Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[C:16]#[N:17]>CN(C)C=O>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=2[C:16]#[N:17])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: N#Cc1cc(Cl)ccc1CBr
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1cc(Cl)ccc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 100 °C
Reaction time: 14 h
Yield: 1.8 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.16 g) in N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-5-chlorobenzonitrile (0.32 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2-4:1). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.[CH2:15]([N:17]([CH2:30][CH3:31])[C:18]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21])[CH3:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:9]3[CH2:10][N:11]([C:20]([C:19]4[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:18]=4[N:17]([CH2:30][CH3:31])[CH2:15][CH3:16])=[O:21])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: Clc1ccc2sc3c(c2c1)CCNC3
Product: CCN(CC)c1ccc([N+](=O)[O-])cc1C(=O)N1CCc2c(sc3ccc(Cl)cc23)C1

Procedure:
The title compound was prepared in analogy to Example 1 using 6-chloro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine [29078-50-0] and 2-(diethylamino)-5-nitro-benzoic acid [727718-14-1]. MS (m/e): 444.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:26][CH2:27][C:28]#[CH:29])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=O)=[CH:4][CH:3]=1.C1C=CC=CC=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:45]2)=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:26][CH2:27][C:28]#[CH:29])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[S:45])=[CH:4][CH:3]=1
Reactant: C#CCOc1ccc(CCNC(=O)C(OCC#C)c2ccc(Cl)cc2)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C#CCOc1ccc(CCNC(=S)C(OCC#C)c2ccc(Cl)cc2)cc1OC
Reaction time: 7 h

Procedure:
2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(prop-2-ynyloxy)-acetamide (0.822 g) and benzene (30 ml) are stirred at +55° C. 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (“Lawesson's reagent”; 1.61 g) is added. The reaction mixture is stirred for additional 7 hours at +55° C. to +60° C. After cooling to room temperature diethylether (100 ml) is added. The mixture is then filtered. The solvent of the filtrate is evaporated. 2-(4-Chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-(prop-2-ynyloxy)-thioacetamide is obtained which is purified by flash-column-chromatography on silica gel using ethyl acetate/hexane. The purified product is in form of a resin. 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.45–2.55(m, 2H), 2.95(t, 2H), 3.85(s, 3H), 3.9–4.2(m, 4H), 4.75(d, 2H), 5.35(s, 1H), 6.65–6.8(m, 2H), 7.0(d, 1H), 7.2–7.4(m, 4H), 8.4–8.6(m, 1H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6](N(CC)CC)C.[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CI>CN(C=O)C>[CH3:6][S:21][C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: CCN(CC)CC
Reactant: S=C=Nc1ccccc1
Solvent: CI
Solvent: CN(C)C=O
Product: CSC(Nc1ccccc1)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To a solution of malononitrile (1.0 g, 15.14 mmol) in DMF 20 mL was added triethylamine (2.099 mL, 15.14 mmol). After the mixture was stirred at room temperature for 5 min, phenylisothiocyanate (2.047 g, 15.14 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete as determined by TLC, methyl iodide (2.149 g, 15.14 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr, at which time the reaction was complete as determined by TLC. The reaction mixture was poured into 100 mL ice water. The resulting precipitate was filtered and dried in an oven overnight to give compound 6 (3.226 g, 98.2% yield, 97.4 purity) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].COC1C=C(O)C=CC=1O.[CH2:17]([NH:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]>CO>[CH2:17]([N:20]([CH2:21][CH2:22][CH3:23])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:18][CH3:19]
Reactant: CCCNCCC
Reactant: C=CC(=O)OC
Agent: COc1cc(O)ccc1O
Solvent: CO
Product: CCCN(CCC)CCC(=O)OC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Methanol (128 g; 4 moles) was added to 344 g (4 moles) of methyl acrylate containing 500 ppm of methoxyhydroquinone and 404 g (4 moles) of dipropylamine were added dropwise thereinto while placed in a water bath and stirred for a period of 30 minutes. After completion of the addition, the temperature of the liquid was raised to 70° C. and the reaction was carried out for three hours. After completion of the reaction, methanol was removed by distillation to give 746 grams of methyl beta-dipropylaminopropionate with a purity of 99%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]([O:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]O)[CH:22]=1)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:16]([O:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:13]2[C:12](=[O:15])[CH:11]=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:14]2)[CH:22]=1)[CH3:17]
Reactant: N#Cc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: CCOC(=O)Nc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C#N)cc3)ccc2=O)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
15 g (76 mmol) of 6-(4-cyanophenyl)-2H-pyridazin-3-one, 22.2 g (114 mmol) of ethyl(3-hydroxymethylphenyl)carbamate and 29.9 g (114 mmol) of triphenylphosphine are dissolved in 250 ml of THF. Under a nitrogen atmosphere, the reaction mixture is cooled to 0° C., 18 ml (174 mmol) of diethyl azodicarboxylate are slowly added dropwise, and the reaction mixture is stirred at room temperature for 72 h. The reaction mixture is evaporated to dryness. 200 ml of isopropanol are added to the residue, and the mixture is stirred for 15 h. The precipitate is filtered off with suction, washed with isopropanol and dried in vacuo.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].C1(N)N[C:10](N)=[N:9][C:7](=[O:8])N=1.CN1CCCC1=[O:20]>>[NH:1]1[C:10](=[O:20])[NH:9][C:7](=[O:8])[NH:4][C:2]1=[O:3]
Reactant: CN1CCCC1=O
Reactant: Nc1nc(=O)nc(N)[nH]1
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Yield: 60 %

Procedure:
300 g of urea prills and 495 g of N-methylpyrrolidone were charged into a 1-liter glass reactor fitted with stirrer, condenser and thermometer. The reaction mixture was heated with a mantle and maintained at reflux for a 2-hour period during which the reaction temperature increased from 185° to 212° C. On cooling, the reaction mixture solidified at about 35° C. The reaction mixture was reheated to about 160° C. to make it stirrable, cooled to 40°-50° C. and filtered. The cake set up in the filter funnel and had to be broken up. On washing with water, the filter cake solidified again into a hard cement-like solid with release of some heat. The solid was broken up, washed further, and dried giving 129 g (60% yield) of impure cyanuric acid containing 5.6% ammelide and 0.4% ammeline.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[C:30]3[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][C:22]=2[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:35]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[C:17]1[CH:16]=[C:15]([NH:14][S:2]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:20]=[CH:19][CH:18]=1)=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:32])[F:33])(=[O:36])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reaction time: 8 h
Yield: 52 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (0.11 g, 0.5 mmol) in 5 mL of THF was added dropwise to a stirred solution of [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.098 g, 0.25 mmol) and triethylamine (0.4 mL, 0.29 mmol) in 5 mL of THF at room temperature. The reaction mixture was stirred overnight, diluted with ethyl acetate, washed with water, and concentrated. The residue was purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 50M; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a brown solid (0.075 g, 50%): MS (EI) m/z 601.1 (M+H)+; 1H NMR (DMSO-d6): δ 7.03 (d, J=7.7 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.39 (t, J=7.8 Hz, 2H), 7.56 (t, J=7.4 Hz, 1H), 7.60-8.75 (m, 9H), 8.06 (d, J=8.6 Hz, 1H), 8.36 (d, J=7.3 Hz, 1H), 9.16 (s, 1H), 10.34 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:37]=[O:38])(C)(C)C.C1C=CC=CC=1.[Pb](=O)=O>ClCCCl.O>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:38][CH3:37])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Agent: O=[Pb]=O
Solvent: O
Solvent: c1ccccc1
Solvent: ClCCCl
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCC(N)=O)Sc3nnn[nH]3)CS[C@@H]21
Reaction time: 0.5 h

Procedure:
A solution of 1.76 g. (4 mmol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.94 g. (4 mmol.) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 150 ml. of dry benzene is refluxed for ca. 4 hours under a Dean-Stark trap until no more water separates. The solution is evaporated uner reduced pressure to give a residue which is dissolved in 150 ml. of 1,2-dichloroethane and cooled to 0°-5° in an ice bath. Freshly prepared lead dioxide (5 g.) is added in 1 g. portions over 30 minutes and the reaction is stirred in the cold until complete consumption of starting material is shown by thin layer chromatography. The mixture is then filtered through Celite and the filter cake is washed with two 30 ml. portions of cold 1,2-dichloroethane. The filtrate is treated with 30 ml. of dry methanol (distilled from magnesium) and the reaction mixture is stirred at ambient temperature until complete consumption of the intermediate and formation of a new product are shown by thin layer chromatography. The reaction mixture is evaporated to dryness and the residue is taken up in 50 m. of methanol and treated with 4.0 g. of Girard reagent T. This solution is stirred at ambient temperature for 3 hours, evaporated under vacuum to a solid residue and partitioned between 150 ml. of ethyl acetate and 100 ml. of 20% aqueous sodium chloride solution. The organic phase is washed with three 100 ml. portions of 10% aqueous sodium chloride, two 100 ml. portions of water and 100 ml. of a saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>O>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Solvent: O
Product: COc1ccc(CNc2ncc(Cl)cc2C(=O)O)cc1
Temperature: 150 °C

Procedure:
A mixture of 2,5-dichloronicotinic acid (30.0 g) and 4-methoxybenzylamine (41.0 ml) was heated at 150° C. under nitrogen for 2 hours. The mixture was cooled to ambient temperature, dissolved in boiling water, acidified to pH 6 and filtered. The collected solid was dried, boiled up with IMS, then filtered to give 5-chloro-2-(4-methoxybenzylamino)nicotinic acid, m.p. 204°-206° C.
Reaction SMILES: [C:1](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(COC)OC=2C=1)=O)(C)(C)C.[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:61])[N:58]([CH3:60])[CH3:59])=[C:53]([F:62])[CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][OH:47])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CI>>[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:61])[N:58]([CH3:59])[CH3:60])=[C:53]([F:62])[CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][O:47][CH3:1])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:32])([CH3:34])[CH3:33]
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(C)(CO)O3)cc1F
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(C(=O)N(C)C)c(F)c3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (229a) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.36 (t, J=8.21 Hz, 1 H) 7.26 (s, 1 H) 7.20 (s, 1 H) 6.78 (dd, J=8.46, 1.89 Hz, 1 H) 6.66 (dd, J=10.74, 1.89 Hz, 1 H) 3.40-3.49 (m, 2 H) 3.39 (s, 3 H) 3.07-3.14 (m, 4 H) 2.97 (s, 3 H) 2.76 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.45 (s, 3 H); LCMS for C25H30FNO6 m/z 482.00 (M+Na)+.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:2])=[CH:10][CH:9]=1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)O
Solvent: COc1ccc(C)cc1
Solvent: O
Product: COc1ccc(C=O)cc1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
Into the same flask as in Example 1 are placed 400 ml of water, 86 g of sulfuric acid and 100 g of p-methoxytoluene, and the mixture is stirred. A 540 ml quantity of water, 54 g of chromic anhydride and 200 g of sulfuric acid are placed in a 1-liter beaker to prepare an oxidizing solution. The solution is slowly added dropwise to the mixture in the flask with stirring while maintaining the reaction temperature constantly at 35° C. After the whole solution has been added, the mixture is stirred for further 20 minutes. The total reaction time is 5 hours and a half. The reaction mixture is treated and distilled to fractions in the same manner as in Example 1, giving 32 g of anisaldehyde and 60 g of recovered unreacted p-methoxytoluene.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.[NH4+].[Cl-].C1C[O:25]CC1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[O:25])=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(C(=O)c2ccc(Cl)nc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 6-chloronicotinonitrile (1.39 g, 10 mmol) in 100 mL of THF was added (4-methoxyphenyl)magnesium bromide (15 mmol) dropwise at 0° C. The mixture was then stirred at 0° C. for 1 h. and then 50 mL sat. NH4Cl solution was added. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography to give the product (1.24 g, 50% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:11])[C:3]=1[F:10]
Reactant: Oc1c(Cl)ccc(Br)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1c(Cl)ccc(Br)c1F
Temperature: 85 °C

Procedure:
To a stirred solution of 3-bromo-6-chloro-2-fluorophenol (4.2 g, 18.63 mmol) in acetonitrile (35 mL) was added potassium carbonate (5.15 g, 37.3 mmol) followed by the addition of methyl iodide (2.330 mL, 37.3 mmol) dropwise at rt. The reaction mixture was heated to 85° C. for 3 h. The volatiles were evaporated; water (50 mL) was added and the solution extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulphate, and concentrated under reduced pressure. The crude material was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 7.05 (m, 1H), 3.98 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:10]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:10][N:24]1[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)OC(=O)CN(CCOS(C)(=O)=O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cn(CCN(CC(=O)OC(C)(C)C)Cc2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 2 (10.73 g; 31 mmol), thymine (7.88 g; 62 mmol) and potassium carbonate (8.64 g; 62 mmol) are suspended in anhydrous N,N-dimethylformamide (325 ml). The suspension is stirred at room temperature for 1 h and then at 80° C. for 6 h. The cooled mixture is codistilled repeatedly with toluene, and the residue is taken up in chloroform (500 ml) and extracted twice with water (150 ml on each occasion). The crude product is purified by chromatography on silica gel (eluent: toluene/ethanol, 27:1). Yield: 5.58 g (48%).
Reaction SMILES: C(S[CH2:7][CH2:8][CH2:9][Cl:10])CC(C)C.ClC1C=[CH:16][CH:15]=[C:14]([C:18](OO)=O)[CH:13]=1.[S:22](S([O-])=O)([O-:25])(=O)=[O:23].[Na+].[Na+]>C(Cl)Cl>[CH2:16]([S:22]([CH2:7][CH2:8][CH2:9][Cl:10])(=[O:25])=[O:23])[CH2:15][CH:14]([CH3:13])[CH3:18]
Reactant: CC(C)CCSCCCCl
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CCS(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Dissolve 3-chloropropyl isopentyl sulfide (800 mg, 4.43 mmol) in methylene chloride (25 mL) and place under nitrogen atmosphere. Add a solution of metachloroperbenzoic acid (1.53 g, 8.85 mmol) in methylene chloride (25 mL). Stir at room temperature overnight. Add additional meta-chloroperbenzoic acid (1.0 g) in methylene chloride (25 mL). Stir at room temperature overnight. Treat with aqueous sodium metabisulfite (until negative starch-iodide test) and separate the layers. Wash the organic phase with saturated sodium hydrogen carbonate until basic and dry (MgSO4). Evaporate the solvent in vacuo to yield 710 mg (75.4%) of 3-chloropropyl isopentyl sulfone as a yellow oil which crystallizes; MS (CI/CH4) m/z 213(M+1), 177(M+1-HCl).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:35]=O.COC(=O)C.[Cl:47]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:47].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: C[C@H](CCNCC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: COC(C)=O
Solvent: CCOCC
Product: COc1ccc(CN(CC[C@@H](C)Oc2cccc(CC(=O)O)c2)CC(c2ccccc2)c2ccccc2)cc1F

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]-1-methyl-propoxy}-phenyl)acetic acid and 3-fluoro-4-methoxybenzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The crude product was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: H2O, UV detection at 254 nm) to afford the free base. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 100 mg (99%). MS (ESI) 542.4 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:16]([CH3:18])=O)[O:7]2.[OH:20][C:21]1[CH:26]=[CH:25]C(S)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:16][C:18]1[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=1)[O:7]2
Reactant: Oc1ccc(S)cc1
Reactant: CC(C)Oc1cc(O)c2c(=O)cc(S(C)=O)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(O)c2c(=O)cc(Sc3ccc(O)cc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of 7.01 g of 5-hydroxy-7-isopropoxy-2-methylsulfinylchromone (24.59 mmol), 3.72 g of 4-hydroxybenzenethiol (29.51 mmol), 4.07 g of potassium carbonate (29.51 mmol) and 170 ml acetone was stirred for 1 hour at room temperature. The reaction solution was neutralized with dilute hydrochloric acid and was then extracted twice with chloroform, and the organic layer was washed with saturated NaCl water and then dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, and the crude product was subjected to recrystallization from ethanol-methanol, to give 6.64 g of 5-hydroxy-2-(4-hydroxyphenylthio)-7-isopropoxychromone (78% yield).