Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].O1CCCC1.Br[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[CH2:19]([O:21][C:22]([O:24][CH2:25][CH3:26])=[CH2:23])[CH3:20]>O.CCOCC>[CH2:19]([O:21][C:22]1([O:24][CH2:25][CH3:26])[C:9]2=[C:18]3[C:13](=[CH:12][CH:11]=[C:10]2[CH2:23]1)[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH3:20]
Reactant: C=C(OCC)OCC
Reactant: Brc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC1(OCC)Cc2ccc3ccccc3c21

Procedure:
9.4 g of sodium amide are introduced into 350 ml of tetrahydrofuran. 25.9 g of 1-bromonaphthalene and 28 g of freshly prepared 1,1-diethoxyethylene are poured in succession into that mixture. The reaction mixture is refluxed for 16 hours and than taken up in water and ether. After washing the organic phase to neutral pH and drying thereof, the expected product is isolated and chromatographed over silica gel (dichloromethane/cyclohexane: 1/1).
Reaction SMILES: [H-].[Na+].C(O)(CC)(C)C.[Cl:9][C:10]1[CH:34]=[CH:33][C:13]([O:14][C:15]2[CH:32]=[CH:31][C:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=O)=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.[C:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36]>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:34]=[CH:33][C:13]([O:14][C:15]2[CH:32]=[CH:31][C:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)cc1OC
Reactant: CC(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Oc3ccc(Cl)cc3)cc2)cc1OC
Temperature: 100 °C

Procedure:
Sodium hydride (with 20% of paraffin oil; 2.25 g, 75 mmol) was stirred under reflux with absolute toluene (50 ml) and tert.-amyl alcohol (7.25 g, 82.5 mmol) was added dropwise within 30 minutes. When the solution had cooled to 100° C., 4-(4-chlorophenoxy)-3',4'-dimethoxy benzophenone (9.22 g, 25 mmol) and acetyl morpholine (16.17 g, 125 mmol) were added and the mixture was stirred under reflux for 8 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:34])=[O:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 27 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.102 mmol) obtained in Example 1, (3), and phenylmethanesulfonyl chloride (29 mg, 0.150 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (13 mg, yield 27%) as slightly brown amorphous.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[C:14](=[O:23])[C:15]2[C:16]([C:20](=[O:22])[CH:21]=1)=[N:17][S:18][N:19]=2>C(O)C>[Cl:12][C:13]1[C:14](=[O:23])[C:15]2=[N:19][S:18][N:17]=[C:16]2[C:20](=[O:22])[C:21]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: O=C1C=C(Cl)C(=O)c2nsnc21
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(Cl)C(=O)c3nsnc3C2=O)CC1
Yield: 14 %

Procedure:
A solution of 332 mg of 1-piperazinecarboxylic acid, ethyl ester and 200.6 mg of 5-chloro-2,1,3-benzothiadiazole-4,7-dione in absolute ethanol was heated at reflux, with stirring. The mixture was then stirred for 2 hours at room temperature, evaporated, chromatographed on silica gel, eluting with chloroform and concentrated to a red oil. This oil was crystallized from dichloromethanehexane, giving 50 mg of the desired product, mp 152°-154° C.
Reaction SMILES: [F:1][C:2]([F:43])([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=2[N+:26]([O-])=O)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:43])([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:33][CH:34]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[NH2:26])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(CCOC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Yield: 71.5 %

Procedure:
5.11 g (8.38 mmol) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenyl]methoxy}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethyl-formamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate is added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yielded 3.30 g of 2-(2,4-diaminophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals. ES+=551 [M+H]; 19F NMR CD3CN 300 MHz; δ=−64.46, −67.44
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:23])=[C:10]([C:12]2[NH:21][C:20](=O)[C:19]3[C:14](=[N:15][CH:16]=[CH:17][N:18]=3)[N:13]=2)[CH:11]=1>C(Cl)(Cl)Cl.CN(C=O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:23])=[C:10]([C:12]2[N:21]=[C:20]([Cl:3])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][N:18]=3)[N:13]=2)[CH:11]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(Br)cc1-c1nc(Cl)c2nccnc2n1
Yield: 99.3 %

Procedure:
Thionyl chloride (371 mg, 3.11 mmol) was added to the stirred suspension of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 (200 mg, 0.623 mmol) in chloroform (5 mL) and dry DMF (100 μL). The reaction mixture was refluxed under nitrogen for 1 h (starting material gone by HPLC). The solvent was removed in vacuo. Then the residue was triturated in Et2O and filtered off to give 210 mg of the title product 106 as a yellow solid (LCMS analysis).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5]
Reactant: COc1cc(F)c(C#N)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: N#Cc1c(F)cc(O)cc1F
Temperature: 180 °C
Reaction time: 1 h

Procedure:
A stirred, homogeneous mixture of finely powdered, compound 27 (17.0 g, 0.10 mol), aluminium chloride (29.4 g, 0.22 mol) and sodium chloride (7.1 g, 0.12 mol) was heated to 180° C. over 25 min and then at 180° C. for 1 h (glc and tlc analyses both revealed a complete reaction). Ice-water was added, and the product was extracted into ether (twice). The combined ethereal extracts were washed with water, and the product was extracted into 10% sodium hydroxide (twice) and the combined basic extracts were acidified with 36% hydrochloric acid. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a fawn solid.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@@H:2]12.[CH2:24]([CH:26]([CH2:29][CH3:30])[CH:27]=O)[CH3:25].C(O)(=O)C.C([BH3-])#N>CO>[CH2:24]([CH:26]([CH2:29][CH3:30])[CH2:27][N:6]1[CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@H:2]2[CH2:1]1)[CH3:25]
Reactant: CCC(C=O)CC
Reactant: O=S(=O)(N[C@H]1C[C@H]2CNCCN2C1)c1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)CN1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 42 (35 mg, 0.1 mmol) in methanol (0.5 mL) was added a solution of 2-ethylbutanal (20 mg, 0.2 mmol) in methanol (0.5 mL). To this solution was added acetic acid (30 μL, 0.5 mmol) followed by MP-cyanoborohydride resin (136 mg). The resulting mixture was shaken at 50° C. overnight and then filtered. The filtrate was concentrated. The residue was dissolved in 1:1 methanol:dimethyl sulfoxide and purified by HPLC (Gilson®, Xbridge™ 50×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/acetonitrile, UV=220 nm) to afford the title compound. 1H NMR (500 MHz, pyridine-d5/D2O) δ ppm 0.82 (t, 6 H, J=7.48 Hz), 1.24-1.36 (m, 4 H), 1.42-1.54 (m, 2 H), 1.83-1.91 (m, 1 H), 2.14-2.29 (m, 6 H), 2.36 (m, 1H), 2.84 (m, 2H), 2.93 (s, 1 H), 3.01 (m, 1H), 4.21 (m, 1H), 7.67 (t, 1H, J=8 Hz), 7.85 (d, 1H, J=8 Hz), 8.36 (d, 1H, J=8 Hz), 8.48 (s, 1 H), 10.02 (d, 1H, J=8 Hz); MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:49]=[C:50]([S:54]([NH2:57])(=[O:56])=[O:55])[CH:51]=CC=1>>[NH2:57][S:54]([C:50]1[CH:51]=[C:23]([CH:24]=[CH:48][CH:49]=1)[NH:22][C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH2:31][CH3:32])=[O:21])(=[O:56])=[O:55]
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1cccc(S(N)(=O)=O)c1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 3-aminobenzenesulfonamide was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [C:1]([CH:4]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:5][C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([CH3:26])=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:27][CH3:28])=[CH:8][C:7]=1[CH2:29][CH2:30][CH3:31])([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:53]([S:56]([NH2:59])(=[O:58])=[O:57])([CH3:55])[CH3:54].N12CCCN=C1CCCCC2>C1COCC1>[CH:53]([S:56]([NH:59][C:1]([CH:4]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:5][C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([CH3:26])=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:27][CH3:28])=[CH:8][C:7]=1[CH2:29][CH2:30][CH3:31])=[O:3])(=[O:58])=[O:57])([CH3:55])[CH3:54]
Reactant: CC(C)S(N)(=O)=O
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(C(=O)NS(=O)(=O)C(C)C)c1ccc2c(c1)OCO2
Temperature: 80 °C
Yield: 27.2 %

Procedure:
A 15 mL capacity high pressure vessel equipped with a magnetic stir bar was charged with a solution of 0.230 g (0.42 mmol) of the product of Example 13 in 4.0 mL of anhydrous THF and 0.172 g (1.06 mmol) of 1,1'-carbonyldiimidazole was added. The vessel was sealed and the contents were stirred and heated at 80° C. for 4 hours. The reaction was then cooled to room temperature, opened and a solution of 0.130 g (1.06 mmol) of isopropylsulfonamide and 158 μL (1.06 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 4 mL THF was added. The reaction vessel was resealed and then stirred and heated at 80° C. overnight. The reaction vessel was then cooled, opened and the contents were partitioned between water and EtOAc. The organic layer was separated washed with 10% aqueous NaHSO4, brine, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted first with 250 mL of CHCl3 /MeOH/NH4OH (95:5:0.5), next with 200 mL of CHCl3 /MeOH/NH4OH (92:8:0.5), and finally with 200 mL of CHCl3 /MeOH/NH4OH (90:10:0.5). Evaporation of the purified fractions and drying in vacuo afforded 0.074 g (27%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[C:15]1([CH3:26])[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23](O)=[O:24])[CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])/[CH:22]=[CH:21]/[C:17]2[CH:16]=[C:15]([CH3:26])[CH:20]=[CH:19][CH:18]=2)=[N:8]1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Reactant: Cc1cccc(/C=C/C(=O)O)c1
Product: Cc1cccc(/C=C/C(=O)Nc2ccn(CCCCC(C)(F)F)n2)c1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-m-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.13 min; [M+H]+=348.31.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:6]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl>CN(C)C=O>[CH3:1][O:2][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:6]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: C[O-]
Reactant: COc1ccccc1Oc1c(Cl)nc(C(F)(F)F)nc1NS(=O)(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(C(F)(F)F)nc1OC
Reaction time: 8 h
Yield: 66.2 %

Procedure:
Sodium methoxide (336 mg) was added to a solution of 320 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]-2-phenylethenesulfonamide in 10 ml of N,N-dimethylformamide followed by stirring overnight. The reaction mixture was poured into a mixture of ice and 1N hydrochloric acid and the solid separated out therefrom was collected by filtration. This solid was purified by a silica gel column chromatography (chloroform) and the resulting oil was crystallized from ether to give 210 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-trifluoromethyl-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: C([N:3](CCCC)[C:4](=[O:6])[CH3:5])#N.[CH2:11]([N:13]([CH2:16][CH2:17][CH2:18]N)[CH2:14][CH3:15])[CH3:12]>O1CCCC1>[CH2:14]([N:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH2:5][C:4]([NH2:3])=[O:6])[CH3:15]
Reactant: CCCCN(C#N)C(C)=O
Reactant: CCN(CC)CCCN
Solvent: C1CCOC1
Product: CCN(CC)CCCCC(N)=O

Procedure:
12.60 g (0.09 mol) of N-cyano-N-butylacetamide are refluxed with 13.4 g (0.1035 mol) of diethylaminopropylamine in 25 ml of tetrahydrofuran for 2 hours, after which, according to investigation by gas chromatography, the educt has completely reacted to give 3-diethylaminopropylacetamide, tri-n-butylisomelamine and another component, which probably consists of butyl cyanamide. The mixture is concentrated on a rotary evaporator, and the oil which remains is left to stand at room temperature and the reaction which subsequently takes place is monitored by gas chromatography. After 5 days, the unknown component, which probably consists of butyl cyanamide, has largely reacted and has formed tributylisomelamine by trimerisation. The mixture is distilled in a bulb tube oven, first under 23.4 mbar and at a maximum temperature of 125° C. and then under 0.156 mbar and at a maximum temperature of 180° C. 6 fractions totalling 24.4 g are thereby obtained, analysis of which by gas chromatography gives a yield of 74.7% of tributylisomelamine and 96.7% of 3-diethylaminopropylacetamide. An analysis sample of tributylisomelamine, which is liquid at room temperature, can be isolated by renewed distillation of the fractions obtained under the high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][NH:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][N:16]([CH:17]1[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25]1)[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCNC1Cc2ccccc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1CCN(c1ncccn1)C1Cc2ccccc2C1

Procedure:
To a stirred solution of compound 44 (1.2 g, 3.48 mmol) in dry toluene (35 mL) were added 2-bromo-pyrimidine (0.55 g, 3.48 mmol) and NaOtBu (0.47 g, 4.88 mmol) and the solution was purged with argon for 30 minutes. Pd2(dba)3 (0.159 g, 0.17 mmol) and Verkade's super base (0.24 g, 0.70 mmol) were then added and the solution refluxed overnight. The reaction mixture was filtered through Celite® reagent and washed with ethyl acetate. The filtrate was washed with water and brine solution, dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatography eluting with 14-15% ethyl acetate-hexane to get compound 47.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1nc(Cl)cc(N(C)C2CCOCC2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(c1cc(Cl)nc(C(=O)O)c1Cl)C1CCOCC1
Yield: 77.4 %

Procedure:
To a stirred solution of methyl 3,6-dichloro-4-[methyl(oxan-4-yl)amino]pyridine-2-carboxylate (114 mg, 0.36 mmol) in THF (5 ml) was added 2M aqueous NaOH (0.89 ml, 1.79 mmol) and the reaction mixture was left to stir at room temperature for 20 h after which time the THF was evaporated in vacuo. The aqueous phase was then treated with an aqueous 10% citric acid solution to pH 5-6 and then extracted with EtOAc (3×50 ml) followed by a solution of 1:1 IPA/CHCl3 (2×50 ml), the combined organic phases were then washed with brine (50 ml) dried with Na2SO4 and evaporated to give the title compound as a white solid (85 mg, 78%). LC-MS 100%, 1.47 min (3.5 minute LC-MS method), m/z=305.5/306.9, 1H NMR (500 MHz, Methanol-d4) δ 7.10 (s, 1H), 4.03 (dd, J=11.5, 4.4 Hz, 2H), 3.99-3.86 (m, 1H), 3.47 (t, J=11.0 Hz, 2H), 2.90 (s, 3H), 2.05-1.90 (m, 2H), 1.74 (d, J=12.4 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([O:13][PH:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: O=[PH](O)CCCCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=[PH](CCCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110 %

Procedure:
To a solution of the compound of example 80 (1.75 g, 8.83 mmol) in dry CH2Cl2 (40 mL) was added benzyl alcohol (1.83 mL, 17.7 mmol), DMAP (108 mg, 0.88 mmol) and EDC (1.91 g, 10.0 mmol). The mixture was then stirred at room temperature for 18 h. The mixture was concentrated in vacuum, taken-up in ethyl acetate and washed with NaHCO3 (5%) and H2O. Drying (Na2SO4) and concentration gave 2.8 g of a pale yellow oil which was purified by flash chromatography (SiO2, ethyl acetate:hexane (1:1)) to give 1.92 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][Br:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: BrCCc1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-benzyloxyphenethyl alcohol (8.29 g) and carbon tetrabromide (24.1 g) in ether (150 ml) is portionwise added triphenylphosphine (19.0 g) and the resulting mixture stirred for about 3 hours. The supernatent is decanted, the solid washed with ether and the combined organic solution concentrated in vacuo. The crude product is purified by passing it through a silica plug to give 4-benzyloxyphenethyl bromide.
Reaction SMILES: [CH3:1][C:2]1(C)[O:9]C(=O)CC(=O)[O:3]1.[C:11]([O:20][CH2:21][CH3:22])(=[O:19])[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=O.C(O)=O.Cl>O.C(N(CC)CC)C>[CH2:17]([O:16][C:14]([CH:12]([C:11]([O:20][CH2:21][CH3:22])=[O:19])[CH2:1][C:2]([OH:9])=[O:3])=[O:15])[CH3:18]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(=O)O)C(=O)OCC
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
After weighing in 14.4 g (0.1 mol) of Meldrum's acid and 17.4 g (0.1 mol, 15.5 ml) of diethyl mesoxalate to 100 ml of the mixture of formic acid and triethylamine prepared as described in Example 1, the reaction mixture was heated to 95° C. during 1 hour and reacted at the same temperature for 2 hours. After cooling the reaction mixture to room temperature, adding 350 ml of water and adjusting the pH value to 2 with concentrated hydrochloric acid, the aqueous solution was extracted with 200 ml and then with 100 ml of chloroform. The combined chloroform extract was stirred with 5 g of sodium sulfate and 1 g of activated charcoal at room temperature for 30 minutes, then filtered and the chloroform was distilled off under reduced pressure. After adding 25 ml of diethyl ether to the evaporation residue the mixture was let stand at 0°-5° C. for 16 hours. After filtering the white solid precipitate, ether was evaporated from the filtrate to give the aimed product as a liquid residue.