Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1[C:3]([Cl:23])=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([S:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=O)[CH:7]=1.CI.C(=O)([O-])[O-].[K+].[K+].[OH2:32].[CH3:33][N:34]([CH:36]=O)[CH3:35]>>[Cl:23][C:3]1[C:36]([N:34]([CH3:35])[CH3:33])=[CH:7][C:6]([S:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:32])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: O
Reactant: CN(C)C(=O)c1ccccc1Sc1cc(N)c(Cl)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CN(C)C(=O)c1ccccc1Sc1cc(N(C)C)c(Cl)cc1[N+](=O)[O-]
Yield: 65 %

Procedure:
2-(5-Amino-4-chloro-2-nitro-phenylthio)-N,N-dimethyl-benzamide (18) (1.0 g, 2.84 mmol) was heated to reflux with methyl iodide 1.0 g) and potassium carbonate (5 g) in 10 mL of anhydrous DMF for 24 h. The mixture was poured into cold water and the precipitate was collected by filtration and purified by silica gel chromatography to yield 22 (Yellow powder, 0.7 g, 65%): IR (cm−1, neat) 2923, 1636, 1577, 1498, 1322, 1299; 1H NMR (200 MHz CDCl3) δ 8.23 (s. 1H), 7.4–7.6 (m, 4H), 6.20 (s, 1H), 3.04 (s, 3H), 2.82 (s, 3H), 2.71 (s, 6H). Anal. (C17H18ClN3O3S-0.5 H2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:42][CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:41][CH2:42][CH2:37][CH2:38][CH2:39]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: OC1CCCCC1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC4CCCCC4)cc3C)c2cc1OC
Yield: 57.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclohexanol (47 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 53%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]1[C@H:16]([CH3:17])[CH2:15][C:14]2[CH:18]=[C:19]3[O:24][CH2:23][O:22][C:20]3=[CH:21][C:13]=2[C:12]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[N:11]1)=[O:4].C([O-])=O.[K+]>C(O)C.CC(C)=O.O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]1[C@H:16]([CH3:17])[CH2:15][C:14]2[CH:18]=[C:19]3[O:24][CH2:23][O:22][C:20]3=[CH:21][C:13]=2[C:12]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=2)=[N:11]1)=[O:4]
Reactant: COC(=O)c1sccc1N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C[C@H]1C)OCO3
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: COC(=O)c1sccc1N1N=C(c2ccc(N)cc2)c2cc3c(cc2C[C@H]1C)OCO3
Reaction time: 0.83 h
Yield: 91.6 %

Procedure:
To a solution of the product of Example 24 (794 mg, 1.71 mmol) in 16 mL of absolute ethanol and 3 mL of acetone under N2 was added 10% Pd/C (400 mg) followed by a solution of potassium formate (513 mg, 6.10 mmol) in 1 mL of H2O. After 50 min, the mixture was filtered through a pad of celite and concentrated by rotary evaporation. The residue was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed by rotary evaporation and the residue was purified by silica gel chromatography (1:1 ethyl acetate hexanes) to afford 682 mg of the desired final product.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][O:10][CH3:11])C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].CCCCCC>COC(C)(C)C.O1CCCC1>[CH3:9][O:10][CH:11]=[C:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COC=C1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
10.4 g of triphenyl-methoxymethyl-phosphonium chloride were suspended in 60 ml of t-butyl methyl ether while gassing with argon in a sulphonation flask provided with a thermometer, mechanical stirrer, dropping funnel and solid substance addition tube and treated at -10° C. within 10 minutes with 3.6 g of solid potassium t-butylate. After completion of the addition, the mixture was stirred at -10° C. to 0° C. for a further 30 minutes and then the deep orange, heterogenous mixture was treated dropwise at 0° C. with a solution of 4.2 g of 4-(p-cyanophenyl)cyclohexanone in 50 ml of absolute tetrahydrofuran. The mixture was subsequently stirred at room temperature for a further 2 hours, then poured into 500 ml of hexane and filtered. Low-pressure chromatography (0.5 bar) of the concentrated residue (7.1 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 4.5 g (94%) of p-[4-(methoxymethylene)cyclohexyl]benzonitrile as a colourless oil; purity 95%, Rf-value (ethyl acetate/petroleum ether vol. 1:9) 0.30.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][O:25][CH2:26][C:27]([NH:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)=[O:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][O:25][CH2:26][C:27]([NH:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)=[O:28]
Reactant: COCC(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Examples 1 and 39 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-methoxymethylcarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)NCC2
Reactant: NC1CCc2ccccc21
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: S1C=CN=C1CSCCN.[C:11]([CH:13]=[C:14](OC)OC)#[N:12].[C:19]([CH:21]=[C:22](OC)[NH:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)#[N:20].C(N)C#C>>[C:19]([CH:21]=[C:22]([NH:12][CH2:11][C:13]#[CH:14])[NH:23][CH2:24][CH2:25][S:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)#[N:20]
Reactant: COC(=CC#N)NCCSCc1nccs1
Reactant: COC(=CC#N)OC
Agent: C#CCN
Agent: NCCSCc1nccs1
Product: C#CCNC(=CC#N)NCCSCc1nccs1

Procedure:
When 2-[(thiazol-2-yl)methylthio]ethylamine is reacted with 1-cyano-2,2-bis(methoxy)ethylene [prepared according to the procedure described in J. Chem. Soc., (Suppl. Issue No. 1), S106-111 (1949)] and the resultant 1-cyano-2-methoxy-2-{2-[(thiazol-2-yl)methylthio]ethylamino}ethylene is reacted with propargylamine in the procedure of Example 1, the title compound is produced.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16](Br)[CH:17]=[N:18][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH2:26][C:27]1[N:28]([CH3:36])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22](=[O:25])[CH:23]=[CH2:24].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16](/[CH:24]=[CH:23]/[C:22](=[O:25])[N:21]([CH3:20])[CH2:26][C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:17]=[N:18][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cc(Br)cnc21
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)NC(=O)CN2C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
A solution of 7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b]pyrazine-4-carboxylic acid tert-butyl ester (494 mg, 1.5 mmol) in propionitrile (12 mL) was treated with N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-acrylamide (685 mg, 3 mmol) and diisopropylethylamine (788 μL, 4.5 mmol) and purged with Argon for 10 min. Pd(OAc)2 (34 mg, 0.15 mmol) and P(o-Tol)3 (92 mg, 0.3 mmol) was added and the Argon purge was repeated. The mixture was heated to 100° C. and stirred for 6 hours under Argon. Upon cooling, solvent was removed and the residue was purified by Flash chromatography (silica, 1-3% MeOH in CH2Cl2) to afford the title compound (480 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 10.81 and 10.73 (rotamers, 2s, br, 1H), 8.46 and 8.41 (rotamers, 2s, 1H), 7.58 (d, J=15.4 Hz, 1H), 7.51 (m, 3H), 7.23 (d, J=15.4 Hz, 1H), 7.11 (m, 1H), 7.03 (m, 1H), 6.45 and 6.20 (rotamers, 2s, 1H), 5.06 and 4.87 (rotamers, 2s, 2H), 4.32 and 4.28 (rotamers, 2s, 2H), 3.74 and 3.71 (rotamers, 2s, 3H), 3.16 and 3.05 (rotamers, 2s, 3H), 1.44 and 1.42 (rotamers, 2s, 9H). MS (ESI) m/e: 476.2 (M+H)+, 420.2 (M-tert-Bu)+.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:30]=[O:31].P(=O)(O)(O)O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[C:9]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:6][C:5]3[CH:21]=[CH:22][C:2]([CH:30]=[O:31])=[CH:3][C:4]=3[O:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: CN(C)C=O
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: -10 °C

Procedure:
5-Bromo-2,2-diphenyl-1,3-benzodioxol (70 g) in 440 ml of tetrahydrofuran are treated at -78° C. with 125 ml of a 1.6M solution of butyllithium in n-hexane. After 10 minutes 40 ml of dimethylformamide are added thereto and the mixture is left to warm to -10° C. Thereafter, 70 ml of 20% aqueous phosphoric acid and 500 ml of ethyl acetate are added, the organic phase is separated and evaporated. The residue is recrystallized from 130 ml of ethanol. 49.5 g of 2,2-diphenyl-1,3-benzodioxol-5-carbaldehyde are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][O:1][C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:33])[F:32])=[CH:24][CH:25]=2)=[CH:9][CH:8]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CC(C)OC(Cc1ccc(CCOC(=O)Nc2ccc(C(F)(F)F)cc2)cc1)C(=O)O

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[CH3:12][C:13](=O)[O:14]CC>C1(C)C=CC=CC=1>[C:13]([CH:6]1[CH2:5][C:4]([CH3:11])([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])(=[O:14])[CH3:12]
Reactant: CCOC(C)=O
Reactant: CC1(C)CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)C1CC(C)(C)CCC1=O
Temperature: 55 °C

Procedure:
To a suspension of NaH (2.88 g, 60% dispersion in mineral oil, 60 mmol) in toluene (25 mL), EA (6.5 mL, 66 mmol) is added. The mixture is stirred at rt for 5 min before a solution of 4,4-dimethyl-cyclohexanone (2.52 g, 20 mmol) in EA (6 mL) is added. The mixture is heated to 55° C. where a vigorous reaction starts. The white to grey suspension turns orange and becomes clear. The clear solution is poured onto ice/water and is extracted with EA. The aq. phase is acidified to pH 4-5 and extracted once more with EA. The combined organic extracts are dried over Na2SO4 and the solvent is removed in vacuo to give 2-acetyl-4,4-dimethyl-cyclohexanone (2.00 g) as a yellow oil; 1H NMR (CDCl3): δ 2.35 (t, J=7.0 Hz, 2H), 2.12 (s, 2H), 2.10 (s, 1H), 1.48 (t, J=7.0 Hz, 2H), 0.98 (s, 6H).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)OCC)C.[H-].[Na+].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[CH:19]1.O>C1COCC1>[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[CH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C(=Cc1ccc(-n2ccnc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.6 %

Procedure:
1.0 g of diethylbenzylphosphonate were dissolved in 50 ml of dry THF under nitrogen gas flow. To this solution, were added 0.21 g of 60% NaH while cooling the solution with ice, and the resultant solution was then stirred for 2 hours at room temperature. After cooling the whole solution with ice, 0.75 g of 4-(imidazole-1-yl)benzaldehyde were added thereto and stirred for 48 hours at room temperature. The solution reacted was condensed under reduced pressure, added with water, and extracted with chloroform. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, for which chloroform is used for the developer, thereby affording 0.5 g of 4-(imidazole-1-yl)stilbene.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[Na:14].[Na].[P:16]([C:20]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:21]=1[NH2:22])([OH:19])([OH:18])=[O:17]>CS(C)=O>[Na:14].[Na:14].[P:16]([C:20]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:8]=[C:7]([C:2]([F:13])([F:12])[F:1])[CH:6]=1)=[O:11])([OH:18])([OH:19])=[O:17]
Reactant: Nc1ccc(Br)cc1P(=O)(O)O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: CS(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Nc1ccc(Br)cc1P(=O)(O)O
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a 30 mL vial containing a stirring bar DMSO-D6 (0.5 mL), pyridine-D5 (1 drop), 3-trifluoromethylphenylisocyanate (14 mg, 0.080 mol) and 2-Phosphono-4-bromoaniline disodium salt (10 mg, 0.036 mmol) were added. The resulting mixture was stirred at 65° C. for 3 hours, resulting in a DMSO solution of the desired urea.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[O:27].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([NH2:28])=[O:27])=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of the 4-adamantan-1-yl-phenoxy acetic acid (114.6 mg, 0.40 mmol) and 3-amino benzamide (81.7 mg, 0.60 mmol) ware dissolved in DMF (4.0 mL), and were added EDCHCl (115.1 mg, 0.60 mmol), HOBt (81.1 mg, 0.60 mmol) and DIPEA (0.15 mL, 0.60 mmol). The reaction mixture was stirred overnight and then partitioned between Ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=9:3:1) gave 3-[2-(4-Adamantan-1-yl-phenoxy)acetyl-amino]-benzamide as a white solid (145.0 mg, 89.6% yield).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH:20]=[CH:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[CH2:18][O:17][C:16]1([CH3:30])[CH3:29])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:18][O:17][C:16]1([CH3:30])[CH3:29])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)CCC=C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@H](C=CCCCO)COC1(C)C
Temperature: -12 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A solution of 11.42 ml of acetic anhydride in 50 ml of dichloromethane is added dropwise at 0°-3° within a period of minutes to a solution of 20.2 g of 2, 16.83 ml of triethylamine and 0.62 g of 4-(dimethylamino)-pyridine in 0 ml of dichloromethane. After 30 minutes, the mixture is washed twice with ice-cold 2 N hydrochloric acid and twice with 10% sodium chloride solution. The aqueous phases are extracted with 100 ml of dichloromethane. The organic phases are dried over sodium sulphate and concentrated by evaporation, and the residue is dissolved hot in hexane/ethyl acetate 4:1. On cooling slowly to approximately 30° there crystallise 1.82 g of racemic (2R*,2S*)-2-formamino-3-acetoxy-4-methyl-4-pentenoic acid ethyl ester having a melting point of 98°-106°. The mother liquor is slowly cooled to -12° C. and kept at that temperature for one hour. Filtration yields 15.04 g of acetate 3, m.p. 73°-75°, [α]D =-75.6° (c=1, CHCl3), analysis by gas chromatography (Chirasil®-L-Val, 160°-180°, 1° per minute): (2R,3S)-isomer 93.5% (Tret =14.5 minutes), (2S,3R)-isomer 2.2% (Tret =14.8 minutes), (2R,3R)-isomer 2.2% (Tret =16.8 minutes), (2S,3S)-isomer 2.1% (Tret =17.1 minutes). 20.64 g of anhydrous potassium carbonate are added at -16° to a solution of (2R,3S)-2-formylamino-3-acetoxy-4-methyl-4-pentenoic acid ethyl ester (3) in 400 ml of absolute ethanol. After stirring at -18° to -11° C. for 4 hours, 500 ml of buffer solution (1 molar, phosphate, pH=7) are added dropwise. The mixture is stirred at room temperature for 0 minutes and extracted three times with 350 ml of dichloromethane each time. The organic phases are dried over sodium sulphate and concentrated by evaporation, and the residue is chromatographed on 1 kg of silica gel using hexane/ethyl acetate 1:2 as eluant, yielding 9.8 g of alcohol 1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][CH2:17][NH2:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CO>[Si:8]([O:15][CH2:16][CH2:17][NH:18][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([C:11]([CH3:13])([CH3:14])[CH3:12])([CH3:10])[CH3:9]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNC1CCOCC1
Reaction time: 1 h
Yield: 345 %

Procedure:
To a stirred cooled solution of tetrahydro-pyran-4-one (2 g, 19.98 mmol) in methanol (30 mL) were added 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (2.5 mg, 13.98 mmol). Stirring was continued for 1 h at room temperature. The reaction mixture was cooled and Na(CN)BH3 (2.5 g, 39.96 mmol) was added portion-wise, followed by stirring at room temperature for 20 h. The reaction mixture was quenched with water and the methanol was removed. The mixture was subsequently extracted with dichloromethane (3×30 mL) and the organic part was concentrated, dried and purified by Combi-Flash column (eluted at 20-50% ethyl acetate in hexane) to get [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amine (8j) (2.5 g, 48.23 mmol) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]=[CH:6][C:7]([F:10])([F:9])[F:8])[CH3:2].CN(C)C(N(C)C)=N.[N+:20]([CH3:23])([O-:22])=[O:21]>C(OC(=O)CC(C)=O)C>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([CH2:23][N+:20]([O-:22])=[O:21])[C:7]([F:9])([F:10])[F:8])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=CC(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(=O)CC(C)=O
Product: CCOC(=O)CC(C[N+](=O)[O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
1.0 g (5.94 mmol) of 4,4,4-trifluoro-2-butenoic acid ethyl ester and 0.15 mL (1.19 mmol) of 1,1,3,3-tetramethyl guanidine and 1.6 mL (29.8 mmol) of nitromethane were mixed. The resulting mixture was cooled to 0° C. and then stirred for 3 hours at room temperature, followed by addition of 100 mL of ethylacetoacetate. The reaction mixture was washed with water, and then an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1.1 g (4.80 mmol) of the title compound in a yield of 81%.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]1[C:16]([C:17]([C:19](=[CH:25]N(C)C)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:18])=[CH:15][C:14]2[C:9](=[C:10]([F:31])[C:11]([F:30])=[C:12]([F:29])[CH:13]=2)[N:8]=1.C1CCN2C(=NCCC2)CC1>ClC(Cl)Cl.C(O)C>[CH2:23]([O:22][C:20]([C:19]1[C:17](=[O:18])[C:16]2[CH:15]=[C:14]3[CH:13]=[C:12]([F:29])[C:11]([F:30])=[C:10]([F:31])[C:9]3=[N:8][C:7]=2[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:25]=1)=[O:21])[CH3:24]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
9.5 g of tert.-butylamine are added at a temperature of about 20° C., in the course of 5 minutes, to a stirred solution of 11.7 g of ethyl 2-(2-chloro- 6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 150 cm3 of trichloromethane at the same temperature. After stirring for 4 hours at about 20° C., the solution is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue obtained is taken up in 100 cm3 of ethanol. 5 g of DBU are added to the solution obtained and the mixture is heated at a temperature close to 75° C. for 3 hours. After cooling to about 20° C., the precipitate obtained is drained and washed with twice 50 cm3 of ethanol and twice 50 cm3 of diisopropyl ether. 9.5 g of 3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a colourless solid melting at 229° C., which is used for the subsequent steps without further purification.