Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[N:30]=[C:29]([CH2:31][NH:32]C(OC(C)(C)C)=O)[CH:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(O)=O>[NH2:32][CH2:31][C:29]1[CH:28]=[N:27][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:30]=1
Reactant: CC(C)(C)OC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Yield: 31.1 %

Procedure:
(2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (82 mg, 0.104 mmol) was stirred with formic acid (2.0 mL) at rt for 5 h, which removed both Boc groups. After concentration in vacuo, the material was dissolved in DCM (1.5 mL), cooled to 0° C. and treated with TFA (0.5 mL, 6.5 mmol) for 1 h, whereupon it was concentrated in vacuo. The crude residue was purified by reverse phase prep HPLC (T3, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (17.2 mg, 31%) as a white solid. LCMS: m/z=529.9 (M−1); 1H NMR (400 MHz, D2O): δ 7.67 (s, 1H), 6.92 (s, 1H), 5.39 (d, J=5.6 Hz, 1H), 4.86-4.74 (m, 3H assumed; obscured by solvent residual peak), 4.16 (s, 2H), 1.25 (s, 3H), 1.23 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=2)CC1.[H-].[Na+].CI.Cl.[O:18]1CCC[CH2:19]1>>[CH3:19][O:18][CH2:1][CH2:4][CH2:5][C:6]1[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(CCC2CC2)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCCCc1ccc(C=O)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 5-(3-hydroxypropyl)thiophene-2-carbaldehyde (Example 58.1; 70 mg, 0.41 mmol) in 1 mL anhydrous tetrahydrofuran under argon at room temperature was added hexanes-rinsed sodium hydride (17 mg of 60% dispersion in oil, 0.45 mmol) as a slurry in 1 mL anhydrous tetrahydrofuran. The resulting suspension was stirred for 15 minutes at room temperature. Methyl iodide (35 μL, 0.57 mmol) was added and the resulting mixture stirred for 2 h at room temperature. The reaction mixture was poured into 30 mL of 0.2 N hydrochloric acid. Organics were extracted with ether (2×30 mL), washed with 5% sodium bisulfite solution, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (8-12% ethyl acetate in hexanes) to give 5-(3-methoxypropyl)thiophene-2-carbaldehyde (17 mg, 23%) as an oil. Used without further characterization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH2:21][CH3:22])[CH:15]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:15][C:16]=1[CH2:21][CH3:22]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCc1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCc1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Yield: 26.6 %

Procedure:
This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.47 g, 2.8 mmol), 4-bromo-2-ethylaniline (432 mg, 2.16 mmol), and (PPh3)4Pd (75 mg, 0.065 mmol) to afford 139 mg (20%) of 4-amino-3-ethyl-3′-nitrobiphenyl. Data for 4-amino-3-ethyl-3′-nitrobiphenyl: 1H NMR (400 MHz, acetone-d6) 8.38 (t, J=2.1, 1H), 8.08 (m, 1H), 8.00 (m, 1H), 7.66 (t, J=8.0, 1H), 7.45 (d, J=2.3, 1H), 7.39 (dd, J=8.3, 2.3, 1H), 6.83 (d, J=8.3, 1H), 4.68 (br s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[C:22]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccncc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)c2ccncc2)CC1

Procedure:
Intermediate 42 (152 mg, 0.5 mmol) was reacted with isonicotinic acid by Method E. Flash chromatography eluted with 9:1 DCM:MeOH afforded compound 47 (204 mg, 100%) as a white solid: Mp 210-212° C. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=6 Hz, 2H), 8.59 (s, 1H), 7.47 (d, J=9 Hz, 2H), 7.38 (d, J=6 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 6.25 (d, J=8 Hz, 1H), 4.30 (d, J=12 Hz, 1H), 3.76 (s, 1H), 3.41 (d, J=12 Hz, 1H), 3.16 (t, J=12 Hz, 1H), 3.05 (t, J=12 Hz, 1H), 1.97-1.88 (m, 1H), 1.84-1.75 (m, 1H), 1.47-1.29 (m, 2H). Purity 92%. HRMS calculated for C19H19F3N4O3−H+ 407.1331. found (ESI(−), [M−H]) 407.1316.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:15][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][OH:7])=[CH:18][CH:17]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)cc1

Procedure:
(Formula II, R1=tert-butyldimethylsilyloxymethylphenyl, R2=4-tert-butyldimethylsilyloxymethylbenzyl). Methyl 4-(hydroxymethyl)benzoate was treated with tert-butyldimethylsilyl chloride using the general procedure described in Journal of the American Chemical Society, 1972, 94, 6190. The resulting product was reduced with lithium aluminium hydride to afford 4-(tert-butyldimethylsilyloxymethyl)benzyl alcohol. This alcohol was converted into the required compound using Method C. 1H NMR (CCl4) δ 0.08 (32H, s), 0391 (18H, s), 4.22 (1H, d, J 2 Hz), 4.68 (5H, br s), 4.90 (2H, a), 7.1-7.6 (8H, m); MS (CH4) 483 (M+−CH3, 52%), 133 100%).
Reaction SMILES: C([CH:4]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:12]2[C:11](=[O:22])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][C:5]1([C:24]([F:27])([F:26])[F:25])O)(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:27][C:24]([F:25])([F:26])[C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:22])[C:12]=2[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:4]=1
Reactant: N#Cc1cccc(C2C3=C(CCCC3=O)NC(O)(C(F)(F)F)C2C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cccc(C2C=C(C(F)(F)F)NC3=C2C(=O)CCC3)c1
Yield: 55.2 %

Procedure:
A suspension of 3-carboxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5(1H)-quinolone (2.25 g) in toluene (100 ml) was treated with p-toluene sulfonic acid monohydrate (0.33 g). The mixture was vigorously refluxed under Dean-Stark conditions for 1.5 hours and then partitioned between water and ethyl acetate. The organic portion was washed (water and brine) and evaporated. The residue was purified by chromatography (hexane/ethyl acetate, 1:1) to yield the title compound (1.04 g) as a white solid; m.p. 182°-183° C.; NMR: 1.80-2.00(m,2, CH2), 2.13-2.30(m,2,CH2), 2.50-2.67(m,2,CH2 4.68(d,1, CH, J=5.2), 5.61(d,1, CH, J=5.3), 7.51(m,2, Ar), 7.60(s,1, Ar), 7.64(m,1, Ar), 9.42(s,1, NH); MS: m/z =318(M); Analysis for C17H13F3N2O: Calculated: C, 64.15; H, 4.12; N, 8.80; Found: C, 64.15; H, 4.10; N, 8.63.
Reaction SMILES: [F:1][C@@:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[S:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C@:2]([F:1])([CH3:6])[C:3]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:4])=[CH:8][CH:9]=1)(=[O:16])=[O:15]
Reactant: CS(N)(=O)=O
Reactant: C[C@](F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@](F)(C(=O)NS(C)(=O)=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 3 (0.5 g, 1.6 mmol) in dry CH2Cl2 (10 ml), N,N-carbonyldiimidazole (0.33 g, 2.0 mmol) was added under vigorous stirring. After 1 h methanesulfonamide (0.19 g, 2 mmol) and triethylamine (0.28 mL, 2 mmol) were added and the resulting mixture was left stirring overnight at room temperature. The organic mixture was washed with a saturated solution of NaHCO3 (2×10 mL) and brine (3×10 mL), dried over Na2SO4 and evaporated under vacuum to give pure 17 as a colourless oil (0.60 g, yield 95%). [α]b=+9 (c=1; CH3OH). 1H-NMR (DMSO-d6) δ 7.70 (d, 2H, J=7 Hz), 7.55 (d, 2H, J=7 Hz), 3.05 (s, 3H), 1.85 (d, 3H, J=23 Hz).
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=O)[CH2:32][CH2:31]1.[CH3:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][C:42]=1[N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1>ClCCl>[CH3:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH:45][C:36]([CH:33]2[CH2:32][CH2:31][CH:30]([C:24]3[C:23]4[C:27](=[CH:28][CH:29]=[C:21]([F:20])[CH:22]=4)[NH:26][CH:25]=3)[CH2:35][CH2:34]2)=[O:38])=[CH:43][C:42]=1[N:48]1[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]1
Reactant: O=C(O)C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C2CCC(c3c[nH]c4ccc(F)cc34)CC2)cc1N1CCN(C)CC1
Reaction time: 1 h

Procedure:
173 μl (1.2 mmol) of triethylamine and 230 mg (1.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride are added to a mixture of 314 mg (1.2 mmol) of 4-(5-fluoro-1H-indol-3-yl)cyclo-hexanecarboxylic acid and 265 mg (1.2 mmol) of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline in 40 ml of dichloromethane. This mixture is initially stirred at 0° for one hour, then at room temperature for 12 h. The reaction mixture is concentrated, the residue is taken up in ethyl acetate, and the mixture is washed with water, 5% citric acid and sat. sodium bicarbonate solution, dried and evaporated. After column chromatographic separation, 4-(5-fluoro-1H-indol-3-yl)-cyclohexanoic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[CH3:27][O:28][C:29]([CH2:31]P(OC)(OC)=O)=[O:30]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:23]=[CH:31][C:29]([O:28][CH3:27])=[O:30])=[CH:25][CH:26]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(C=O)cc1
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccc4ccccc4c3)oc2C)cc1

Procedure:
According to the method described for Reference Example 22, 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzaldehyde was allowed to react with trimethyl phosphonoacetate to give methyl 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]cinnamate. Recrystallization from chloroform-ether gave colorless prisms, m.p.185°-186° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([O-:21])[CH:11]=[C:12]([C:14](=[O:20])[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].F[C:24]1[C:29]([F:30])=[C:28]([F:31])[CH:27]=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33]>>[F:30][C:29]1[C:24]([O:21][C:10]2[CH:9]=[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[C:12]([C:14](=[O:20])[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)=[C:25]([N+:32]([O-:34])=[O:33])[CH:26]=[CH:27][C:28]=1[F:31]
Reactant: CC(C)(C)NC(=O)c1cc([O-])cc(C(=O)NC(C)(C)C)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Na+]
Product: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1

Procedure:
In another embodiment of the present invention there is provided a process for the preparation of a compound according to formula III wherein R2 is 3,5-dicyano-phenyl which process further comprises (i) contacting sodium 3,5-bis-tert-butylcarbamoyl-phenolate with 2,3,4-trifluoronitrobenzene in an appropriate solvent at temperatures from about −30° C. up to about 40° C. to afford a 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene; and (ii) contacting 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene with phosphorus oxychloride or a similar dehydrating agent to afford 3,4-difluoro-2-(3,5-dicyano-phenoxy)nitrobenzene 111 (R2=3,5-dicyanophenyl). The ether can be convert to IV (R2=3,5-dicyanophenyl) as described below.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:9]([C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:13])=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: Nc1ccc(F)cc1F
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C(Nc1ccc(F)cc1F)c1cc([N+](=O)[O-])ccc1O
Yield: 32.4 %

Procedure:
A solution of 5-nitrosalicylic acid (1.4 g, 7.7 mmol) and 2,4-difluoroaniline (0.8 mL, 7.7 mmol) in chlorobenzene (40 mL) was treated with PCl3 (0.338 mL, 3.8 mmol). The solution was heated at reflux under an argon atmosphere. After 2 h. the solution was filtered hot and the filtrate was left standing at RT. After 18 h the solution was filtered and the solid was recrystallized from MeOH to give the title compound (0.733 g, 35% yield): 1H NMR (400 MHz, DMSO-d6) δ 2.5-2.6 (s, 3H), 7.1-8.9 (m, 6H), 10.6-10.7 (s, 1H)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][OH:40])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:41]([C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=1)[CH2:46]Br)#[N:42].O>O1CCCC1>[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][O:40][CH2:46][C:45]1[CH:48]=[CH:49][CH:50]=[C:43]([C:41]#[N:42])[CH:44]=1)[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(C#N)c1)OCCCCCCCCCCCCCCCC
Reaction time: 0.33 h

Procedure:
Sodium hydride (50% mineral oil dispersion; 1.056 g, 0.022 mole) was added to a solution of 1,2-di-O-n-hexadecyl glycerol in tetrahydrofuran (150 ml) and stirred for 20 minutes under nitrogen. m-Cyanobenzylbromide (4.0 g, 0.020 mole) was added to the mixture and allowed to react to room temperature overnight. Water (200 ml) and then cautiously added and the aqueous mixture extracted with ethyl acetate (3×150 ml). The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil (12 g), which was chromatographed on silica gel (eluted with benzene/hexane, 8/2) resulting in pure 1,2-Di-O-(n-hexadecyl)-3-O-(3-cyanobenzyl)-glycerol (8.0 g): oil; ir(CHCl3) 2230 cm-1.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[O:37])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(c1ccc(O)cc1)C1CCCC1
Product: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CCCC1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of cyclopentyl 4-hydroxyphenyl ketone are treated as described in Example 76.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[OH2:11].[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:11])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CCO
Product: CC(C)(C)c1ccc(C=O)cc1
Temperature: 45 °C
Yield: 60 %

Procedure:
17 g of hexamethylenetetramine, 9 ml of water, 6 ml of ethanol and 21.5 g of 95% p-tert-butylbenzyl chloride are added to a three-necked flask provided with a thermometer, magnetic stirrer and reflux condenser. The mixture is now warmed slowly to 45° C. while stirring. At this temperature the mixture is initially slurry-like and thereafter thinly liquid. An exothermic reaction occurs. The temperature is held at 45° C. with the aid of an ice-bath until the reaction fades away. Thereupon the mixture is stirred with renewed warming at 45° C. for 30 minutes. The reflux condenser is now replaced by a distillation bridge and 5 ml of ethanol are distilled off from the mixture under a slight vacuum (70 Torr). Thereupon, the distillation bridge is removed and a water separator is attached, thus enabling the separated water to flow back into the reaction vessel. The water separator is filled with about 60 ml of water and 10 ml of toluene and the mixture is treated with 60 ml of water. The mixture is heated to 140° C. At the beginning of the steam distillation the pH-value is adjusted to 4.5-5 by means of 60% sulphuric acid. The liquid in the water separator is renewed several times. The organic phases are separated from the distillates and the aqueous fractions are extracted with ether. The ether extracts and organic phases are in each case combined and washed with, in each case, about 20 ml of 15% sulphuric acid, water, 10% sodium carbonate solution and finally again with water and then concentrated. There are thus obtained a total of 14.7 g of crude product which are fractionated at 17 Torr over a 5 cm Widmer column and give 11.8 g (60%) of p-tert-butylbenzaldehyde with a purity of 92% (NMR/GC).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][O-:13].[Na+].O>CO>[CH3:12][O:13][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A roundbottom flask was charged with a solution of 6-chloro-2-methyl-3-nitropyridine (12.0 g, 69.36 mmol) in methanol (100 ml). Sodium methanolate (5.6 g, 103.70 mmol) was added and the resulting solution was stirred at room temperature for 24 hours. The mixture was poured into 100 ml of water and the solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH:9]([CH:11]([CH3:17])[C:12](OCC)=O)=[O:10]>>[CH3:17][C:11]1[C:9](=[O:10])[O:7][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:12]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)C(C)C=O
Product: Cc1cc2c(oc1=O)CCCC2=O

Procedure:
Prepared analogously to Example C(a) from cyclohexan- 1,3-dione and ethyl 2-formyl-propionate.
Reaction SMILES: [CH:1]1([N:4]([CH3:23])[C:5]2[C:6]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=4[S:16][C:7]=3[N:8]=[C:9]([CH2:11][O:12]C(=O)C)[N:10]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.O>[CH:1]1([N:4]([CH3:23])[C:5]2[C:6]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=4[S:16][C:7]=3[N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1nc(CO)nc2sc3c(c12)CCCC3)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of acetic acid 4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (4 g, 0.012 mol) in THF (10 ml) and water (5 ml) was added lithium hydroxide monohydrate (1.48 g, 0.036 mol). The solution stirred at room temperature for 4 h. The volatiles were removed by distillation, and the residue was diluted with water, and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over anhydrous sodium sulphate, concentrated, and purified by chromatography on 60-120 silica gel using 25%-ethyl acetate in hexane to give the desired product [4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]-methanol (2.5 g, 72%) as off-white solid. 1H NMR (400 MHz, CDCl3): δ 0.45-0.50 (m, 2H), 0.72-0.80 (m, 2H), 1.72-1.80 (m, 2H), 1.88-1.94 (m, 2H), 2.82-2.94 (m, 5H), 3.07 (s, 3H), 3.94 (t, 1H), 4.70 (d, 2H); LC-MS: [M+H]=290.0 m/z.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][NH:6][C:5]([NH2:8])=[N:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[N:18][CH:17]=1>C(O)C>[F:1][C:2]1([F:9])[CH2:7][N:6]2[C:24](=[O:25])[CH:23]=[C:22]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][N:18]=3)[N:8]=[C:5]2[NH:4][CH2:3]1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: NC1=NCC(F)(F)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncn2)nc2n1CC(F)(F)CN2

Procedure:
To a suspension of 2.17 g (16.12 mmol) of 5,5-difluoro-1,4,5,6-tetrahydro-2-pyrimidinamine and 1.81 g (16.12 g) of potassium carbonate in 30 ml of ethanol was treated with 2.55 g (13.13 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate. The reaction mixture was heated at reflux temperature during 32 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[C:33]([Cl:35])[C:32](Cl)=[N:31][CH:30]=1.N12CCN(CC1)CC2>C(N(CC)CC)C>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[N:31][CH:30]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 163, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with methyl-5,6-dichloronicotinate in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as a colorless solid. MS (m/e)=545.2 [M+H+].