Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[C:26]([F:39])[C:25]=1[OH:40]>>[ClH:1].[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]2)[CH:27]=[C:26]([F:39])[C:25]=1[OH:40]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](O)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](O)CC1
Product: Cl

Procedure:
Following general procedure II, 1-[6-chloro-4-(trans-4-hydroxycyclohexylamino)-1,5-naphthyridin-3-yl]ethanone (160 mg, 0.50 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (160 g, 0.60 mmol) followed by formation of the hydrochloride salt to afford the desired product (120 mg, 57%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.11 (s, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.30 (d, J=9.0 Hz, 1H), 8.11 (s, 2H), 5.60 (dq, J=10.1, 4.5 Hz, 1H), 4.94-4.83 (m, 1H), 3.75 (tt, J=7.6, 3.9 Hz, 1H), 3.66 (s, 2H), 3.41-3.31 (m, 1H), 2.75 (s, 3H), 2.38 (dd, J=9.0, 5.3 Hz, 2H), 2.14-2.07 (m, 2H), 2.03 (s, 1H), 1.74-1.57 (m, 4H); ESI MS m/z 446 [M+H]+; HPLC 96.7% (AUC), tR=11.1 min.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C:8]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:17][O:16][C:14]([C:8]1([CH2:7][C:6]([OH:18])=[O:5])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:15]
Reactant: COC(=O)C1(CC(=O)OC(C)(C)C)CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(CC(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.5 %

Procedure:
To a solution of methyl 4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.1 g, 4.26 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (5.0 mL) and the resulting solution was stirred at rt for 5 h. The mixture was concentrated under reduced pressure to afford [4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid (900 mg, 94%), which was used in the next step without further purification. LC-MS ret. time 0.93 min, m/z 202.9 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.60-1.70 (m, 2H), 2.10-2.15 (m, 2H), 2.68 (s, 2H), 3.62-3.71 (m, 2H), 3.72 (s, 3H), 3.79-3.86 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[S:14][C:13]([CH2:15][NH:16][CH2:17][C:18]3[NH:19][C:20](=[O:28])[C:21]4[CH2:27][O:26][CH2:25][CH2:24][C:22]=4[N:23]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[F:29][C:30]1[CH:47]=[CH:46][C:33]([C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]2)=[O:35])=[CH:32][CH:31]=1.CC#N.O>C(O)=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([CH:36]2[CH2:37][CH2:38][N:39]([CH2:42][C:43]([N:16]([CH2:15][C:13]3[S:14][C:10]([S:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)(=[O:9])=[O:8])=[CH:11][CH:12]=3)[CH2:17][C:18]3[NH:19][C:20](=[O:28])[C:21]4[CH2:27][O:26][CH2:25][CH2:24][C:22]=4[N:23]=3)=[O:44])[CH2:40][CH2:41]2)=[O:35])=[CH:46][CH:47]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c(CNCc2ccc(S(=O)(=O)N3CCOCC3)s2)nc2c1COCC2
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)Cc2ccc(S(=O)(=O)N3CCOCC3)s2)CC1

Procedure:
Following general procedure of Example 5, the title compound was prepared (0.044 g) from 2-(((5-(morpholinosulfonyl)thiophen-2-yl)methylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. 1H NMR (400 MHz, MeOD) δ ppm 8.04-8.16 (m, 2H), 7.33-7.59 (m, 1H), 7.23-7.31 (m, 2H), 7.05-7.15 (m, 1H), 4.84-4.89 (m, 2H), 4.54-4.63 (m, 2H), 4.36-4.52 (m, 4H), 3.85-3.98 (m, 2H), 3.67-3.83 (m, 6H), 3.17-3.28 (m, 3H), 2.87-2.98 (m, 4H), 2.47-2.67 (m, 2H), 1.98-2.26 (m, 4H). HRMS calculated for C31H37F1N5O7S2 674.2118. found (ESI, [M+H]+) 674.2119. MS (ESI) m/z 674.2. (M+H)+. Retention time: 3.3 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [O:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([CH2:13][N:14]2[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]2=[O:24])[CH2:5][N:4]3[CH2:3][CH2:2]1.[Br:25]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:25][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([O:1][CH2:2][CH2:3][N:4]3[CH2:5][CH:6]2[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cccc1c32
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cc(Br)cc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (rac)-2-(2,3,5,6-tetrahydro[1,4]oxazino[2,3,4-hi]indol-6-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.030 g, 0.094 mmol) in DMF (1.0 mL) was added the solution of N-bromosuccinimide (0.018 g, 0.098 mmol). The reaction mixture was stirred at room temperature for 1 hour and water (10.0 mL) was added. The aqueous solution was extracted with EtOAc (3×) and the combined EtOAc solution was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness to give 0.035 g (94%) of light yellow oil as the desired product: 1H NMR (400 MHz, CDCl3) δ 7.82-7.79 (m, 2 H), 7.70-7.63 (m, 2 H), 6.81 (s, 1 H), 6.70 (s, 1 H), 4.34-4.29 (m, 2 H), 3.93-3.81 (m, 2 H), 3.63-3.59 (m, 1 H), 3.27-3.23 (m, 1 H), 3.19-3.15 (m, 1 H), 3.05-3.00 (m, 1 H), 2.98-2.89 (m, 1 H); MS (EI) m/z 399 (M++H), 401 (M++H).
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[OH:8][CH2:9][CH2:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C>[CH:12]1([N:11]([CH2:10][CH2:9][OH:8])[C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][Br:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OCCNC1CCCCC1
Reactant: O=C(Cl)/C=C/CBr
Solvent: CCOCC
Product: O=C(/C=C/CBr)N(CCO)C1CCCCC1

Procedure:
Into 100 ml of diethylether was added 19 g of γ-bromocrotonylchloride, while the mixture was stirred at 0°-10° C., 25 g of N-(2-hydroxyethyl)cyclohexylamine was added dropwise. After the addition then the reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was extracted with ether and the ether extract was washed with 2 N-HCl, a diluted NaHCO3 aqueous solution saturated with NaCl, and water in this order. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed by distillation. 17.5 Grams of N-cyclohexyl-N-(2-hydroxyethyl)-γ-bromocrotonamide was obtained as an oil substance. The chemical stracture of this substance was identified by the NMR spectrum and the data of elementary analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1ccccc1F
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccccc1F
Temperature: 25 °C

Procedure:
To a mixture of 3-(2-fluorophenyl)propionic acid (18.64 g, 0.111 mol) and dimethylformamide (5 drops) at room temperature was added dropwise oxalyl chloride (60 mL). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-fluorophenyl)propionyl chloride. A solution of the 3-(2-fluorophenyl)propionyl chloride in dichloromethane (230 mL) was added dropwise to a mixture of aluminum chloride (16.25 g, 0.12 mol) in dichloromethane (230 mL), and the mixture was refluxed for 3.5 h. The reaction mixture was poured into ice water (1200 mL), and the two phases were separated. The dichloromethane phase was washed successively with 0.1N aqueous sodium hydroxide (2×100 mL), water (200 mL), and brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual oil was chromatographed on silica gel eluting with hexane:dichloromethane (9:1) to give 11.0 g of crude 4-fluoro-1-indanone as a yellow solid. Recrystallization from acetone:water mixtures gave 8.02 g (48%) of 4-fluoro-1-indanone as a pale yellow solid: m.p., 71-72° C.; NMR (DMSO-d6): d 7.51 (m, 3H, Ar), 3.13 (t, 2H, CH2), 2.74 (t, 2H, CH2).
Reaction SMILES: O[C:2]([C:5]1[S:9][C:8](=[O:10])[S:7][C:6]=1[C:11]1[C:12](=[O:21])[NH:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:4])[CH3:3].C(OC(Cl)=O)C1C=CC=CC=1>C(Cl)Cl>[CH3:4][C:2]1([CH3:3])[O:21][C:12]2[C:11](=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]2[S:7][C:8](=[O:10])[S:9][C:5]1=2
Reactant: CC(C)(O)c1sc(=O)sc1-c1nc2ccccc2[nH]c1=O
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC1(C)Oc2nc3ccccc3nc2-c2sc(=O)sc21
Reaction time: 8 h

Procedure:
3-(5-(2-Hydroxypropan-2-yl)-2-oxo-1,3-dithiol-4-yl)quinoxalin-2(1H)-one (6) (130 mg, 0.405 mmol) was partially dissolved in CH2Cl2 (10 mL). Benzylchloroformate (125 μL, 0.81 mmol) and triethylammine (120 μL) were added and the resulting yellow solution was stirred overnight. The volume of the solution was reduced to ca. 3 mL and it was purified by chromatography (silica gel, CH2Cl2) to give pure 4,4-Dimethyl-4H-5-oxa-1,3-dithia-6,11-diaza-cyclopenta[a]anthracen-2-one (7). Yield: 82 mg (70%).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5]1=[O:20].[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH2:33][O:34][CH2:35][O:36][CH3:37])[C:28]=1[S:29]([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[CH:17]1([CH2:16][NH:15][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]([OH:14])=[C:4]([C:3]3[NH:23][C:24]4[S:25][CH:26]=[C:27]([CH2:33][O:34][CH2:35][O:36][CH3:37])[C:28]=4[S:29](=[O:31])(=[O:30])[N:32]=3)[C:5]2=[O:20])[CH2:18][CH2:19]1
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Reactant: CSC(SC)=C1C(=O)c2ccccc2N(NCC2CC2)C1=O
Solvent: C1COCCO1
Product: COCOCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Yield: 52.3 %

Procedure:
A solution of the product of Example 353B (500.3, 1.5 mmol) and the product of Example 309G (377.62 mg, 1.5 mmol) in dioxane (15 mL) was stirred at reflux for 1.5 hours and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 0% to 10% ethyl acetate/dichloromethane to give the title compound (384.7 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 1.01 (m, 1 H) 2.84 (d, J=6.99 Hz, 2 H) 4.64 (s, 2 H) 4.71 (s, 2 H) 6.36 (br s, 1 H) 7.42 (m, 2 H) 7.86 (m, 1 H) 8.07 (d, J=8.46 Hz, 1 H) 8.16 (m, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O>>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCOS(C)(=O)=O)CC1

Procedure:
tert-Butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (Intermediate 121, 2.38 g, 9.8 mmol) was reacted with methanesulfonyl chloride (0.91 mL, 11.7 mmol) in the presence of triethylamine (1.9 mL, 13.7 mmol) as described for Intermediate 6. The crude product was used without further purification for the next step.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Sc1ccccc1Cl
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cc(C)cc(Sc2ccccc2Cl)c1
Yield: 86.4 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), 2-chlorothiophenol (145 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3,5-dimethylphenyl 2-chlorophenyl sulfide (215 mg, 87% yield) as colorless liquid. Column chromatographic solvent (hexane). Rf=0.5 (hexane/ethyl acetate=50/1). 1H NMR (CDCl3, 300 MHz) δ 7.32-7.36 (m, 1 H), 7.05-7.10 (m, 4 H), 6.97 (s, 1 H), 6.88-6.92 (m, 1 H), 2.30 (s, 6 H). 13C NMR (CDCl3, 75 MHz) δ 139.5, 137.4, 132.7, 131.7, 131.5, 130.6, 129.8, 129.6, 127.3, 126.9, 21.6. IR (neat, cm−1) 3060, 3037, 2950, 2917, 2860. MS (EI) m/z (relative intensity) 250 (30), 248 (100).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1OCCOCC1CC1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1ccc(OCCOCC2CC2)cc1
Yield: 74 %

Procedure:
Following the procedure of Example I, 1-{4-[2-(cyclopropylmethoxy)-ethoxy]-phenoxy}-2,3-epoxy-propane is prepared and then treated with t-butylamine. 7.6 g (yield=74%) of crude 1-{4-[2-(cyclopropylmethoxy)-ethoxy]phenoxy}-3-t-butylamino-propan-2-ol are thus obtained, and this material is converted to the fumarate by mixing stoichiometric amounts of the base and of the acid in solution in isopropanol. The neutral fumarate which has precipitated is filtered off and recrystallised from ethanol (yield=80%), M.p.=158°-160° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f22) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH3:22]>O1CCCC1.CN(C)C=O>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:22])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccc(OC(F)F)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(OC(F)F)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 8.70 g (40.6 mmol) 3-(4-difluoromethoxy-phenyl)-acrylic acid in 60.0 ml tetrahydrofuran and 0.6 ml N,N-dimethylformamide a solution of 5.14 ml (60.9 mmol) oxalyl chloride in 10 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 150 ml of a 25% aqueous ammonia solution. The separating oil was collected and stirred for 30 min. with water. The precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 4.7 g (54%) 3-(4-Difluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: Br[CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:2]2[S:23][C:22]([NH2:24])=[N:21][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[CH:15][CH:16]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(Br)Cc2ccc(F)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)sc2Cc2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-3-(4-fluoro-phenyl)-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 2 hours, hold overnight, filtered, washed with water, and dried to obtain a product. A single spot was shown by TLC. The product was not further purified. The product was a white solid in a yield of 81.9%, mp: 199-201 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 3.76 (3H, s, OCH3), 4.03 (2H, s, CH2), 6.84 (2H, s, NH2), 6.94 (2H, d, J=8.96 Hz, ArH), 7.13 (2H, t, 3JFH=3JHH=8.96 Hz, ArH), 7.23 (2H, dd, 3JHH=8.72, 4JFH=5.64 Hz, ArH), 7.46 (2H, d, J=8.96 Hz, ArH); EI-MS m/e (%): 314.2 (M+, 100), 109.1 (12); HREI-MS Calcd. for C17H15FN2OS: 314.0889. found: 314.0890. Anal. Calcd. for C17H15FN2OS: C, 64.95; H, 4.81; N, 8.91. found: C, 65.10; H, 5.24; N, 8.98.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br:7][C:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([Cl:17])[C:11]=2[NH:10][C:9]=1[CH3:19].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>CN(C=O)C.ClCCl>[Br:7][C:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([Cl:17])[C:11]=2[N:10]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[C:9]=1[CH3:19]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc(Cl)c2[nH]c(C)c(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1nc(Cl)c2c(n1)c(Br)c(C)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.82 g; 45.60 mmol; 60% in oil, washed with hexane), is suspended in dry DMF (125 mL) and dry DMSO (25 mL). To the stirring suspension 7-Bromo-4-chloro-2,6-dimethyl-5H-pyrrolo[3,2-d]pyrimidine from example A8 (10.00 g; 38.00 mmol) dissolved in dry DMF (125 mL) is added dropwise within 30 minutes at ambient temperature. After complete addition the reaction mixture is stirred for one hour at ambient temperature. To the resulting solution 2-(trimethylsilyl)ethoxymethylchloride (8.74 mL; 49.40 mmol) is added dropwise and the reaction mixture is stirred for one hour at ambient temperature. After diluting with water/ice and dichloromethane, the organic layer is separated and the aqueous layer is extracted with dichloromethane (2×400 mL). The combined organic layers are dried over MgSO4 and filtered through a plug of neutral alumina (act. 2-3). The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (cyclohexane:ethylacetate/9:1) affording the title compound as a white solid.
Reaction SMILES: NNC(=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])C1C=CC(S(C)(=O)=O)=CC=1.[O:22]=S(Cl)Cl.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33].C(N(CC)CC)C.Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:21][C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Cl:26])=[O:22])=[N:14][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(=Nc2ccccc2Cl)NN)cc1
Reactant: Nc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Cl)c1ccc(Cl)cn1
Reaction time: 2 h

Procedure:
A mixture of 5-chloropyridine-2-carboxylic acid 5 (1.0 g, 6.35 mmol) and SOCl2 (2.4 mL) in DCM (10 mL) was stirred for 2 hours and concentrated. The residue was dissolved in DCM (20 mL). To the solution was added 2-chlorobenzenamine (1.0 g, 7.84 mmol) and then triethylamine (2.0 mL, 14.43 mmol). The reaction mixture was stirred overnight at ambient temperature and ethyl acetate (50 mL) was added followed by 1N HCl (10 mL). The organic phase was washed with water and brine, dried and concentrated under reduced pressure to yield a light yellow solid. Yield: 0.8 g, 47%. 5-chloro-N-(2-chlorophenyl)pyridine-2-carboxamide 6 was used for the next step without further purification.
Reaction SMILES: CS(C)=O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([C@H](N)C(O)=O)CC(N[C@H](C(NCC(O)=O)=O)CS)=O.[CH3:45][CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]([OH:69])/[CH:51]=[CH:52]/[C@@H:53]1[C@@H:57]([CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65])[C@H:56]2[O:67][O:68][C@@H:54]1[CH2:55]2>C(O)(C)C>[CH3:45][CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]([OH:69])/[CH:51]=[CH:52]/[C@@H:53]1[C@@H:57]([CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65])[C:56](=[O:67])[CH2:55][C@H:54]1[OH:68]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H]2C[C@H]1OO2
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 0.01 h

Procedure:
Prostaglandin E synthase microsomal fractions are prepared from CHO—K1 cells transiently transfected with plasmid encoding the human mPGES-1 cDNA. Microsomes are then prepared and the PGES assay begins with the incubation of 5 μg/ml microsomal PGES-1 with compound or DMSO (final 1%) for 20-30 minutes at room temperature. The enzyme reactions are performed in 200 mM KPi pH 7.0, 2 mM EDTA and 2.5 mM GSH-reduced form. The enzymatic reaction is then initiated by the addition of 1 μM final PGH2 substrate prepared in isopropanol (3.5% final in assay well) and incubated at room temperature for 30 seconds. The reaction is terminated by the addition of SnCl2 in 1N HCl (1 mg/ml final). Measurement of PGE2 production in the enzyme reaction aliquots is done by EIA using a standard commercially available kit (Cat #: 901-001 from Assay Designs).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[OH-:9].[Na+].[CH2:11]([NH2:14])[CH2:12][NH2:13].Cl>O>[CH2:11]([NH:14][CH:3]([C:4]([OH:6])=[O:5])[CH2:2][C:1]([OH:7])=[O:9])[CH2:12][NH:13][CH:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: NCCN
Reactant: O=C(O)/C=C\C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(NCCNC(CC(=O)O)C(=O)O)C(=O)O
Temperature: 140 °C

Procedure:
A beaker was charged with maleic acid (120.5 g, 1.03 mole); deionized water (120 g); and 50 percent aqueous NaOH (167 g, 2.08 mole). The mixture was stirred until dissolution occurred; the resulting solution was transferred to a 1-liter, stainless-steel autoclave, using 40 g deionized water as a rinse. Ethylenediamine (31.0 g, 0.51 mole) was added over a ten-minute period; and the autoclave was sealed. The mixture was stirred and heated at 140° C. for nine hours and then allowed to cool to ambient temperature. The product solution was acidified to a pH of about 2 with 37 percent aqueous HCl, resulting in the precipitation of racemic/meso EDDS acid. When the precipitation was complete, the product was removed by filtration; washed with deionized water (2×300 mL); and dried overnight under vacuum at 60° C. The yield of EDDS acid, shown to be pure by 1H- and 13C-nmr, was 108 g (0.37 mole, 72 percent).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12](Cl)[N:7]2[N:6]=1)=[N+:2]=[N-:3].NC(N)=[S:18]>C(O)C>[N:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:18])[N:7]2[N:6]=1)=[N+:2]=[N-:3]
Reactant: NC(N)=S
Reactant: Cc1cc(Cl)n2nc(CN=[N+]=[N-])nc2n1
Solvent: CCO
Product: Cc1cc(S)n2nc(CN=[N+]=[N-])nc2n1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
2-Azidomethyl-7-chloro-5-methyl[1.2.4]triazolo-[1,5-a]pyrimidine (2.98 g) are suspended in 70 ml of ethanol, treated with 1.1 g of thiourea and heated at reflux for 45 minutes. The reaction mixture is stirred in an ice bath for 30 minutes. The resulting precipitate is filtered off under suction and dried in a vacuum at 40° C. There are obtained 2.76 g of 2-azidomethyl-5methyl[1.2.4]triazolo[1,5-a]pyrimidine-7-thiol as yellow crystals of melting point 214°-215° C.