Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(N(CC)CC)C.[F:19][C:20]1[C:25]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])=[CH:24][C:23]([S:37](Cl)(=[O:39])=[O:38])=[C:22]([O:41][CH3:42])[CH:21]=1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:19][C:20]1[C:25]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])=[CH:24][C:23]([S:37]([N:1]2[C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[CH2:4][CH2:5][CH2:6][CH2:7]2)(=[O:38])=[O:39])=[C:22]([O:41][CH3:42])[CH:21]=1
Reactant: c1ccc2c(c1)CCCCN2
Reactant: COc1cc(F)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(F)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-benzo[B]azepine (0.24 g), triethylamine (0.23 mL) and 4-dimethylaminopyridine (17 mg) in methylene chloride (8 mL) was added 4-fluoro-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-methoxybenzenesulfonyl chloride (0.5 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 5-fluoro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)anisole (0.57 g). This material was dissolved in tetrahydrofuran (11 mL). To the solution was added hydrazine monohydrate (0.29 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) to give the title compound (0.32 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH2:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH2:20][C:21]2[C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=2)[CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: c1ccc(-c2ccc3c(c2)CCNC3)cc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3c(c2)CCN(Cc2c[nH]c4ncccc24)C3)cc1
Yield: 17 %

Procedure:
A mixture of 6-phenyl-1,2,3,4-tetrahydroisoquinoline (prepared by the method of L. N. Pridgen, J. Heterocyclic Chem. 1980, 17, 1289) (0.5 g, 2.38 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.4 g, 2.28 mmol) in toluene (5 ml) was heated at reflux under nitrogen for 18 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from ethyl acetate afforded the title compound (0.13 g, 17%), m.p. 211°-213° C.; (Found: C, 80.15; H, 6.30; N, 12.32. C23H21N3.0.3H2O requires C, 80.11; H, 6.31; N, 12.18%); δH (DMSO-d6) 2.73 (2H, br s, CH2CH2Ph), 2.87 (2H, br s, NCH2CH2), 3.61 (2H, s, ArCH2N), 3.83 (2H, s, NCH2Ph), 7.02 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.18 (1H, d, J 3.2 Hz, 2-H), 7.30-7.45 (6H, m, ArH), 7.60 (2H, d, J 7.6 Hz, ArH), 8.05 (1H, d, J 7.6 Hz, 4-H), 8.20 (1H, dd, J 6.1, 1.4 Hz, 6-H), and 11.48 (1H, br s, NH); m/z (CI+, NH3) 340 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH2:2]1.BrC1C=CC=CN=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1O>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:8][C@@H:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C@@H:3]1[O:4][CH2:5][CH2:6][NH:1][CH2:2]1
Reactant: Oc1ccc(F)cc1F
Reactant: OC(c1cccnc1)C1CNCCO1
Agent: Brc1ccccn1
Product: Fc1ccc(O[C@@H](c2cccnc2)[C@H]2CNCCO2)c(F)c1

Procedure:
(R)-2-[(S)-(2-,4-Difluoro-phenoxy)-pyridin-3-yl-methyl]-morpholine was synthesized via morpholin-2-yl-pyridin-3-yl-methanol from 2-bromopyridine and 2,4-difluorophenol according to general procedure C and was isolated as a gummy oil. MS (APCI): 307 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][C:4]([NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O)(C)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N+:19]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].O.ON1C2C=CC=C[C:37]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:37])=[C:4]([NH:11][C@H:12]([C@H:16]([OH:18])[CH3:17])[C:13]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:30]=[CH:31][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: On1nnc2ccccc21
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)[C@@H](NC1(C)C=CC(C#N)=C(Cl)C1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -50 °C
Reaction time: 1 h
Yield: 119.2 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (8.3 g, 30.9 mmol), 4-nitrobenzohydrazide (6.16 g, 34.0 mmol) and anhydrous THF (200 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −50° C. 1-Hydroxybenzotriazole hydrate (4.2 g, 30.9 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (7.34 g, 38.3 mmol) at −50° C. followed by triethylamine (5.3 mL, 38.3 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h the mixture was filtered under vacuum and the residue washed with THF (50 mL). The THF solution was concentrated to ca. 20 mL, whereupon ethyl acetate (200 mL) was added followed by water (100 mL). The phases were partitioned and the organic phase washed with water (150 mL), brine (150 mL), dried (Na2SO4) and concentrated to furnish a light yellow solid as the title compound (15.9 g, 80%) that was used without further purification. 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.88 (br s, 2H), 8.35 (d, 6.7 Hz, 2H), 8.16 (d, J=6.7 Hz, 2H), 7.53 (d, J=7.5 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 5.56 (d, J=6.6 Hz, 1H), 4.46-4.36 (m, 4.18-4.10 (m, 1H), 3.26 (s, 3H), 1.37 (d, J=7.4 Hz, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[N+:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O)([O-:41])=[O:40].C(=O)([O-])O.[Na+].CN(C)C=O>ClCCl.C(OCC)(=O)C>[N+:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:20])=[O:21])[CH:9]=2)[NH:4][N:3]=1)([O-:41])=[O:40]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccccc3[N+](=O)[O-])c2c1
Yield: 16.2 %

Procedure:
N-[3-(2-Nitrophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 47 from 620 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 202 mg 2-nitrophenylboronic acid, 2 ml of a saturated aqueous sodium hydrogencarbonate solution, 31.7 mg of tetrakis(triphenylphosphine)palladium[0] and of 20 ml of dimethylformamide. 70 mg of N-[3-(2-nitrophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a yellow solid (Rf=0.53 silica gel thin layer chromatography, eluent: dichloromethane/ethyl acetate (80-20 by volume)).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:15]([OH:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH2:19](O)[CH3:20]>>[F:6][C:7]1[C:15]([OH:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:8]=1[C:9]([O:11][CH2:19][CH3:20])=[O:10]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)c(F)c(O)c1F

Procedure:
5 ml of concentrated sulfuric acid were added to a solution of 20.0 g (0.104 moles) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F] (prepared as described in Preparation 13) in 500 ml of ethanol, and the mixture was heated under reflux for 4 hours. The ethanol was then removed by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure, to give 16.9 g of ethyl 2,4,5-trifluoro-3-hydroxybenzoate as a colorless powder.
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.COC1C=C(C=CC=1OC)C[NH2:32]>CC(N(C)C)=O.FC(F)(F)C(O)=O.C(OC(=O)C)C>[NH2:32][C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Reactant: COc1ccc(CN)cc1OC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 170 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
A stirred solution of Example 5 (0.055 g, 0.143 mmol) in dimethylacetamide (2 ml) was treated with 3,4-dimethoxybenzylamine (0.22 ml, 1.43 mmol). The solution was heated to 170° C. for 30 min in a microwave reactor. The cooled solution was reduced in vacuo and taken up in neat trifluoroacetic acid (3 ml). The mixture was stirred at 70° C. for 48 h, cooled and reduced in vacuo. The residue was taken up in ethylacetate (25 ml), washed with saturated sodium bicarbonate solution (15 ml), dried over sodium sulfate and reduced in vacuo. Silica gel (10 g) column chromatography (10% MeOH in EtOAc) afforded the title compound as an orange solid in 9% yield, >95% purity. LC-MS m/z=368.0 [M+H]+; RT=2.58; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 4.67 (2H, bd), 5.81 (1H, s), 7.23-7.25 (1H, m), 7.33-7.36 (1H, m), 7.51 (2H, b), 7.79 (1H, bd), 8.09 (1H, bd), 8.38-8.62 (4H, bm)
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-:13])(=O)=O)=CC=1.[CH2:14]([O:16][C:17](=[O:27])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH3:15].CCOCC.CS(C)=O.[H-].[Na+]>CCOCC.O>[CH2:14]([O:16][C:17]([C:18]1[C:19]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:13][NH:12][CH:11]=1)=[O:27])[CH3:15]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c[nH]cc1-c1ccc(C)cc1
Reaction time: 3 h
Yield: 74.5 %

Procedure:
A solution of TosMIC (15.7 g, 80.5 mmol) and 5 (14.6 g, 76.7 mmol) in a dry ether/DMSO (2:1) (154 mL) solution was added dropwise under argon to a stirred solution of NaH (2.39 g, 99.7 mmol) in ether (70 mL). The mixture started to reflux due to the exothermic reaction. After 3 h, water (200 mL) was carefully added to the mixture and the aqueous phase was extracted with ether and CH2Cl2. The combined organic extracts were dried (Na2SO4), concentrated, and chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to give a light brown solid (13.1 g, 74%): mp 154-155° C.; 1H NMR δ 1.25 (t, J=7.2 Hz, 3H), 2.36 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 6.75-6.77 (m, 1H), 7.16 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.46-7.48 (m, 1H), 8.38-8.54 (br, 1H); 13C NMR δ 14.5, 21.4, 59.8, 113.9, 118.3, 125.4, 126.8, 128.6, 129.4, 132.0, 136.3, 165.2; Anal, Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.11; H, 6.59; N, 6.12.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](O)=[O:16])[C:10](=[O:18])[CH:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(OC(Cl)=O)C(C)C.Cl.[NH2:50][CH2:51][C:52]([NH:54][C@H:55]([C:63]([NH:65][CH3:66])=[O:64])[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:53]>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:50][CH2:51][C:52]([NH:54][C@H:55]([C:63]([NH:65][CH3:66])=[O:64])[CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[O:53])=[O:16])[C:10](=[O:18])[CH:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][CH:21]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)C(=O)C1Cc1ccc(OCc2ccccc2)cc1
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of piperazinone acetic acid 5a (0.45 g, 1.0×10-3 mole) and dry THF (3 ml) at -10° C. under argon is added in turn Et3N (0.16 ml. 1.1×10-3 mole) and isobutylchloroformate (0.15 ml, 1.1×10-3 mole). After stirring 10 minutes at -10° C., a freshly neutralized solution of glycyl-L-phenylalanine methyl amide 9a hydrochloride (0.30 g, 1.1×10-3 mole), Et3N (0.28 ml, 2.0×10-3 mole), THF (3 ml), and H2O (1.5 ml) is added in one portion. The cooling bath is then removed and the reaction allowed to warm to room temperature. After stirring overnight the reaction is quenched into 0.5M aqueous HCl. The aqueous mixture is extracted with Et2O (2 times) and CH2Cl2 (2 times). The ethereal extracts are combined and washed with saturated aqueous NaHCO3 as are the CH2Cl2 extracts. The ethereal and CH 2 Cl2 extracts are then combined and dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate give 10a which is purified by chromatoraphy, and the structure corroborated by NMR. NMR (CDCl3) δ1.26 (S, 9, t-boc), 2.64 (d, 3, methylamide), 3.08, 3.90 (m, 12, methylenes), 4.68 (m, 2, C3 --H and phenylala--Ch), 4,98 (S, 2, benzyloxy methylene), 6.6-7.8 (m, 17, aromatic and amide NH's).
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16](O)=O)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([NH2:26])[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.[OH-].[K+]>O>[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]3[NH:26][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N:25]=3)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 0.83 h

Procedure:
To 73 parts of hot (70° C.) polyphosphoric acid were added 27 parts of 1-(phenylmethyl)-4-piperidineacetic acid hydrochloride: temperature rose to 100° C. When the addition was complete, there were added portionwise 14 parts of 1,2-benzenediamine and stirring and heating was continued for 50 minutes at 170° C. The hot reaction mixture was poured into 300 parts of warm water. The acid solution was alkalized with a potassium hydroxide solution. The precipitated free base was filtered off, washed with water and extracted with trichloromethane. The extract was dried and evaporated. The solid residue was recrystallized from a mixture of 2-propanone and methanol, yielding 17 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-benzimidazole; mp. 221.5°-222° C. (compound 1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)=[CH:37][CH:36]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1ccc(OC2CCOCC2)cc1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OC5CCOCC5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-(tetrahydropyran-4-yloxy)phenyl borate (141 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(tetrahydropyran-4-yloxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 68) (274 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.N1([C:16]([N:18]2[CH:22]=[CH:21]N=C2)=[O:17])C=CN=C1.Cl.NCC([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1)=O>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[CH2:22][NH:18][C:16]3=[O:17])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COc1cccc(C(=O)CN)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Product: COc1cccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)c1

Procedure:
The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.532 g, 4 mmol), di(1H-imidazol-1-yl)methanone (0.713 g, 4.4 mmol), TEA (1.67 mL, 12 mmol), aminomethyl-(3-methoxyphenyl)ketone hydrochloride (0.807 g, 4 mmol), TEA (1.12 mL, 8 mmol), PdC (10%, 0.02 g) as described in method 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:2]([NH:1][C:32]([C:31]5[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: COc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C)nn1C
Yield: 53.6 %

Procedure:
Using N-[6-(3-amino-4-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.59 mmol), N,N-dimethylacetamide (4.0 mL) and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (113 mg, 0.71 mmol), and in the same manner as in Example 120, the title compound (146 mg, 54%) was obtained as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)([O-:13])=[O:12]
Reactant: NCCCSc1ncc[nH]1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])NCCCSc1ncc[nH]1

Procedure:
By the procedure of Example 4(i), 2-(3-aminopropylthio)-imidazole (from the dihydrobromide (3.8 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) to give 1-nitro-2-methylthio-2-[3-(2-imidazolylthio)propylamino]ethylene which, on treatment with methylamine according to the procedure of Example 3(ii) gives the title compound.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[CH3:18])C=CC=CC=1.[CH3:20][C:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:27]=1.CCCCCC>C1(C)C=CC=CC=1>[CH3:20][C:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:27]=1)[C:8]([NH:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=1[CH3:16])=[O:19]
Reactant: CC(C)(C)CCNCc1ccc(CC(C)(C)C)cc1
Reactant: Cc1cc(Cl)cc(C)c1NC(=O)Oc1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C)c1NC(=O)N(CCC(C)(C)C)Cc1ccc(CC(C)(C)C)cc1

Procedure:
A solution of 825 mg of phenyl-N-(4-chloro-2,6-dimethylphenyl)carbamate and 782 mg of N-(3,3-dimethylbutyl)-4-(2,2-dimethylpropyl)benzenemethanamine in 40 ml of toluene was heated to reflux for 1 hour, cooled, and the solution was washed with 1N sodium hydroxide, brine, dried, and evaporated to dryness to yield a solid. The solid was recystallized from hexane to yield 1-[3,3-dimethylbutyl]-1-[[4-(2,2-dimethylpropyl)phenyl]methyl]-3-[4-chloro-2,6-dimethylphenyl]urea as a white solid, mp 148°-150° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([C:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]=3)=[CH:17][C:10]=12.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH:19]=3)=[CH:17][C:10]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)c4F)ccnc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(-c2ccnc3[nH]c(C4=CCNCC4)cc23)c1F
Reaction time: 3 h

Procedure:
A solution of Example 222B (0.255 g, 0.620 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (0.477 mL, 6.20 mmol) and the mixture was stirred for 3 hours and concentrated. The residue was dissolved in 2 mL methanol and treated slowly with 2 mL 2M hydrogen chloride in ether. The suspension was diluted with ether and stirred for 10 minutes. The solids were filtered, washed with ether, and dried to give the title compound as a hydrochloride salt. MS (ESI+) m/z 312.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]2[N:6]([CH3:24])[C:7]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15]N(CC4C=CC=CC=4)[CH2:13][CH2:12]3)=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+].[H][H]>[Pd].O1CCCC1>[CH3:24][N:6]1[C:5]2[C:25]3[C:30]([CH:2]=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:26]([C:25]2[CH:30]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:15][CH2:16]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: [H][H]
Reactant: Cn1c(CCN2CCN(Cc3ccccc3)CC2)nc2cc(Br)c3ccccc3c21
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(CCN2CCC(c3ccccc3)CC2)nc2ccc3ccccc3c21

Procedure:
A mixture of 8.32 g (0.0185 mole) of the compound of Example 16, 0.9 g of 10% Pd-C catalyst, and 150 cc of tetrahydrofuran containing 20 cc of 1M NaOH is shaken in a Paar hydrogenator under about 5.4 atm. of hydrogen pressure until hydrogenolysis is completed. The catalyst is filtered and the mother liquor is concentrated to remove the solvent. The residue is taken up with methylene chloride, and washed with water. Upon evaporating the solvent, 6.1 g of a crude product are obtained which is recrystallized from acetone yielding 4.74 g of the compound of the title. M.p. 181.5°-182.5° C.