Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.Cl[C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)(=[O:45])=[O:44])=[CH:39][N:38]=1.C(N(CC)CC)C>ClCCl>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][C:6]2[N:7]=[N:8][N:4]([CH2:3][CH2:2][NH:1][C:37]3[CH:42]=[CH:41][C:40]([S:43]([N:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)(=[O:45])=[O:44])=[CH:39][N:38]=3)[N:5]=2)=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCc2nnn(CCNc3ccc(S(=O)(=O)N4CCOCC4)cn3)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.33 g), 2-chloro-5-(4-morpholinylsulphonyl)pyridine (145 mg) and triethylamine (65 mg) in dichloromethane (15 ml) was heated under reflux for 2 hours, then stirred at room temperature for 16 hours and evaporated. The residue was purified by chromatography on silica (6 g) using dichloromethane plus from 0 to 5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (84 mg), m.p. 112°-114° C. Found: C,56.32; H,5.90; N,10.45. C31H36Cl2N8O8S requires: C,56.13; H,5.80; N,10.48%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:11][CH:10]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(C2OCCO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C2OCCO2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled stirred solution of (4-(1,3-dioxolan-2-yl)phenyl)methanol (prepared as described in WO2012168359, which is incorporated herein by reference in its entirety, 1.2 g, 6.6 mmol) and triethylamine (2.8 mL, 20.0 mmol) in DCM (40 mL) was added dropwise a solution of methanesulfonyl chloride (0.77 mL, 10.0 mmol) in DCM (10 mL). The reaction mixture was stirred at this temperature for 40 minutes and then at room temperature for 18 hours. The reaction mixture was washed with water and the organic phase dried (magnesium sulfate). The filtrate was evaporated at reduced pressure to afford the title compound which was used immediately without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH:16][S:17](=[O:27])(=[O:26])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[NH:39][N:38]=[N:37][N:15]=3)[CH:9]=2)[N:5]=[C:4]([NH:16][S:17](=[O:26])(=[O:27])[NH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:3]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)NCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1NS(=O)(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
Benzylsulfamic acid [6-chloro-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide (4.17 g) was dissolved in DMF (55 ml). Sodium azide (5.2 g) and ammonium chloride (4.28 g) were added and the mixture was stirred for 20 h at 80° C. Then the mixture was pored onto water and extracted with EtOAc. The layers were separated and the water layer was acidified with acetic acid to pH ˜5 and extracted with EtOAc. The combined organic layers from the 2nd extraction were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude material was purified by chromatography over silicagel with EtOAc/MeOH/ammonia=5/1/0.5 to give benzylsulfamic acid [6-chloro-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl]-amide (1.67 g). LC-MS: tR=5.02; [M+H]+=566.36.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:24])[CH3:23])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[OH:8].Cl[CH2:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:23])[CH3:24])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[O:8][CH2:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][N:31]=1
Reactant: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Reactant: Fc1cnc(CCl)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ncc(F)cc2F)c(Cl)c1=O
Temperature: 60 °C
Yield: 37.1 %

Procedure:
To a solution of Intermediate 1 (505 mg, 1.31 mmol) in N,N-dimethylformamide (3 mL) was added 2-chloromethyl-3,5-difluoro-pyridine from Step C (214 mg, 1.31 mmol), potassium carbonate (452 mg, 3.27 mmol) and 18-crown-6 (40 mg). The slurry was heated at 60° C. for eighteen hours. After cooling the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a colorless oil (250 mg, 37% yield). MS (M+H): 514; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.16 (s, 3H), 2.21 (s, 3H), 5.62-5.72 (m, 2H), 7.28-7.30 (m, 1H), 7.54-7.58 (m, 2H), 7.92 (s, 1H), 8.14 (d, J=8.21 Hz, 1H), 8.40 (s, 1H), 8.78 (d, J=5.47, 1H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].Cl[C:5]1[N:10]=[C:9]([C:11]2[C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:8]=[CH:7][CH:6]=1.[H-].[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:1]([S:3][C:5]1[N:10]=[C:9]([C:11]2[C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:8]=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCS
Reactant: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCSc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Yield: 91.5 %

Procedure:
Add ethanethiol (0.71 mL, 0.96 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (37 mg, 0.1 mmol) in DMF (2.5 mL) at 0° C. Add sodium hydride (38 mg, 0.96 mmol), stir the mixture at room temperature for 72 hours. Dilute the reaction mixture with methylene chloride (50 mL) and wash with water (2×50 mL), brine (1×50 mL). Dry the combined organic layers with sodium sulfate and concentrate. Purify the residue by flash column chromatography (SiO2, 50% ethyl acetate/hexanes) to give the title compound 35 mg (91%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:24])=[O:13]
Reactant: COc1ccccc1Sc1ccccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccccc1Sc1ccccc1OC
Temperature: 25 °C

Procedure:
Dissolve 115 g of the acid of Step A in 3.5 l of methanol and add slowly 25 ml of sulfuric acid. Stir under reflux for 72 hours. Cool the reaction mixture to room temperature and add 100 g of sodium bicarbonate in portions. Stir for an additional hour and strip to dryness. Dissolve the residue in methylene chloride and wash the solution three times with water. Dry the solution and strip to an oil which solidifies. (m.p. 82°-84° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24](O)=[O:25].Cl.[CH3:28][O:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH2:32][CH2:33][NH:34][CH2:35]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[N:6]=[C:5]2[C:24]([N:34]1[CH2:33][CH2:32][C:31]2[C:36](=[CH:37][CH:38]=[CH:39][C:30]=2[O:29][CH3:28])[CH2:35]1)=[O:25]
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Reactant: COc1cccc2c1CCNC2
Agent: Cl
Product: COc1cccc2c1CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccc(F)cc13)C2
Yield: 41.1 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 104 (41.1% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.88 and 3.03 (2t, 2H), 3.55 and 4.02 (2t, 2H), 3.72-3.3.77 (m, 6H), 3.86 and 3.92 (2s, 6H), 4.48 and 4.92 (2s, 2H), 6.63-7.27 (m, 3H), 7.62-7.85 (m, 3H), 7.98-8.07 (m, 1H), 8.23-8.26 (m, 1H); MS (ESI) m/z 504 ([M+H]+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)[CH3:7])[N:3]=[CH:2]1.[C:17]([NH:24][C@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[NH:1]1[CH:5]=[C:4]([C@H:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][O:15][C:33](=[O:34])[CH:25]([NH:24][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:7])[N:3]=[CH:2]1
Reactant: Cc1c(CO)cccc1[C@H](C)c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cc1c(COC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)cccc1[C@H](C)c1c[nH]cn1

Procedure:
The title compound was prepared from (S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg, 1.0 mmol), Boc-L-Phenylalanine (795 mg, 3.0 mmol), EDCl (671 mg, 3.5 mmol) and DMAP (427 mg, 3.5 mmol) according to the procedure described in Example 3. Intermediate 12 was purified by a column chromatography using 35-100% ethyl acetate in hexane.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][C:26]3[CH:27]=[C:28]([CH2:36][OH:37])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[F:38][C:39]([F:49])([F:48])[C:40]1[C:41]([CH:46]=O)=[N:42][CH:43]=[CH:44][CH:45]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:35][C:32]([F:33])([F:34])[C:30]1[CH:29]=[C:28]([CH2:36][OH:37])[CH:27]=[C:26]([CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[CH:16]([NH:15][CH2:46][C:41]2[C:40]([C:39]([F:48])([F:38])[F:49])=[CH:45][CH:44]=[CH:43][N:42]=2)[CH2:17][CH2:18]3)[CH:31]=1
Reactant: NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21
Reactant: O=Cc1ncccc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCc1cc(Cc2ccc3c(c2)CCC3NCc2ncccc2C(F)(F)F)cc(C(F)(F)F)c1
Yield: 45.7 %

Procedure:
Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added to a solution of (3-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (30 mg, 0.093) and 3-trifluoromethyl-2-formylpyridine (15 mg, 0.086 mmol) in DCM (1 mL). The reaction was stirred at rt for 24 h before aq. sat. NaHCO3 (2 mL) was added to the mixture was filtered over a phase separator. The organic filtrate was evaporated to dryness in a Genevac. The crude material was purified by prep. LCMS to afford the title compound (18.9 mg, 42.1%). MS (ESI): m/z [M+H]+ 481.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([C:28]#[N:29])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:30])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:28][NH2:29])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])c(C#N)n2)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Reaction time: 8 h
Yield: 130.7 %

Procedure:
To a solution of (6-cyano-5-nitro-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (1.06 g, 2.56 mmol) in THF (10 mL) and acetic acid (20 mL) was added Pd/C (10%, 200 mg) and the reaction mixture was hydrogenated overnight. The catalyst was filtered and the filtrate evaporated to afford (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (1.3 g) as the acetate salt, which was used without further purification. MS: [M+H]+=389.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C[N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([CH:17]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[C:18]1[CH:28]=[CH:27][C:21]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH2:12][CH2:13]2>C1(C)C=CC=CC=1.C(O)(=O)C.[Zn]>[CH:9]12[NH:8][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12][N:11]([CH:17]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[C:18]1[CH:28]=[CH:27][C:21]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH2:10]2
Reactant: COc1cccc(C(c2ccc(C(=O)N(C)C)cc2)N2CCC3CCC(C2)N3C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cccc(C(c2ccc(C(=O)N(C)C)cc2)N2CCC3CCC(C2)N3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
0.4 ml of 2,2,2-trichloroethylchloro formate and 0.52 g of K2CO3 were added to a solution of the compound obtained in Example 4.10 (1.02 g) in toluene (25 ml), kept under argon inert atmosphere. The mixture was heated at reflux for 16 hours and at the end cooled at room temperature. The mixture is washed in sequence with water, with an aqueous solution of 15% citric acid and then with brine. At the end of the washings the organic phase was recovered and dehydrated on sodium sulphate. After solvent evaporation 1.21 g of a light yellow oil (carbamate) were obtained. The oil was dissolved in 25 ml of glacial acetic acid. To the solution 0.82 g of zinc in powder were added. The mixture was kept under stirring at room temperature for 16 hours and at the end diluted with about 25 ml of toluene. The solvent was evaporated under vacuum. The residue was dissolved in the minimum volume of dichloromethane. The solution was extracted three times with an aqueous solution of 15% w citric acid. The aqueous phases were shaken with dichloromethane, then brought to an alkaline pH with conc. NH4OH and extracted again with dichloromethane. The pooled organic phases were dehydrated with sodium sulphate and the solvent evaporated. 0.52 g of the compound 4-[(3,9-diazabicyclo[4.2.1]non-3-yyl)-(3-methoxy-phenyl)methyl]-N,N-dimethylbenzamide were obtained. Yield: 62%; IR (nujol) (λ=cm−1) 1646 (C═O), 3120 (NH); 1H-NMR (CDCl3): δ 1.39-1.65 (m, 3H), 1.74-1.97 (m, 1H), 2.11-2.30 (m, 2H), 2.66 (bs, 1H), 2.75 (dd, 1H, J=2.2 and 11.0 Hz), 2.81-3.04 (m, 3H), 3.05 (s, 6H), 3.11-3.32 (m, 2H), 3.81 (s, 3H), 4.27 (s, 1H), 6.63-6.79 (m, 1H), 7.00-7.20 (m, 5H), 7.55 (d, 2H, J=8.1 Hz). Anal. calc. for C24H31N3O2: C, 73.25; H, 7.94; N, 10.68. Found: C, 73.11; H, 7.92; N, 10.65.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22](O)=[O:23])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.Cl.[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:31]([C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32]>>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:31]([C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:23])[CH2:37][CH2:38]1)=[O:32]
Reactant: O=C(O)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Reactant: COCCNC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A77) and trans-4-amino-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide hydrochloride (A196) the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.7 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-nonadienoic acid (3.12 g) and 4-nitrophenol (2 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.49 g) and the mixture was stirred at room temperature for 3 days. After the normal work up, crystallization of the crude product from 2-propanol yielded 3.55 g of (E,E)-5-(4-methoxyphenyl)-2,4nonadienoic acid 4-nitrophenyl ester, mp 78°-80° C., resolidified and remelted at 115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1I.[CH3:16][N:17](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]=1[F:1])#[N:17]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)c1ccc(I)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)C(C)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of ethyl 2-(3-fluoro-4-iodophenyl)propanoate (1.15 g, 3.570 mmol) in DMF was added Zn(CN)2 (629 mg, 5.355 mmol) and Pd(PPh3)4 (825 mg, 0.714 mmol). The reaction mixture was refluxed for 8 hours and then cooled to room temperature. The mixture was filtered through a plug of Celite and concentrated. The residue was diluted with EtOAc and washed with 10% HCl solution. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography to afford the pure compound ethyl 2-(4-cyano-3-fluorophenyl)propanoate (520 mg, 66%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[CH:11]([C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH2:10][CH2:9][C:1]#[N:2]
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
563 mg (8.64 mmol) of potassium cyanide were added to 1.98 g (4.32 mmol) of the compound from Example 57A in 26 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.42 g (84% of theory) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]=3[CH:27]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[ClH:28]>CO.O1CCOCC1>[ClH:28].[O:19]1[C:13]2[CH:12]=[CH:11][C:10]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:8]=3)=[CH:27][C:14]=2[CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CNCCO3)s1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 1,1-dimethylethyl 7-[2-(acetylamino)-1,3-thiazole-5-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.77 mmol) in a mixture of methanol (2 mL) and 4 N hydrogen chloride in dioxane (2 mL) was refluxed for 1 min. After cooling to room temperature the reaction mixture was concentrated, and azeotroped with methanol (3×) to give N-[5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide hydrochloride (221 mg, 88% yield) as a colorless solid. MS (EI) for C14H15N3O2S: 290 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.F[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: Fc1ccccn1
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](Nc2ccccn2)CC1
Temperature: 165 °C
Reaction time: 2 h

Procedure:
A mixture of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (100 mg, 0.23 mmol), 2-fluoropyridine (0.5 mL) and diisopropylethyl (0.2 mL) was placed in a microwave tube and heated to 150° C. in the Personal Chemistry Microwave for 1 h, 165° C. for 1 h, then 185° C. for another 2 h. The reaction mixture was concentrated and the resulting residue was diluted with ethyl acetate. The organic phase was washed with 10% citric acid and brine. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 29 mg of the title compound, m/z 518.9 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][CH:28]1[CH2:33][CH:32]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:31][CH2:30][O:29]1>>[CH3:27][CH:28]1[CH2:33][CH:32]([N:34]2[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:36]3[N:37]=[CH:38][N:39]=[C:35]23)[CH2:31][CH2:30][O:29]1
Reactant: CC1CC(Nc2nnc[nH]2)CCO1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)C2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.2 g) and N-(2-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 56%).