Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)ccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(F)cc1CBr
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
Reaction SMILES: O1C=CC([C:6]2S[C:9]([S:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:24]([O:26]C)=O)[CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=N1.CO.Cl.[NH2:31][OH:32].[OH-].[K+]>CS(C)=O>[CH2:9]([S:11]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([NH:31][OH:32])=[O:26])[CH:20]=2)[CH2:15]1)(=[O:12])=[O:13])[CH2:8][CH2:7][CH3:6]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)CCN(S(=O)(=O)c1ccc(-c3ccon3)s1)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CCCCS(=O)(=O)N1CCc2cc(C(=O)NO)ccc2C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
To a solution of methyl 2-[(5-isoxazol-3-yl-2-thienyl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxylate obtained in step 1 in methanol (2 mL, 50 mmol) was added hydroxylamine hydrochloride (80 mg, 1 mmol) and potassium hydroxide (200 mg, 4 mmol). The reaction was left to stir for 2 hours at 80° C. Upon cooling to room temperature the solvent was removed in vacuo. The residue obtained was dissolved in DMSO (1 mL), the residual solids were removed by filtration and the resulting residue following evaporation was purified via reverse phase prep HPLC to afford the title compound as a white solid after lyophilization (Yield: 6.1%). LCMS (FA) ES+ 313; 1H NMR (400 MHz, d6 DMSO) δ: 0.87 (t, J=7.32, 7.46 Hz, 3H), 1.38 (q, J=7.545, 7.25, 7.57 Hz, 2H), 1.63 (q, J=7.76, 7.55, 7.80 Hz, 2H), 2.91 (t, J=5.29, 6.47 Hz, 2H), 4.44 (s, J=8.06, 7.81 Hz, 2H), 3.49 (t, 2H, 6.03 Hz, J=5.95), 4.44 (s, 2H), 7.24 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), and 7.58 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[C:25]2[C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[CH:37]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][C:24]2[C:25]3[C:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[CH:37]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)OCCOc1cc2ccccc2c2ccccc12
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3c3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 2-(9-phenanthrenyloxy)ethyl methanesulfonate (1.26 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and the solids were filtered off, dissolved in dichloromethane, dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from dichloro-methane-diethyl ether provided 0.8 g of alpha-oxo-4-[[2-(9-phenanthrenyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a yellow solid, mp 147°-148° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][C:23]=2[O:22]1>>[O:22]1[C:23]2[CH:24]=[CH:25][C:26]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[N:3]=3)=[CH:27][C:28]=2[O:29][CH2:21]1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2ccc3c(c2)OCO3)OC1(C)C
Product: COc1cccc(Nc2nc(-c3ccc4c(c3)OCO4)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with 3,4-methylenedioxyphenylboronic acid pinacol ester using General Procedure A. Purification on silica yielded 119. NMR: (CDCl3): 3.88 (s, 3H, CH3), 4.10 (s, 3H, CH3), 6.07 (s, 2H, CH2), 6.86 (dd, H, ArH, J=1.81, 8.3), 6.93 (d, H, ArH, J=8.2), 7.13 (m, 2H, 2×ArH), 7.33 (s, H, NH), 7.38 (t, H, ArH, J=8.11), 7.47 (s, H, ArH), 8.06 (d, H, ArH, J=1.54), 8.17 (dd, H, ArH, J=1.63, 8.21). MS: (ESI+) MH+=376.18
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3](O)[OH:4].S(O)(O)(=O)=O.[NH2:13][C:14]1[N:15]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH2:29][CH2:30][CH3:31])[NH:17][C:18](=[O:21])[C:19]=1[NH2:20]>CO>[CH2:29]([O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:16]1[NH:17][C:18](=[O:21])[C:19]2[NH:20][C:3](=[O:4])[CH:2]=[N:13][C:14]=2[N:15]=1)[CH2:30][CH3:31]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCOc1ccccc1-c1nc2ncc(=O)[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A solution of chloral hydrate (1.74 g) in 50% aqueous methanol (10 ml) was added over 10 minutes to a stirred solution of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.89 g) in 50% aqueous methanol (60 ml) at 80° C. and the reaction mixture was stirred at 80° C. for 1.5 hours. The cooled reaction mixture was filtered to remove an orange brown solid which was discarded. On standing overnight the filtrate afforded a crude solid product (0.96 g) which was collected and washed with dilute aqueous potassium bicarbonate and water. The crude product together with another sample (0.20 g) similarly prepared was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to afford a solid (0.54 g) which was recrystallised from acetonitrile to afford the title compound, 0.39 g, m.p. 232°-233.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([O:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:31]=2)[CH:27]=[CH:28]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 90 °C
Yield: 50.7 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (200 mg, 0.6 mmol), (prepared as described for the starting material in Example 50), and 6hydroxyindole (97 mg, 0.73 mmol) in DMF (3 ml) containing potassium carbonate (125 mg, 0.91 mmol) was heated at 90° C. for 2.5 hours. After cooling, water was added. The precipitate was filtered, washed with water and dried under vacuum. The residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(indol-6-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (130 mg, 50%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=1>CN(C)C=O>[Cl:16][C:15]1[C:10]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: SCc1ccccc1
Reactant: Clc1cccnc1Cl
Solvent: CN(C)C=O
Product: Clc1cccnc1SCc1ccccc1
Temperature: 70 °C

Procedure:
42.0 Grams (0.338 mole) of benzyl mercaptan were dissolved in 350 ml dimethylformamide which had been dried over molecular sieves. The solution was placed under a nitrogen atmosphere and 16.2 grams (0.338 mole) of a 50 percent dispersion of sodium hydride was slowly added. Stirring was continued until hydrogen gas evolution stopped. Thereupon, the resulting solution was added slowly, again with stirring, to a solution of 50.0 grams (0.338 mole) of 2,3-dichloropyridine in 200 ml dry dimethylformamide. The mixture was heated at 70° C. for 4 hours.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:4]=1[O:15]C)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[OH:15][C:4]1[CH:5]=[C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCOC(=O)Cc1ccc(CC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(CC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of ethyl 4-ethyl-3-methoxyphenylacetate (4f; 3.0 g; 13.50 mmol) and CH2Cl2 (80 mL) cooled to −78° C. and a solution of BBr3 (5.10 mL; 53.94 mmol; 1.0 M in CH2Cl2) over 30 min. After 1 h at −78° C. the reaction was allowed to warm to rt and stirred for 12 h. The reaction was cooled in an ice-water bath and the reaction quenched with 20 mL of water. The aqueous phase was extracted with CH2Cl2:EtOAc (4:1 v/v), dried (Na2SO4), filtered and evaporated. The crude product was purified by silica gel chromatography and eluted with a CH2Cl2:EtOAc gradient (100:1→100:4) to yield 5b (2.0 g; 71%): m.s. 209.2 (M+H)+.
Reaction SMILES: N[C:2]1[C:3]([I:15])=[C:4]([CH2:13][OH:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[OH-].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+].[Cu][C:28]#[N:29].[C-]#N.[K+].Cl>O>[C:28]([C:2]1[C:3]([I:15])=[C:4]([CH2:13][OH:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])#[N:29]
Reactant: N#C[Cu]
Reactant: Nc1c(I)c(CO)c(I)c(C(=O)O)c1I
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1c(I)c(CO)c(I)c(C(=O)O)c1I
Reaction time: 2 h
Yield: 81 %

Procedure:
171 g of 5-amino-3-hydroxymethyl-2,4,6-triiodobenzoic acid is suspended in 3 1 of water and dissolved by adding dilute sodium hydroxide solution. Then a pH of 2.5 is set by the addition of semiconcentrated sulfuric acid, and under cooling a solution of 28 g of sodium nitrite in 96 ml of water is added dropwise within 20 minutes in such a way that the reaction temperature ranges between 0° and +5° C. Thereafter the pH value is again set at 2.5 with semiconcentrated sulfuric acid, and the mixture is stirred for 2 hours in an ice bath. Subsequently the reaction mixture is neutralized under cooling with dilute sodium hydroxide solution, and poured into a solution of 143 g of copper(I) cyanide and 267 g of potassium cyanide in 1.3 1 of water, during which step strong frothing occurs. The mixture is agitated for 30 minutes at room temperature, brought to pH 2.8 by adding concentrated hydrochloric acid, the precipitated copper salts are vacuum-filtered, the filtrate is brought to pH 0.5 by further addition of hydrochloric acid, and the mixture is agitated for several hours in an ice bath. The thus-formed precipitate is vacuum-filtered and, after washing with water, suspended in 3 1 of water, extensively dissolved by adding concentrated ammonia, active carbon is added, and the mixture is allowed to stand under agitation at room temperature for 30 minutes. The mixture is vacuum-filtered, the filtrate is combined with excess concentrated hydrochloric acid, allowed to stand under agitation in an ice bath for several hours, and the precipitate is vacuum-filtered and dissolved in water-moist form in 1.3 1 of acetone. After several hours of agitation in an ice bath, the crystallized product is vacuum-filtered, washed with ice-cold acetone, and dried at 50° C., thus obtaining 141 g (=81% of theory) of 5-cyano-3-hydroxymethyl-2,4,6-triiodobenzoic acid as a white powder, mp 250-252° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([NH:40][S:41]([C:44]1[S:48][C:47](Br)=[CH:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])[CH3:38].CCCCCC>C1(C)C=CC=CC=1>[C:37]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=3)[CH:22]=2)=[CH:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:36])[CH3:38]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)cc3)cc(C(F)(F)F)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
A stirred mixture of 4-(4-fluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.14) (0.34 g, 0.57 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.19 g, 0.63 mmol), tetrakis(triphenyl-phosphine)palladium (0.039 g, 0.033 mmol) in toluene (5 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.37 g) as a white solid.
Reaction SMILES: [K].[SH:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Br[CH2:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][N:15]=1>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:21][O:20][C:19]1[C:14]([CH2:13][S:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[N:15][CH:16]=[CH:17][C:18]=1[O:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCOc1ccnc(CBr)c1OC
Reactant: Sc1nc2ccccc2[nH]1
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of potassium salt of 2-mercaptobenzimidazole (0.4 g) in dimethylformamide (5 ml), was added dropwise a solution of 2-bromomethyl-3-methoxy-4-propoxypyridine (0.4 g) in dimethylformamide, and stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform (50 ml), washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol (50:1)) to give 2-[(3-methoxy-4-propoxypyrid-2-yl)methylthio]benzimidazole (0.35 g) as a light brown oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH2:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>O.CO>[OH:31][C@@H:21]1[C@H:22]([OH:30])[C@@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH2:24][C@H:20]1[N:17]1[CH:16]=[N:15][C:14]2[C:18]1=[N:19][C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)=[N:12][C:13]=2[NH:32][CH2:33][CH:34]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)c1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)O)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution comprising 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 173 step 1) (0.4 g, 0.64 mmol) in water (3 ml) is treated with 1M KOH in MeOH (6 ml) and stirred at room temperature for 48 h. The solvent is removed in vacuo and the resulting crude product is dissolved in water (5 ml) and acidified to pH 3-4 with 1.5N HCl. The solution is extracted with EtOAc and the organic portion is dried over sodium sulphate and concentrated in vacuo. Purification by chromatography on silica eluting with 5% MeOH in chloroform affords the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][CH:19]=1)#[N:2].[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C>[NH:36]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:19]=2)=[N:2][N:38]=[N:37]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1Sc1ccccc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Sc1ccccc1-c1nnn[nH]1)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 64.6 %

Procedure:
In 20 ml of DMF were dissolved 1.35 g of N-[2-(2-cyanophenylthio)phenyl]-4-(4-phenylbutoxy)benzamide, 0.55 g of sodium azide and 0.46 g of ammonium chloride, and the mixture was stirred at 110°-115° C. for 5 hours. Then, 0.18 g of sodium azide and 0.15 g of ammonium chloride were further added and the mixture was stirred at 110° to 115° C. for 2 hours. After addition of ice-water, the reaction mixture was neutralized with diluted hydrochloric acid and the precipitate was collected by filtration and recrystallized from ethanol to give 0.95 g of the title compound, m.p. 156°-159° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10]([CH2:13][CH:14]1[CH2:17][NH:16][CH2:15]1)(=[O:12])=[O:11].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.CCOC(C)=O.C(OCC)C.O>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10]([CH2:13][CH:14]1[CH2:15][N:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:21])[CH2:17]1)(=[O:12])=[O:11]
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1F
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=C(CN1CC(CS(=O)(=O)c2ccc(F)cc2F)C1)c1ccc(F)cc1
Yield: 13.6 %

Procedure:
3-{[(2,4-Difluorophenyl)sulfonyl]methyl}azetidine hydrochloride (60 mg, 0.21 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (52 mg, 0.23 mmol) were stirred together at room temperature with K2CO3 (90 mg, 0.65 mmol) in DMF (3 mL) under an inert atmosphere. Water was added to the mixture after 5.5 h and the mixture was then extracted with EtOAc. The organic extracts were washed with water and saturated brine then dried (MgSO4), filtered and concentrated in vacuo. The resultant material was purified using preparative thin layer chromatography on silica eluted with 50% EtOAc-isohexane to give the free base. This was then dissolved in EtOAc and treated with 1M HCl in diethyl ether. The solids was filtered off and dried in vacuo to give 2-(3-{[(2,4-difluorophenyl)sulfonyl]methyl}azetidin-1-yl)-1-(4-fluorophenyl)ethanone hydrochloride as a colourless solid (12 mg). 1H NMR (500 MHz, d6-DMSO) δ 3.09–3.19 (2H, m), 3.95 (2H, d, J=7.1 Hz), 4.01–4.16 (2H, br s), 4.17–4.29 (2H, m), 5.06 (2H, s), 7.40–7.47 (3H, m), 7.70–7.75 (1H, m), 7.91–7.94 (1H, m), 7.99–8.02 (2H, m), 10.72 (1H, br s). m/z (ES+) 384 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2(O)[CH:22]=[CH:21][NH:20][C:19](=[O:23])[NH:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]>C(O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2(O)C=CNC(=O)N2)cc1OC1CC2CCC1C2
Solvent: CCO
Product: COc1ccc(-c2cc[nH]c(=O)n2)cc1OC1CC2CCC1C2
Temperature: 25 °C
Yield: 31.5 %

Procedure:
The hydroxypyrimidinone of Example 60 (0.2 g, 0.61 mmol) is dissolved in 5 ml ethanol, treated with 2.5 ml 1N NCl and refluxed for 6 hours. The reaction is cooled to room temperature, quenched with water and the product extracted 3× ethyl acetate. The organics are washed, dried, filtered and concentrated in vacuo to yield a crude substance which is crystallized from ethyl acetate to give 60 ml (31.5%) of the pyrimidinone as a crystalline solid. This material is a 7:3 mixture of endo-exo bicycloalkyl isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([S:13]([NH2:16])(=[O:15])=[O:14])[S:10][N:9]=1.[C:17](OCC)(OCC)([O:19][CH2:20][CH3:21])[CH3:18]>>[CH2:17]([O:19][C:20](=[N:16][S:13]([C:11]1[S:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:12]=1)(=[O:14])=[O:15])[CH3:21])[CH3:18]
Reactant: NS(=O)(=O)c1nc(-c2ccccc2Cl)ns1
Reactant: CCOC(C)(OCC)OCC
Product: CCOC(C)=NS(=O)(=O)c1nc(-c2ccccc2Cl)ns1

Procedure:
A mixture of 3 g of 3-(2-chlorophenyl)-1,2,4-thiadiazole-5-sulfonamide and 11 ml of triethyl orthoacetate was warmed to reflux for 3.5 hours. The mixture was cooled, triturated with hexane (25 ml) and filtered to give 3.13 g of solid, m.p. 70°-72° C.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[OH:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1B(O)O)([CH3:44])[CH3:43]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:25]([OH:26])[C:3]2[C:4]3[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:7](=[O:21])[N:6]([CH3:22])[C:5]=3[N:23]=[CH:24][C:2]=2[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH:42]([CH3:44])[CH3:43])=[CH:28][CH:29]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Reactant: CC(C)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)c1ccccc1-c1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 80 °C
Yield: 93 %

Procedure:
To a mixture of 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 0.093 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol) and aq. 2N K3PO4 (0.4 mL) in dioxane (2 mL) was added 2-isopropylphenylboronic acid (30 mg, 0.183 mmol). The reaction was heated at 80° C. for 18 h, cooled to RT and filtered. The filtrate was extracted with EA (2×20 mL). The combined organic layers were washed with water (20 mL) and brine (15 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give 5-((4-chloro phenyl) (hydroxy)methyl)-6-(2-isopropylphenyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 93% yield) as a white solid.