Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]([O:5][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CCCCCCCCCCCCCCCO
Product: C=CC(=O)OCCCCCCCCCCCCCCC
Temperature: 60 °C

Procedure:
Pentadecyl acrylate was prepared by esterification of acrylic acid with 1-pentadecanol under standard conditions. Crude monomer was recrystallized from three volumes of ethanol and dried in vacuo. Ten grams of pentadecyl acrylate was dissolved in 20 ml of oxygen free ethylacetate containing 0.10 grams of azobis-isobutylnitrile (hereinafter AIBN) and stirred in a sealed bottle maintained at 60° C. for 24 hours. The resulting polymer was isolated by precipitation into cold ethanol and dried in vacuo. Analysis of the polymer showed it to have a first order transition temperature of 29° C., a heat of fusion of 59 J/g and a molecular weight of about 175,000 in an uncured state.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].B1C2CCCC1CCC2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:33]1[C:34]([CH3:72])([CH3:71])[C@H:35]2[C@:48]([CH3:51])([CH2:49][CH:50]=1)[C@@H:47]1[C@:38]([CH3:70])([C@@:39]3([CH3:69])[C@H:44]([CH2:45][CH2:46]1)[C@H:43]1[C@H:52]([C:55]([CH3:57])=[CH2:56])[CH2:53][CH2:54][C@:42]1([NH:58][CH2:59][CH2:60][N:61]1[CH2:66][CH2:65][S:64](=[O:68])(=[O:67])[CH2:63][CH2:62]1)[CH2:41][CH2:40]3)[CH2:37][CH2:36]2)(=O)=O.C(Cl)Cl>C1COCC1.O1CCOCC1.O.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]>[O:68]=[S:64]1(=[O:67])[CH2:65][CH2:66][N:61]([CH2:60][CH2:59][NH:58][C@:42]23[CH2:54][CH2:53][C@@H:52]([C:55]([CH3:57])=[CH2:56])[C@@H:43]2[C@@H:44]2[C@@:39]([CH3:69])([CH2:40][CH2:41]3)[C@@:38]3([CH3:70])[C@@H:47]([C@:48]4([CH3:51])[C@@H:35]([CH2:36][CH2:37]3)[C:34]([CH3:71])([CH3:72])[C:33]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])=[CH:50][CH2:49]4)[CH2:46][CH2:45]2)[CH2:62][CH2:63]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CCCCC(=O)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCCCCC(=O)OC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
A solution of methyl hex-5-enoate (21.4 mg, 0.167 mmol) in THF (3 mL) under argon was cooled to 0° C. and 9-BBN (0.5 M in THF) (0.356 mL, 0.178 mmol) was added dropwise. The reaction mixture was warmed to rt and was stirred for 2 h. A solution of potassium phosphate tribasic (1M) (0.278 mL, 0.278 mmol) was added to the reaction mixture followed by a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (80 mg, 0.111 mmol) in dioxane (3.00 mL). PdCl2(dppf).CH2Cl2 adduct (4.5 mg, 5.6 μmol) was then added and the reaction mixture was stirred for 16 h at 85° C. The reaction mixture was cooled to room temperature and was diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (sodium sulfate) and concentrated under vacuum. The product was purified by column chromatography on silica gel (0%>50% ethyl acetate in hexanes) to afford methyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)hexanoate (48.2 mg, 62% yield). LC/MS: m/e 699.5 (M+H)+, 2.45 min (method 3).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[NH2:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18]([Cl:25])[N:17]=1>C1(C)C=CC=CC=1>[C:5]([N:22]1[CH:21]=[N:20][C:19]2[C:23]1=[N:24][C:16]([NH2:15])=[N:17][C:18]=2[Cl:25])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)n1cnc2c(Cl)nc(N)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 204.2 g (2.00 mol) of acetic anhydride, 202.4 g (2.00 mol) of triethylamine and 169.6 g (1.00 mol) of 2-amino-6-chloropurine was stirred at 80° C. for 1 hour. The resulting suspension was cooled at 25° C., and thereafter diluted with 400 mL of toluene, and the diluted solution was filtered. The resulting crystals were suspended in 300 mL of isopropanol, and the suspension was filtered again. The resulting crystals were dried at 60° C. under reduced pressure, to give 211.8 g of white powder of 9-acetyl-2-amino-6-chloropurine (yield 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[CH3:14].[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:15]([C:13]1[C:2]([CH3:1])=[C:3]([CH3:14])[C:4]2[O:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]=2[CH:12]=1)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1ccc2c(c1C)OC(C(=O)O)C2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(C(=O)CC(C)C)cc2c(c1C)OC(C(=O)O)C2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,3-dihydro-6,7-dimethylbenzofuran-2-carboxylic acid (9 g.) and isovaleryl chloride (7.5 g.) in dichloromethane (100 ml.) at 5°C. is added aluminum chloride (20 g.) in portions over a 1 hour period. The reaction mixture is stirred at 25° for 18 hours then poured into a mixture of ice (300 g.) and hydrochloric acid (50 ml.) affording 9 lg. of 2,3-dihydro-5-isovaleryl-6,7-dimethyl-benzofuran-2-carboxylic acid which melts at 117° after recrystallization from methylcyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: Clc1cccc2cc[nH]c12
Agent: Cl
Solvent: O
Product: Clc1cccc2c(C3=CCNCC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 7-chloroindole (0.70 g, 4.6 mmol) and 4-piperidone hydrochloride hydrate (1.4 g, 9.2 mmol). The product was isolated as a yellow solid. Yield 0.80 g (75%). mp 205°-208° C. FDMS m/e=234 (M+ of free base).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH2:31]([O:33][C:34]1[N:39]=[CH:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][N:35]=1)[CH3:32].CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:37]3[CH:36]=[N:35][C:34]([O:33][CH2:31][CH3:32])=[N:39][CH:38]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(OCC)nc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 120 °C
Yield: 67.1 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.17 mmol), 2-ethoxy-5-tributylstannanyl-pyrimidine (107 mg, 0.26 mmol) and PdCl2(PPh3)2 (24 mg, 0.034 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-15% EtOAc/CH2Cl2) to give 58 mg of the title compound. MS: (+) m/z 509.44 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[Cl:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:18])=[CH:14][C:13]=1[Cl:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Nc1ccc(C(=O)O)cc1Cl)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(NC(=O)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
4-Benzyloxycarbonylamino-3-chlorobenzoic acid (0.80 g) was dissolved in N,N-dimethylformamide (24.0 ml) and admixed at room temperature with t-butyl glycinate (0.44 g) and triethylamine (0.77 ml). Diethyl cyanophosphate (0.43 ml) was added with ice-cooling, and the mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined and washed three times with water and then twice with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield t-butyl N-(4-benzyloxycarbonylamino-3-chlorobenzoyl)glycinate (0.93 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([F:26])([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-])=O)[C:9](OC)=[O:10])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2([F:26])[C:13]3[C:14](=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[NH:23][C:9]2=[O:10])[CH:7]=1
Reactant: COC(=O)C(F)(c1cc(Cl)ccc1OC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1(F)C(=O)Nc2cc(C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A 250-mL 3-necked round-bottomed flask, equipped with a stir bar and thermocouple was charged with 5-chloro-α-fluoro-2-methoxy-α-[2-nitro-4-(trifluoromethyl)-phenyl]benzeneacetic acid, methyl ester (12.5 g, 29.64 mmol) and dissolved in THF (50 mL). Tetrabutylammonium chloride (0.84 g, 3.01 mmol) was dissolved in water (50 mL) and added to the THF solution. The reaction mixture was heated to about 60° C. and sodium dithionite (24.0 g, 118 mmol) was added portion wise as a solid over 75 minutes while stirring vigorously. After 5 minutes HPLC analysis showed that the reaction was complete. The reaction mixture was cooled to room temperature and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic layers were treated with 1N methanolic HCl (15 mL) and heated to 55° C. for a few minutes. HPLC analysis showed that the cyclization was complete. THF and methanol were removed by concentrating on a rotary evaporator and the resultant residue was dissolved in ethyl acetate (100 mL) and hexane (100 mL). The organic layer was washed with 1N NaOH (2×50 mL), 1N HCl (2×50 mL), water (2×50 mL), saturated sodium chloride solution (50 mL), and dried over MgSO4. The solution was then diluted with hexane (100 mL), treated with activated charcoal (5.0 g), heated to about 60° C. for 5 minutes, cooled to room temperature, filtered through Celite, and concentrated on a rotary evaporator to afford 10.54 g (99%) of crude product as a foam. This material was dissolved in ethanol (20 mL) and heated to reflux and water was slowly added (10 mL). Preferably, a seed crystal of the title compound was added resulting in crystallization of the product at about 75° C. The material was stirred for 16 hours at room temperature and then filtered, washed with 1:1 ethanol/water (40 mL), air and vacuum dried to afford 7.77 g of the title compound (73% yield, 97.5% by HPLC) as a white crystalline solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:9][C:10]([C:12]1[S:16][CH:15]=[N:14][CH:13]=1)=[O:11])[CH2:7][CH3:8].[Cl:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][CH2:24]S(C2C=CC(Cl)=CC=2)(=O)=O)=[CH:20][CH:19]=1.C(OC(=O)C)C>CCCCCC.O1CCCC1>[CH2:6]([N:9]([CH2:24][CH2:23][O:22][C:21]1[CH:35]=[CH:36][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:10]([C:12]1[S:16][CH:15]=[N:14][CH:13]=1)=[O:11])[CH2:7][CH3:8]
Reactant: O=S(=O)(CCOc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCCNC(=O)c1cncs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(CCOc1ccc(Cl)cc1)C(=O)c1cncs1
Yield: 74.5 %

Procedure:
Butyl lithium (1.6 M, 7.5 ml) in hexane was added to a solution of the N-propyl thiazole-5-carboxamide (1.7 g, 10 mmol) obtained in A in tetrahydrofuran (80 ml) at -78° C. under an atmosphere of nitrogen. The resultant solution was stirred for 10 minutes and then allowed to warm to room temperature whereupon the 2-(4-chlorophenoxy)-1-(4-chlorophenylsulphonyl)ethane (5.20 g, 15 mmol) obtained in B dissolved in tetrahydrofuran (40 ml) was added. The resultant solution was then refluxed for 5 days. On cooling, the solvent was evaporated and the residue dissolved in 1:4 water: ethyl acetate (500 ml). The organic layer was washed with saturated sodium chloride solution, dried (MgSO4) and the solvent evaporated to leave an oil which, after flash chromatography on silica gel with 1:2 ethylacetate: petroleum ether as the eluant, yielded the desired product (2.42 g). Mass spectroscopy revealed the mass/charge ratio of the parent molecule ion, M+, to be 324 thereby confirming the molecular weight of the product to be 324.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1.BrN1C(=O)CCC1=O.N1C=CC=CC=1.NC1NC(=O)C2C3C=C(Br)C=CC=3C=CC=2N=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1cc(Br)ccc1CC2
Agent: Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1

Procedure:
A mixture of 9-Bromo-5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-one (1.0 g, 3.4 mmoles), N-bromosuccinimide (0.63 g, 3.5 mmoles) and pyridine (0.3 ml, 3.7 mmoles) in dry benzene (350 ml) was reacted in the same manner as for the corresponding 3-pivalamide (Example 2). After cooling, benzene and excess pyridine were removed under reduced pressure. The residue was triturated with methanol:water (1:1) and filtered to leave a crude product which was recrystallized from methanol to give 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one as an off-white solid. (0.47 g, 37%) 1H NMR (DMSO-d6, 200 MHz) δ: 2.57 (s, 3H, CH3); 7.73 (d, J=9.0 Hz, 1H, Ar); 7.86 (dd, J=8.6, 2.0 Hz, 1H, Ar); 8.09 (d, J=8.7 Hz, 1H, Ar); 8.41 (d, J=8.8 Hz, 1H, Ar); 9.92 (d, J=2.0 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)[CH:8]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(4-fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, 3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-1-(6-methoxypyridin-3-yl)propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless solid, MS (ESI+): m/z=416.05 [M+H]+.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:23]([NH:22][CH2:20][CH3:21])=[O:24])#[N:3]
Reactant: CCN=C=O
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCNC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 95 %

Procedure:
Prepared as in Example 165b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 165c) and ethyl isocyanate in 95% yield as a light yellow solid. MS 319 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:29]C)=[CH:10][C:11]([O:27]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:14][C:13]3=[O:26])[CH2:6][CH2:5][N:4]1[CH3:31].Cl.N1C=CC=CC=1>>[OH:27][C:11]1[CH:10]=[C:9]([OH:29])[C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([CH3:31])[C@H:3]2[CH2:2][OH:1])=[C:17]2[C:12]=1[C:13](=[O:26])[CH:14]=[C:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=1)[O:16]2
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc(C#N)cc3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc(C#N)cc4)oc23)[C@@H]1CO

Procedure:
Compound of example 83 (0.50 g, 1.19 mmol) reacted with pyridine hydrochloride (5 g, 43.29 mmol) as described in example 17, afforded the title compounds.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[C:7]([CH2:8][NH2:9])[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[N:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: NCc1cc(-c2ccc(Cl)cc2)cnc1Br
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ncc(-c2ccc(Cl)cc2)cc1CN

Procedure:
The product was prepared analogously to Example 7.1c starting from [2-bromo-5-(4-chlorophenyl)pyridin-3-yl]methylamine and trimethylsilylacetylene. Yield: 0.23 g (91% of theoretical); C17H19ClN2Si (M=314.884); calc.: molpeak (M+H)+:315/317 (Cl); found: molpeak (M+H)+:315/317 (Cl).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I-].[K+].CC(C)([O-])C.[K+].[CH3:18][O:19][CH2:20][CH2:21]Cl>CN(C=O)C>[CH3:18][O:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCCl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
146.5 g (1.2 mol) of 4-hydroxybenzaldehyde are dissolved in DMF, and 20 g (0.12 mol) of potassium iodide, 134.6 g (1.2 mol) of potassium tert-butoxide and 170.2 g (1.8 mol) of 2-chloroethyl methyl ether are added. The reaction mixture is stirred at 80° C. for 16 h. For work-up, the reaction mixture is concentrated under reduced pressure. The residue is taken up in 1 l of ethyl acetate and extracted with 0.5 l of 1N aqueous sodium hydroxide solution. The ethyl acetate phase is dried using magnesium sulphate and concentrated under reduced pressure. The residue obtained after concentration is distilled under high vacuum (b.p.=100° C. at 0.45 mbar). This gives 184.2 g (85% of theory) of product.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:21])[C:18](O)=[O:19])[CH:11]=[CH:10]2.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:21])[C:18]([Cl:3])=[O:19])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Yield: 88.7 %

Procedure:
Compound 2 was prepared from the corresponding carboxylic acid. Thionyl chloride (1.24 g, 10.42 mmoles) was added to a solution of (S)-(+)-2-(6-methoxy-naphthalen-2-yl)-propionic acid (Naproxen, 2 g, 8.69 mmoles) in 8.2 mL chloroform in a round bottom flask equipped with magnetic stirring. A drop of DMF was added and the mixture was refluxed for 3 hours. Chloroform and excess thionyl chloride were distilled from the reaction mixture while methylene chloride was added. Evaporation of residual solvent yielded (S)-2-(6-methoxy-naphthalen-2-yl)-propionyl chloride (1.918 g, 88.8% yield). Rf=0.2 (1:1 hexanes:ethyl ether). 1H NMR (400 MHz, CDCl3) δ 9.98 (br, 1H), 7.78 (t, 2H), 7.36 (d, 1H), 7.18 (d, 1H), 7.14 (m, 2H), 4.25 (q, 1H), 3.93 (s, 3H), 1.68 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:17]([N:23]=[C:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([NH:23][C:24]([N:13]1[CH:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15])=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc(-c2c[nH]c(=O)[nH]c2=O)cc1
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)n1cc(-c2ccc(OC)cc2)c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 17 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 6, starting from 5-(4-methoxyphenyl)-1H-pyrimidine-2,4-dione (0.06 g, 0.27 mmol); 5.4 equivalents of hexyl isocyanate were used herein, splitted into three aliquots (1.8 equiv each) and the reaction mixture was heated under microwave irradiation to 100° C. for 1 hr (3 cycles of 20 min each). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 80:20) to afford the title compound (0.02 g, 17% over two steps) as white powder. 1H NMR (400 MHz, CDCl3) δ 0.90 (d, J=6.8 Hz, 3H), 1.29-1.43 (m, 6H), 1.58-1.67 (m, 2H), 3.41 (td, J=7.1, 5.5 Hz, 2H), 3.83 (s, 3H), 6.89-7.00 (m, 2H), 7.41-7.57 (m, 2H), 8.46 (s, 1H), 8.51 (s, 1H), 9.11 (t, J=5.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 14.63, 22.47, 26.85, 29.26, 31.63, 41.34, 55.37, 11414, 116.32, 123.66, 129.39, 134.34, 149.83, 150.71, 159.87, 161.58.