Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)=[O:10].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.O>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:12]=1)=[O:10]
Reactant: Clc1nccc2ccccc12
Reactant: COC(=O)c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccn(-c2nccc3ccccc23)c1
Temperature: 100 °C
Reaction time: 22 h
Yield: 88.5 %

Procedure:
1.04 g (7.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.376 g (3 mmol) of 3-methoxycarbonyl-1H-pyrrole and 0.49 g (3 mmol) of 1-chloroisoquinoline dissolved in 6 mL of dimethyl sulphoxide. After stirring at 100° C. for 22 hours, the reaction mixture is poured into 15 mL of water and is then allowed to crystallise for 1 hour at 20° C. After filtering the reaction mixture and air-drying the solid residue, 0.67 g of 3-methoxycarbonyl-1-(isoquinol-1-yl)-1H-pyrrole is obtained in the form of a beige-coloured solid melting at 86° C. Mass spectrum (EI): m/e 252 (M+.), m/e 221.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>[Zn].C(O)C>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([OH:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: OC1c2ccccc2CCc2ccccc21
Reaction time: 2 h

Procedure:
A mixture of 208 g of 10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-one, 2 l of ethanol, 200 g of sodium hydroxide and 300 g of zinc powder is heated to boiling under reflux while stirring for 2 hours. The still warm mixture is filtered over kieselguhr while back-washing with about 1 l of methanol. After concentration of the yellow solution to about 1 l, the thick paste obtained is partitioned between 2 l of chloroform and 1 l of water. The alkaline-aqueous phase is adjusted to pH 3 to 4 with about 400 ml of concentrated hydrochloric acid while cooling with ice and extracted with 1 l of chloroform. The combined chloroform extracts are washed with water until they are neutral and subsequently dried over magnesium sulfate in the presence of a small amount of active carbon. After filtration and concentration of the clear, light yellowish solution, there is obtained 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol as an almost white, crystalline mass with a melting point of 89°-91°.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[C:12](/[CH:15]=[CH:16]/[C:17]([N:19]([CH3:31])[CH2:20][C:21]3[S:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:22]=3[CH3:30])=[O:18])[CH:13]=[N:14][C:8]=2[NH:7][C:6]1=[O:32].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH3:31][N:19]([CH2:20][C:21]1[S:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[CH3:30])[C:17](=[O:18])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[N:14][C:8]2[NH:7][C:6](=[O:32])[N:5]([CH2:4][CH:3]=[O:2])[CH2:10][C:9]=2[CH:11]=1
Reactant: COC(CN1Cc2cc(/C=C/C(=O)N(C)Cc3sc4ccccc4c3C)cnc2NC1=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CC=O)C(=O)N3)sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
A suspension of (E)-3-[3-(2,2-dimethoxy-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]-N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide (450 mg, 0.937 mmol) in CH2Cl2 (20 mL) was treated with TFA (1 mL) and H2O (1 mL). The reaction was allowed to stir overnight at room temperature. The solution was washed with saturated NaHCO3 (2×15 mL). The aqueous solutions were extracted with CH2Cl2 (40 mL). The combined CH2Cl2 solutions were washed with brine, dried over Na2SO4, and concentrated to give the title compound (440 mg, 99%) as a white solid and as amide rotomers: 1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.54 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.53-7.31 (m, 4H), 5.11-4.88 (m, 2H), 4.51 (s, 2H), 4.18 (s, 2H), 3.15-2.93 (m, 3H), 2.42 (s, 3H); MS (ESI) m/e 435 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[H-].[Na+].I[CH3:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH3:18])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CI
Reactant: COc1ccc(CCO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
To a solution of 2-(4-methoxy-2-nitrophenyl)ethanol (1 g; 5.07 mmol; 1 eq) in THF (50 mL) is added sodium hydride (406 mg; 10.14 mmol; 2 eq) at 0° C. and the reaction mixture is stirred at 0° C. for 10 min before adding iodomethane (0.63 mL; 10.14 mmol; 2 eq). The reaction mixture is stirred overnight. It is quenched by addition of water. The product is extracted with EtOAc and the organic phase is dried over MgSO4. The solvent is evaporated under reduced pressure and the residue is purified by flash chromatography using a mixture of petrol ether and EtOAc (70/30) as eluent. The solvents are evaporated to afford 680 mg (63%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 7.35 (d, J=3.0 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 6.98 (dd, J=9.0, 3.0 Hz, 1H), 3.76 (s, 3H), 3.54 (t, J=9.0 Hz, 2H), 3.24 (s, 314), 3.01 (t, J=9.0 Hz, 2H), HPLC (max plot) 94%; Rt 4.18 min.
Reaction SMILES: [C:1]([NH2:4])([NH2:3])=[O:2].[OH:5][OH:6].C1(=O)[O:12][C:10](=O)[CH2:9]C1.C(NC1C=CC=CC=1)(=[O:16])C.OC1C=CC=C2C=1N=CC=C2.OO>>[C:1]([NH2:4])([NH2:3])=[O:2].[OH:5][OH:6].[OH:16][CH2:9][CH:10]([CH2:1][OH:2])[OH:12]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: NC(N)=O
Agent: OO
Agent: Oc1cccc2cccnc12
Product: OCC(O)CO

Procedure:
The stabilities of further test formulations prepared in the same manner as described above, containing 6.5% urea peroxide, and 0.5% added succinic anhydride (Example 9), 0.5% acetanilide (Control D) and 0.5% 8-hydroxyquinoline (Control E) were compared by storage for varying periods at 40° C. and measurement of the residual hydrogen peroxide contents as aforesaid. The following results were obtained:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3ncccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyrimidyl)piperazine instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 66(3) instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)=[O:26])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1ncc[nH]1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(Cc1ncc[nH]1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-(1H-imidazol-2-ylmethyl)-amine
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][N:16]([CH3:29])[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=O)=[CH:19][CH:18]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:15][N:16]([CH3:29])[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:19][CH:18]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N(C)C)c4ccccc34)nc2c1
Yield: 26 %

Procedure:
2-(4-(Dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-dimethylamino-1-naphthaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one (75 mg, 26%) was isolated as a yellow solid. Selected data: MS (m/z): 376.07; MP 269-271° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH:13]([C:14]([C:15]1[CH:11]=[CH:12][C:22]3[C:17](=[CH:9][CH:10]=[C:25]([O:24][CH3:23])[CH:21]=3)[CH:16]=1)=[O:18])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C1CCc2cc(OCc3ccccc3)ccc21
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cc(C(=O)C3Cc4cc(OCc5ccccc5)ccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-Benzyloxyindanone (1.5 g, 6.29 mmol) was treated with NaH (60%, 377 mg) in THF (50 mL), and then Example 168A (1.59 g) was added. The reaction was stirred for 6 hours at room temperature. The precipitates were collected by filtration and dissolved in water, acidified with concentrated HCl, and the resulting precipitates were collected, washed with water and dried to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)=[CH:18][C:17]=1[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3([CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[NH:7][C:6]4=[O:14])[CH2:30][CH2:31]3)[C:25](=[O:32])[NH:24][CH2:23]2)=[CH:18][C:17]=1[CH3:33]
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: Cc1cc(N2CNC(=O)C23CCNCC3)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1cc(N2CNC(=O)C23CCN(CCCn2c(=O)[nH]c4ccccc42)CC3)ccc1Cl
Yield: 36.7 %

Procedure:
A mixture of 4.21 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1-(4-chloro-3-methylphenyl)-1,3,8-triazaspiro [4,5] decan-4-one, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 6 hours with water-separator. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of methanol and N,N-dimethylformamide. The product is filtered off and dried, yielding 3 parts (36.7%) of 1-(4-chloro-3-methylphenyl)-8-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-1,3,8-triazaspiro [4,5]decan-4-one; mp. 208.6° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:4](=[O:15])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH:7]=[CH:8]1.[H][H]>[Pd].CCOC(C)=O>[CH3:1][C:2]1([CH3:24])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(c2ccccc2)CC=CC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N(c2ccccc2)CCCC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 2-neck round bottom flask was added (Z)-tert-butyl 4,4-dimethyl-2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (7 mg, 0.02 mmol), 10% Pd/C (2.3 mg, 0.021 mmol) and EtOAc (1 mL). The reaction was then charged with hydrogen with a balloon and then stirred at rt for 2 hr. The reaction was filtered through CELITE® and the filtrate was concentrated to give tert-butyl 4,4-dimethyl-2-oxo-1-phenylazepan-3-ylcarbamate (6.5 mg, 0.020 mmol, 92% yield) as a clear film. Anal. Calcd. for C19H28N2O3 m/z 332.2. found: 333.2 (M+H)+.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1)=[O:45].Cl[C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[C@@H:37]1[CH2:36][NH:35][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 426 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([OH:31])=[C:26]([F:32])[CH:25]=1)=[O:19])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:31][C:27]3[C:26]([F:32])=[CH:25][C:24]([CH2:23][CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:29][C:28]=3[F:30])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1Cc1cc(F)c(O)c(F)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: O=C(O)C1CC1Cc1cc(F)c(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 88.2 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.023 g, 0.10 mmol) obtained in Step C of Preparation Example 27 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.026 g, 0.10 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.037 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O-:15].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([O:15][CH3:14])[C@H:12]([OH:11])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: [Na+]
Solvent: CO
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3 g, 16 mmol) was dissolved in 2-Me-THF (10 mL) and a solution of sodium methoxide in methanol (10 mL of a 25% solution) was added and the reaction stirred at rt overnight. Reaction was quenched with sat. NH4Cl and concentrated, then after extraction with EtOAc, residue was purified by column chromatography on SiO2 (35% EtOAc/heptane) which gave the title compound IIa as a clear oil (1.05 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>O1CCOCC1>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:6][CH:3]([CH2:2][NH2:1])[CH2:4][CH3:5])[C:11]=1[C:12]#[N:13]
Reactant: CCC(O)CN
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(CN)Oc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.01 g (22 mmol) 1-amino-2-butanol are dissolved in 6.5 ml 1,4-dioxane, combined with 880 mg (7.8 mmol) sodium hydride and stirred for 30 min at ambient temperature. 2 g (14.7 mmol) of 2-amino-6-fluorobenzonitrile are added to this reaction mixture and it is stirred for 24 h at 50° C. Then the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[F:21][C:22]1[C:27]([F:28])=[C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:21][C:22]1[C:27]([F:28])=[C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=[CH:24][C:23]=1[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: CCCCCCOc1ccc(-c2cnc(Cl)nc2)cn1
Reactant: CCCCCCCCc1ccc(B(O)O)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OCCCCCC)nc3)cn2)c(F)c1F
Yield: 39 %

Procedure:
The reaction of 2.5 mmol of 2-chloro-5-(6-hexyloxypyridin-3-yl)pyrimidine, 2.5 mmol of 2,3-difluoro-4-octylphenylboronic acid, 5 mmol of sodium carbonate and 0.025 mmol of tetrakis(triphenylphosphine)palladium(0) in 8 ml of toluene, 4 ml of ethanol and 4 ml of water is carried out analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using dichloromethane/ethyl acetate 98:2 (v/v) as eluent and is recrystallized from acetonitrile, giving 0.47 g (39%) of colorless crystals, X 94.5 SC 125.5 SA 156 I.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:5]=1[O:11][CH3:12].[OH-].[Na+]>O1CCCC1>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[C:5]([O:11][CH3:12])[CH:6]=1
Reactant: COC(=O)c1ccc(I)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(I)ccc1C(=O)O
Yield: 97.3 %

Procedure:
The 4-iodo-2-methoxybenzoic acid methyl ester of Step A (2.7 g, 9.24 mmol) was dissolved in tetrahydrofuran (40 mL) and 1 N sodium hydroxide (20 mL, 20 mmol) was added. The reaction mixture was heated at reflux for 3 hours, then cooled and concentrated in vacuo to give an orange oil that was partitioned between ethyl acetate and 2 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2.5 g of title product as a yellow-orange solid, m.p. 144–146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[C:25]1([C:31]2([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:34]2[CH2:33][CH2:32][C:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]2)=[O:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1ccc(-c2cc(C(=O)O)sc2-c2ccc(Cl)cc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cc(C(=O)N3CCC(C(N)=O)(c4ccccc4)CC3)sc2-c2ccc(Cl)cc2Cl)cc1
Reaction time: 3 h

Procedure:
2 g of the compound obtained in stage 1E), 1.27 g of 4-phenylpiperidine-4-carboxamide (Preparation 2), 2.22 ml of Et3N and 1.86 g of TBTU are added to 40 ml of CH2Cl2. The mixture is stirred at AT for 3 hours. It is evaporated to dryness, water is added and extraction is carried out with ethyl acetate. The organic phase is dried and then evaporated. After purifying by chromatography on silica (eluent: heptane-AcOEt (gradient from 0% to 30%)), 2.8 g of the expected compound are obtained.
Reaction SMILES: [O:1]([C:4]1[CH:5]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[C:39]([O:41][CH2:42]C)[C:38]([O:44][CH2:45]C)=[C:37]([O:47][CH2:48]C)[CH:36]=5)=[CH:31][N:30]=4)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:7]=[C:8]([O:13][CH2:14]C)[C:9]=1[O:10][CH2:11]C)[CH2:2]C.[CH3:50][S:51]([OH:54])(=[O:53])=[O:52]>C(O)C.C(Cl)(Cl)Cl>[CH3:50][S:51]([OH:54])(=[O:53])=[O:52].[CH3:50][S:51]([OH:54])(=[O:53])=[O:52].[CH3:42][O:41][C:39]1[CH:40]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([N:25]3[CH2:26][CH2:27][CH2:28][N:22]([C:19]4[CH:18]=[CH:17][C:16]([C:6]5[CH:5]=[C:4]([O:1][CH3:2])[C:9]([O:10][CH3:11])=[C:8]([O:13][CH3:14])[CH:7]=5)=[CH:21][N:20]=4)[CH2:23][CH2:24]3)=[N:30][CH:31]=2)[CH:36]=[C:37]([O:47][CH3:48])[C:38]=1[O:44][CH3:45]
Reactant: CCOc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OCC)c(OCC)c(OCC)c5)cn4)CC3)nc2)cc(OCC)c1OCC
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(OC)c(OC)c5)cn4)CC3)nc2)cc(OC)c1OC

Procedure:
To a solution of 1,4-bis[5-(3,4,5-triethoxylphenyl)-2-pyridyl]hexahydro-1,4-diazepine (72.4 g, 0.120 mol) in ethanol-chloroform (1:3, 600 mL) was added methanesulfonic acid (24.9 g, 0.258 mol), and the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to yield the title compound as a slightly yellow crystalline powder (melting point: 204.0–206.0° C.) (88.2 g, yield: 92%).