Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[N:44]=[CH:43][C:42]3[C:37](=[CH:38][C:39]([O:52][CH3:53])=[C:40]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:41]=3)[N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[CH:69]=[C:68]([C:70](O)=[O:71])[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[N:44]=[CH:43][C:42]3[C:37](=[CH:38][C:39]([O:52][CH3:53])=[C:40]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:68]5[O:67][N:66]=[C:65]([CH3:64])[CH:69]=5)=[O:71])[CH2:50][CH2:51]4)[CH:41]=3)[N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(C(=O)O)on1
Reactant: COc1cc2nc(Nc3cccc(Cl)c3F)ncc2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nc(Nc3cccc(Cl)c3F)ncc2cc1OC1CCN(C(=O)c2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.9 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolinamine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3-methyl-5-isoxazolecarboxylic acid (0.126 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-5-yl)carbonyl]piperidin-4-yl}oxy)quinazolinamine as a white solid (0.145 g). 1H NMR Spectrum: (DMSO d6 373K) 1.89 (m, 2H), 2.10 (m, 2H), 2.35 (s, 3H), 3.64 (m, 2H), 3.88 (m, 2H), 3.99 (s, 3H), 4.82 (m, 1H), 6.73 (s, 1M), 7.29 (m, 1H), 7.29 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.93 (s, 1H), 8.39 (s, 1H), 9.28 (br s, 1H); Mass Spectrum: (M+H)+ 512.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])#[N:2].[OH:16]O.[OH-].[Na+].Cl>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])(=[O:16])[NH2:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1ccc(C(=O)O)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
3-Cyano-4-isopropoxy-benzoic acid (50 mg, 0.24 mmol), hydrogen peroxide (280 μL of 30% w/v, 2.4 mmol), and 10% NaOH (240 μL of 10% w/v, 0.61 mmol) were combined and stirred at room temperature for 16 h. The mixture was acidified with 4M HCl and was extracted with ethyl acetate (2×7 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to give 3-carbamoyl-4-isopropoxy-benzoic acid (45 mg, 83%). ESI-MS m/z calc. 223.1. found 224.3 (M+1)+; Retention time: 1.49 minutes (4 min run).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[N+:7]([C:10]1[CH:25]=[CH:24][C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>CCOCC.O1CCCC1>[N:30]1[CH:31]=[CH:32][C:27]([NH:26][C:1](=[O:5])[C:2]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([CH2:14][C:13]3[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:25][CH:24]=3)[CH:16]=2)=[O:3])=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(Cn2ccc3ccccc32)cc1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1ccncc1)C(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A solution of 4.50 ml of oxalyl chloride in 50 ml of ether is treated dropwise with a solution of 10.09 g (0.04 mol) of 1-(4-nitrobenzyl)indole in 50 ml of ether at OC [sic] and under a nitrogen atmosphere. The mixture is heated at reflux temperature for 2 hours and the solvent is then evaporated. 100 ml of tetrahydrofuran are added to the residue, it is cooled to −5° C. and a solution of of [sic] 9.32 g (0.099 mol) of 4-aminopyridine in 400 ml of tetrahydrofuran is added dropwise. The mixture is heated to reflux for 3 hours and allowed to stand at room temperature overnight. The 4-aminopyridine hydrochloride is filtered off with suction, the precipitate is washed with tetrahydrofuran, the filtrate is concentrated in vacuo and the residue is recrystallized from ethyl acetate.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([O:11][C:12](=[O:21])[CH:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4]2.[CH:22]([C:24]1[S:28][C:27]([C:29]([O:31][CH:32]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH2:52][CH3:53])[CH:44]=2)[CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][N+:37]([O-:41])=[CH:36][C:35]=2[Cl:42])=[O:30])=[CH:26][CH:25]=1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:40][C:39]1[CH:38]=[N+:37]([O-:41])[CH:36]=[C:35]([Cl:42])[C:34]=1[CH2:33][CH:32]([O:31][C:29]([C:27]1[S:28][C:24]([CH2:22][NH:20][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:21])[O:11][C@@H:5]2[CH:6]3[CH2:7][CH2:8][N:3]([CH2:10][CH2:9]3)[CH2:4]2)=[CH:25][CH:26]=1)=[O:30])[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH2:52][CH3:53])[CH:44]=1
Reactant: CCOc1cc(C(Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)ccc1OC
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(C(Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)s2)ccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of [(3R)-quinuclidin-3-yl]2-amino-2-phenylacetate bis hydrochloride salt (273 mg, 0.82 mmol) in ethanol (10 mL) was added the single enantiomer 2 of [2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)ethyl] 5-formylthiophene-2-carboxylate (Intermediate 75, 135 mg, 0.27 mmol) and acetic acid (40 μL, 0.68 mmol). The resulting mixture was stirred at room temperature for 16 h. Sodium cyanoborohydride (45 mg, 0.68 mmol) was added and the reaction mixture was stirred at room temperature for a further 24 h. The solvent was removed by evaporation under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid (3 mL) and ethyl acetate (3 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×3 mL). The aqueous phase was basified with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (2×3 mL). The combined organic fractions were extracted with 1 M aqueous hydrochloric acid (2 mL). Brine (2 mL) was added and the aqueous layer was extracted with chloroform (5 mL and 2 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate solution (2 mL), passed through a hydrophobic frit and the solvent was removed by evaporation under reduced pressure. Purification by preparative HPLC gave the title compound as an off-white solid (50 mg, 25%).
Reaction SMILES: [N:1]([CH:4]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[N:14]([CH2:17][C@@H:18]([NH:20]C(=O)OCC2C=CC=CC=2)[CH3:19])[N:13]=[CH:12]3)[O:7][CH2:6][CH:5]1Br)=[N+]=[N-].C[OH:33]>[Pd]>[NH2:1][CH:4]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[N:14]([CH2:17][C@@H:18]([NH2:20])[CH3:19])[N:13]=[CH:12]3)[O:7][CH2:6][CH:5]1[OH:33]
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)C(N=[N+]=[N-])C(Br)CO3)NC(=O)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: C[C@H](N)Cn1ncc2ccc3c(c21)C(N)C(O)CO3
Reaction time: 18 h
Yield: 96 %

Procedure:
The product from step B (0.26 g, 0.30 mmol) and Pd/C (10%, 0.026 g) were mixed with methanol (5 mL) and placed under a hydrogen atmosphere for 18 h. The mixture was filtered and evaporated to give a yellowish solid (0.155 g, 96%): mp 84-88° C.; LC/MS (+APCI) m/z 263 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]([CH2:15][CH2:16][Br:17])[C:11](OC)=[O:12].O>CN(C)C=O>[Br:17][CH2:16][CH2:15][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(Br)CCBr
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2SC1CCBr
Temperature: 25 °C

Procedure:
To a solution of 4.6 g of 2-aminothiophenol in 50 ml of dimethylformamide was added dropwise 9.55 g of methyl 2,4-dibromobutyrate with stirring at room temperature. After stirring one hour, the reaction mixture was poured into water to give crystals of 2-(2-bromoethyl)-2H-1,4-benzothiazin-3(4H)-one. The crystals were collected by filtration and washed with water, n-hexane and cold methanol. The yield was 6.32 g (63.3%). Recrystallization from ethyl acetate gave prisms, m.p. 151°-152° C.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)SC)#[N:2].[CH3:17][NH2:18]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)=[N:18][CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1ccsn1)NC#N
Reactant: CN
Product: CN=C(NC#N)NCCSCc1ccsn1

Procedure:
The reaction of N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea (0.27 g.) with excess methylamine according to the procedure described in Example 3(c) and recrystallisation of the product from isopropyl acetate afforded N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-N"-methylguanidine (0.12 g.), m.p. 91°-93° (Found: C, 42.4; H, 5.1; N, 27.3; S, 25.2. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]([O:21][CH3:22])(=[O:20])[CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:28]([O:27][C:25](=[O:26])[CH2:24][CH:14]([C:13]([O:21][CH3:22])=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)CCCC(=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CCC(=O)O)CC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of n-BuLi (2.5 M, 2.6 mL, 71.5 mmol) in anhydrous THF (200 mL) was added anhydrous diisopropyl amine (9.6 mL, 68.30 mmol) at −78° C. After 20 minutes of stirring, a solution of monomethyl glutarate (5 g, 32.5 mmol) in anhydrous THF (20 mL) was added drop wise under controlled temperature. After 30 minutes, a solution of tert-butyl bromoacetate (4.9 mL, 32.50 mmol) in anhydrous THF (20 mL) was slowly added followed by the addition of HMPA (8 mL). The reaction mixture was stirred at −78° C. for an additional 2 h followed by 24 h at room temperature. The reaction mixture was partitioned between HCl (2N, excess) and ethyl acetate. The organic phase was separated and the aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was extracted with brine, dried over sodium sulfate, filtered, and evaporated. The residue was first flashed with chloroform and then with 2-5% methanol in chloroform. The product was obtained as a light yellow oil. 1H-NMR(CDCl3, 400 MHz: 1.42(s, 9H); 1.89(m, 2H); 2.24(m, 2H); 2.64(m, 2H); 2.84(m, 1H); 3.69(s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11](OC)=[O:12])[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[N:19]=2)[N:3]=1.[O:34]([CH2:36][CH2:37][CH2:38][NH2:39])[CH3:35].N1C=NC=N1.C1CCN2C(=NCCC2)CC1>>[O:34]([CH2:36][CH2:37][CH2:38][NH:39][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([CH2:7][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=4)[N:19]=3)=[N:5]2)[CH:9]=1)[CH3:35]
Reactant: COCCCN
Reactant: COC(=O)c1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Agent: c1nc[nH]n1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCCNC(=O)c1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 70 °C
Yield: 87.1 %

Procedure:
A mixture of methyl 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzoate (46 mg, 0.1 mmol) and 3-methoxylpropylamine (27 mg, 0.3 mmol) was treated with 1,2,4-triazole (7 mg, 0.1 mmol) and DBU (15 mg, 0.1 mmol), and heated to 70° C. overnight. The crude product was purified by a silica gel column with EtOAc to give N-(3-methoxylpropyl)-3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzamide as a white solid (45 mg, 87%). MS (ES+) C24H23F3N6O4 requires: 516. found: 517 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 7.77 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 5.50 (s, 2H), 3.60-3.55 (m, 4H), 3.38 (s, 3H), 2.55 (s, 3H), 1.91-1.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8](=[O:16])[C:9]([CH2:14][CH3:15])([CH3:13])[CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=1)[C:8](=[O:16])[C:9]([CH2:14][CH3:15])([CH3:13])[CH2:10][CH2:11][Cl:12]
Reactant: BrBr
Reactant: CCC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
110 g (0.38 mole) of 1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone are dissolved in 400 ml of chloroform. 60.8 g (0.38 mole) of bromine are added dropwise at room temperature such that the solution is always decolorized. The reaction mixture is then subsequently stirred at room temperature for 30 minutes and concentrated by distilling off the solvent. 138.5 g (99% of theory) of 1-bromo-1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone of refractive index nD20 1.5250 are obtained. ##STR100##
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][SH:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH2:22][C:23]([C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:35][CH2:36][C:37](O)=[O:38])=[C:31]([Cl:34])[C:32]=1[Cl:33])=[O:26])=[CH2:24]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:17][C:37](=[O:38])[CH2:36][O:35][C:30]1[CH:29]=[CH:28][C:27]([C:25](=[O:26])[C:23](=[CH2:24])[CH2:22][CH3:21])=[C:32]([Cl:33])[C:31]=1[Cl:34])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(CS)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Solvent: ClCCl
Product: C=C(CC)C(=O)c1ccc(OCC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C2CCCC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 19.2 g (63.8 mmol) of N-(3-mercapto-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester and 19.3 g (63.7 mmol) of ethacrynic acid in 20 ml of methylene chloride at 0° C. was added a solution of 13.2 g (64.0 mmol) of N,N-dicyclohexylcarbodiimide in 20 ml of methylene chloride. The solution was allowed to warm to room temperature and to stir overnight. The solution was filtered and the filtrate was concentrated in vacuo. Purification of the product by HPLC [10% ethyl acetate in hexanes] afforded N-[3-[2,3-dichloro-4-(2-methylene-1-oxobutyl) phenoxy] acetylthio-2-methylpropanoyl]-N-cyclopentyl glycine t-butyl ester as a viscous oil.
Reaction SMILES: [SH2:1].[CH3:2][C:3]([C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]([C:17]#[N:18])[N:7]=1)([CH3:5])[CH3:4].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:5][C:3]([C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]([C:17](=[S:1])[NH2:18])[N:7]=1)([CH3:2])[CH3:4]
Reactant: S
Reactant: CC(C)(C)c1nc(C#N)nc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)c1nc(C(N)=S)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Hydrogen sulfide is bubbled through a solution of 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbonitrile (4.5 g, 19.3 mmol) and triethylamine (4.3 g, 42.4 mmol) in pyridine (20 nil) at room temperature for 6 hours. The reaction mixture is stirred at room temperature overnight. The solvent is evaporated under vacuum and the residue is recrystallized from ether/hexane to give pure 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbothioamide (3.0 g, 58%); mp 169°-171° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[C:24]1(/[CH:30]=[CH:31]/B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2](/[CH:31]=[CH:30]/[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: CCCCc1nc2c(N)nc3cc(/C=C/c4ccccc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and trans-2-phenylvinylboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from toluene followed by chromatography on silica gel (8% methanol in CH2Cl2) afforded 2-butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 215–216° C.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:23])=[CH:25][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1cc2c(o1)CCNC2
Reactant: CCCCCCCc1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCc1ccc(C(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.264 g (1.2 mmol) of 4-heptylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. This solution was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].C(OC(CC1C=CC(O[CH2:34][C:35]2[N:36]=[C:37]([C:40]3[CH:45]=[CH:44][C:43]([CH:46]([CH3:48])[CH3:47])=[CH:42][CH:41]=3)[S:38][CH:39]=2)=C(C)C=1)C(O)=O)C.[C:50]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:50][CH2:34][C:35]2[N:36]=[C:37]([C:40]3[CH:41]=[CH:42][C:43]([CH:46]([CH3:47])[CH3:48])=[CH:44][CH:45]=3)[S:38][CH:39]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(Cc1ccc(OCc2csc(-c3ccc(C(C)C)cc3)n2)c(C)c1)C(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(C)C)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-2-(4-isopropyl-phenyl)-thiazol-4-yl]-ethanol (prepared from 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole (example 5) according to the sequence described in examples 13 a]to d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-isopropyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-isopropyl-phenyl)-thiazol-4-yl)-ethoxy}-phenyl)-propionic acid as light yellow solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:12][CH:11]([C:13]2[O:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:10]2=[C:19]3[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]3=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[N:9]2[CH2:8]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>C(#N)C.O>[N:43]1([CH2:6][C@@H:7]2[O:12][C@@H:11]([C:13]3[O:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:10]3=[C:19]4[N:32]([CH3:33])[C:31](=[O:34])[N:30]([CH3:35])[C:29](=[O:36])[C:20]4=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[N:9]3[CH2:8]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)O[C@@H](COS(C)(=O)=O)C3
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)[C@H](c1ccc(Cl)o1)O[C@@H](Cn1ccnc1)C3
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of ((8R)-10-(5-chlorofuran-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl methanesulfonate (117 mg, 0.217 mmol), cesium carbonate (142 mg, 0.435 mmol) and imidazole (22.51 mg, 0.331 mmol) in acetonitrile (6 mL) was heated at 80° C. for 16 hours, then at 85° C. for 3.5 hours. Further portions of imidazole (22.51 mg, 0.331 mmol) and cesium carbonate (142 mg, 0.435 mmol) were added and the mixture heated for a further 2 hours. The mixture was cooled to room temperature, diluted with water (30 ml) and extracted with DCM (2×30 ml). The combined organic extracts were washed with brine (30 ml) passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane then with 0-10% MeOH/DCM, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:11]2[CH:10]=[C:9]([O:8][C:7]3[C:6]([CH3:17])=[CH:5][C:4]([N+:18]([O-:20])=[O:19])=[CH:3][C:2]=3[CH3:1])[CH:14]=[CH:13][C:12]=2[O:15][CH3:16])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of 4.5 g (16.5 mmol) of 3,5-dimethyl4-(4'-methoxyphenoxy)nitrobenzene and 6.63 g (41.8 mmol) of p-fluorobenzoyl chloride in 100 ml methylene chloride is added 15.8 g (83.3 mmol) of titanium tetrachloride. The reaction mixture is stirred for 8 days at room temperature, then poured into ice water (300 ml) and stirred 2 hours. The organic layer is separated, washed with 5% aqueous sodium carbonate, water, dried (CaSO4) and evaporated. The residue is triturated with ether-petroleum ether and recrystallized from methanol to give (4-fluorophenyl)[2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone, m.p. 167°-168°.