N)ccn1
Product: Cc1cc(NC(=O)C(=O)c2ccccc2)ccn1

Procedure:
In analogy to the procedure described for the synthesis example 41 (step 1), the title compound N-(2-methyl-pyridin-4-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 241.2 [M+H]+) was prepared from 4-amino-2-picoline and benzoylformic acid chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.107 g, 0.5 mmol) in N-methyl 2-pyrolidone (2 mL) was added powdered potassium hydroxide (0.224 g, 4.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyridine (0.065 g, 0.55 mmol) was added and stirred for further 24 h. at 120 deg C., After completion of TLC, Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (8% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as brown oil (0.034 g, 20% yield). 8-Ethyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.034 g, 0.102 mmol) was dissolved in THF (0.5 mL). A solution of oxalic acid dihydrate (0.013 g, 0.102 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.015 g, 32% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1CBr
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid methyl ester (8.4 g, 37 mmol) in 100 mL CCl4 was added N-bromosuccinimide (7.8 g, 44 mmol) and benzoylperoxide (0.5% as catalyst). The mixture was heated at reflux for 2 h and then was cooled to room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether) to afford 5-bromo-2-bromomethyl-benzoic acid methyl ester (5.2 g, 46%). 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.60 (d, J=8.0, 1H), 7.32 (d, J=8.0, 1H), 4.89 (s, 2H), 3.94 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:17]1([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of 4-bromo-2-nitroaniline 17 (1.0 g, 4.67 mmol), tributylphenyl tin (2.2 g, 6.07 mmol), bis(triphenylphosphine)palladium (II) chloride (164 mg, 0.234 mmol), and triphenylphosphine (613 mg, 2.34 mmol) in DMF (15 ml) was heated under N2 at 120° C. overnight. After the solution was cooled to room temperature, the reaction mixture was directly chromatographed on silica gel eluting with 2-5% EtOAc/Hexane to give 752 mg (75%) of 5 as a yellow solid: mp 169-171° C.; IR (CHCl3) 3517, 3398, 3022, 1635, 1525, 1250; 1H NMR δ 8.38 (1H, d, J=2.2), 7.66 (1H, dd, J=8.7, 2.2), 7.59-7.54 (2H, m), 7.49-7.34 (3H, m), 6.90 (1H, d, J=8.8), 6.13 (NH, brs); 13C NMR δ 144.2, 139.3, 135.0, 130.9, 129.5, 127.8, 126.8. 124.4, 119.8, 112.8; Anal. Calcd for C12H10N2O2 : C, 67.28; H, 4.70; N, 13.08. Found: C, 67.38, H, 4.76; N, 13.01.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC(Cl)=CC=3)C=2)=[O:7])=[CH:4][N:3]=1.C[C@H]1CNC[C@@H](C)N1>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:26]=[CH:27][CH:2]=[N:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)cc2)c1)c1ccc(Cl)nc1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: NC(=O)c1cccnc1

Procedure:
6-chloro-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide (0.19 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.57 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-chlorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)-nicotinamide. MS (Q1) 498.0 (M)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC1C=CC=CC=1)C#C.[C:37]1([C:43]#[CH:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:23]([N:12]1[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:44]#[C:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:3]=2)=[N:9][CH2:10][C:11]1=[O:25])[CH3:24]
Reactant: C#Cc1ccccc1
Reactant: CCN1C(=O)CN=C(c2cccc(Br)c2)c2cc(OC)c(OC)cc21
Agent: C#CCOCc1ccccc1
Product: CCN1C(=O)CN=C(c2cccc(C#Cc3ccccc3)c2)c2cc(OC)c(OC)cc21
Yield: 33 %

Procedure:
By replacing 5-(4-bromophenyl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbl) in example IIbn by 5-(3-bromophenyl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbm), and [(prop-2-ynyloxy)methyl]benzene by phenylacetylene, and proceeding in the same manner, the abovenamed product is obtained. Yield: 33%. M: 100–102° C. 1H-NMR (CDCl3, 200 MHz): d 1.13 (s, 3H, CH3), 3.51–3.82 (m, 5H, 1H NCH2+1H CH2+OCH3), 3.97 (s, 3H, OCH3), 4.24–4.34 (m, 1H, NCH2), 4.74–4.80 (m, 1H, CH2), 6.66 (s, 1H Ar), 6.84 (s, 1H Ar), 7.26–7.83 (m, 9H Ar).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])C.[OH-].[Na+]>C(O)C>[C:23]1([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:4]([OH:31])=[O:3])=[CH:22][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CCCCCCCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 38 g of α-[p-(1-cyclooctenyl)-phenoxy]-dodecanoic acid ethyl ester in 150 ml of ethanol are added 150 ml of 2N sodium hydroxide solution and the mixture is stirred for 2 hours at room temperature. The reaction mixture is then evaporated to dryness in vacuo and the residue partitioned between N hydrochloric acid and ether. The organic phases are washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is distilled under a high vacuum at 0.05 mm and 235°-239° C. The distillate is cyrstallised from pentane to yield the α-[p-(1-cyclooctenyl)-phenoxy]-dodecanoic acid of the formula ##STR14## which melts at 45°-48° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=32)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([NH:2][CH:3]1[CH2:12][CH:11]2[N:6]([CH2:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=32)[CH2:5][CH2:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN2CCc3ccccc3C2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCN2CCc3ccccc3C2C1
Temperature: 25 °C
Yield: 76 %

Procedure:
To 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine hydrochloride (1.38 g), suspended in a solution of triethylamine (2 ml) in dichloromethane (10 ml) stirred at room temperature was added methane sulphonyl chloride (0.570 g) in dichloromethane (5 ml). After stirring for 18 hours, the solution was washed with water and the organic phase separated, dried and evaporated to yield the title compound (1.06 g) as an oil, which was converted in ethanolic hydrogen chloride to the hydrochloride (0.395 g) m.p. 244.8° C. C14H20N2O2S.HCl requires C, 53.06; H, 6.68; N, 8.84%. Found: C, 53.07; H, 6.77; N, 8.64%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:13]S(C)(=O)=O.[OH-].[Na+].CO.O>C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:13]
Reactant: COC(=O)c1cc(Cl)c(N)c(OS(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1c(O)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 73.7 %

Procedure:
In a 2-liter round-bottomed flask were placed methyl 4-amino-5-chloro-3-methylsulfonyloxybenzoate (8.7 g, 31.1 mmole), 50% aqueous sodium hydroxide (10.1 g, 126 mmole), methanol (250 ml) and water (550 ml). The resulting mixture was refluxed for 3 hours. The reaction mixture was cooled down to room temperature and poured into a mixture of water and ethyl acetate. The aqueous layer was separated, neutralized to pH 6 with concentrated aqueous hydrochloric acid, and extracted with ethyl acetate (3×400 ml). The combined organic layers were washed with water (2×200 ml), dried over anhydrous magnesium sulfate and the solvent eliminated in the rotary evaporator yielding 4.3 g of the expected 4-amino-5-chloro-3-hydroxybenzoic acid (intermediate XII). (1H-NMR, DMSO-d6 12.5(1,bs); 10(1,bs); 7.22(1,s); 5.4(2,s))
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH2:14]([N:16]([CH2:22][CH3:23])[C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH3:15]>>[CH2:14]([N:16]([CH2:22][CH3:23])[C:17](=[O:21])[C:18]([C:19]#[N:20])=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[CH3:15]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CCN(CC)C(=O)CC#N
Product: CCN(CC)C(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of N,N-diethylcyanoacetamide. Yield 2.23 g (73%), m.p. 153-156° C.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[N+:3]([CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)#[C-:1]
Reactant: O=CNCc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]Cc1nc2ccccc2o1
Reaction time: 0.75 h

Procedure:
To 2.83 g (16.1 mmol) of 2-(N-formylaminomethyl)benzoxazole, 7.39 ml (53.0 mmol) of triethylamine, and 30 ml of dichloromethane stirred at 0° are added dropwise 2.71 g (17.7 mmol) of phosphorous oxychloride in 5 ml of dichloromethane. The reaction mixture is stirred at 0° for 45 min and then 2.81 g of sodium carbonate dissolved in 20 ml of water is added. The mixture is stirred for 30 min and then partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated and the crude product is chromatographed on silica gel (325 ml) eluting with ethyl acetate/hexane (10/90), the appropriate fractions are pooled and concentrated to give the title compound, mp 57.0°-57.5°; MS (m/z) 158; IR 766, 2166, 987, 1167 and 1230 cm-1 ; NMR (CDCl3) 4.94, 7.42, 7.58 and 7.76 δ.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([NH2:15])[N:7]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[CH2:27][P:28]([CH3:33])(=[O:32])[O:29][CH2:30][CH3:31]>CN(C=O)C>[NH2:15][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH2:23][C:24]1[CH:25]=[C:26]([CH2:27][P:28]([CH3:33])(=[O:32])[O:29][CH2:30][CH3:31])[CH:34]=[CH:35][CH:36]=1
Reactant: CCCCNc1nc(N)c2nc[nH]c2n1
Reactant: CCOP(C)(=O)Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2ncn(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 64 (300.0 mg, 1.45 mmol) and K2CO3 (200.0 mg, 1.45 mmol) was dissolved in DMF (5 mL) and to it was added 65 (420.0 mg, 1.45 mmol). The mixture was left to stir over night at room temperature, solvent was evaporated by rotary evaporation. The remaining solid was taken up in water and the product extracted with DCM (3×50 mL). Combined organic layers were washed with water (1×50 mL) and brine (2×50 mL) and dried over Na2SO4. Product was purified by flash column eluting 0-20% methanol in ethyl acetate to give 299.4 mg (50%) 66 as a solid. 1H NMR (300 MHz, CDCl3) δ 0.818 (t, 3H), 1.15 (t, 3H), 1.24 (d, 3H), 1.27 (m, 2H), 1.43 (m, 2H), 2.99 (d, 2H), 3.28 (m, 2H), 3.87 (m, 2H), 4.01 (m, 2H), 5.09 (s, 2H), 7.11 (m, 4H), 7.36 (s, 1H). LCMS: m/z for C20H29N6O2P++H observed 417.3 at 1.76 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[OH:20])=[O:4].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>C(Cl)Cl.[Ag-]=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][C@@H:6]1[O:20][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=[O:4]
Reactant: Cc1ccc(CBr)cc1
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1O
Agent: O=[Ag-]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1OCc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 59.3 %

Procedure:
A mixture of (1R,2R,4R) and (1S,2S,4S)-4-(2-chloro-benzenesulfonyl)-2-hydroxy-cyclopentanecarboxylic acid methyl ester (80 mg, 0.251 mmol, example 48, step 5), 1-(bromomethyl)-4-methylbenzene (232 mg, 1.25 mmol) and silver(I) oxide (116 mg, 0.502 mmol) in DCM (2 ml) was stirred at room temperature for 60 h. The reaction mixture was filtered through a pad of Celite, the pad was washed with DCM and the filtrate was evaporated. The remaining grey oil was purified by silica gel chromatography (heptane/EtOAc 80:20-70:30) to obtain the title compound (63 mg, 56%) as colorless oil. MS (EI): 423.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](Cl)[CH:25]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][S-:32].[Na+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([S:32][CH3:31])[CH:25]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(Cl)c2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ccn1
Temperature: 70 °C

Procedure:
4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide (475 mg, 1.0 mmol) was dissolved in 10 mL dry THF and treated with solid sodium thiomethoxide (355 mg, 5 mmol) and the mixture heated at 70° C. for 16 h. The solvent was concentrated to about 2 mL and added to 5 mL cold 1M HCl. The light yellow solid precipitate was collected by filtration and product was purified by HPLC. 1H-NMR (400 MHz, CDCl3): δ 1.26 (s, 9H), 2.61 (s, 3H), 6.86 (d, 1H, J=5.2 Hz), 7.18 (s, 1H), 7.28 (d, 1H, J=2.4 Hz), 7.39 (d, 2H, J=8.8 Hz), 7.51 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.67 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.56 (d, 1H, J=5.2 Hz), 10.13 (s, 1H). MS: m/z 476.1 (M++1).