Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:30]S(C(C)(C)C)=O)([C:24]2[N:25]([CH3:29])[CH:26]=[N:27][CH:28]=2)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=2)=[CH:5][C:4]=1[F:37])#[N:2].B(Br)(Br)Br.O>C(Cl)Cl>[NH2:30][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:37])[CH:5]=1)([C:24]1[N:25]([CH3:29])[CH:26]=[N:27][CH:28]=1)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1
Reactant: COc1cccc(CCNCCCC(NS(=O)C(C)(C)C)(c2ccc(C#N)c(F)c2)c2cncn2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1cncc1C(N)(CCCNCCc1cccc(O)c1)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-propane-2-sulfinic acid [1-(4-cyano-3-fluoro-phenyl)-4-[2-(3-methoxy-phenyl)-ethylamino]-1-(3-methyl-3-H-imidazol-4-yl)-butyl]-amide (0.075 g, 0.1427 mmol) was dissolved in CH2Cl2 (7 mL) with cooling in an ice-H2O bath, then treated with BBr3 (1 mL of a 1M solution in CH2Cl2, 1 mmol). After 15 min., H2O (3 mL) was added and the reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH and stirred at ambient temperature for 15 min. Concentration to dryness gave the title compound which was used without further purification. MS (M+1) 408.
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([C:11]([OH:13])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[CH:44]12[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH:45]1[NH2:54])[CH2:51]2>CN(C)C=O.C(Cl)Cl>[CH:44]12[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH:45]1[NH:54][C:11]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:9]=1[Cl:10])=[O:13])[CH2:51]2
Reactant: CC(C)(C)n1ncc(C(=O)O)c1Cl
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a stirred solution of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (3.040 g; 15.0 mmol) in N,N-dimethylformamide/methylene chloride (1:4 ratio, 20 mL) at room temperature was added diisopropylethylamine (21.2 mL; 120.4 mmol). TSTU (5.420 g; 18.0 mmol) was then added. The resulting mixture was allowed to stir at room temp. for 2 hr and then 2-adamantylamine hydrochloride (2.844 g; 15.0 mmol) was added. The mixture was allowed to stir over the weekend at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting light yellow gum was triturated with diethyl ether to provide 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (4.02 g, 80%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:9]I)=[CH:4][C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[CH2:24]([NH:31][CH2:32][CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:24]([N:31]([CH2:32][CH2:33][OH:34])[CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:4]=1)[O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(Cl)c(NS(C)(=O)=O)c1
Reactant: OCCNCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC[Si](CC)(CC)O[C@@H](CN(CCO)Cc1ccccc1)c1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(R)-N-(2-chloro-5-(2-iodo-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (3 g) and 2-(benzylamino)ethanol (6 mL; manufactured by Tokyo Chemical Industry Co., Ltd.) were mixed, and the mixture was stirred overnight at 100° C. The reaction solution was cooled to room temperature, and then toluene and Et2O were added thereto. The mixture was washed three times with water, and the organic layer was dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=84:16→64:36), and thus the title compound (2.1894 g) was obtained.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[C:10]([F:12])[CH:11]=1)=[O:5].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[NH:16]([C:2]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[C:10]([F:12])[CH:11]=1)=[O:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: O=C(C=C(Cl)Cl)c1cc(F)c(Cl)nc1Cl
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a 0° C. solution of 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (6.70 g, 23.2 mmol) in dioxane (50 mL) was added TEA (9.7 mL, 69.6) followed by aniline (6.3 mL, 69.6 mmol). After I h the reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with CH2Cl2 (2×). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel Biotage chromatography provided 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one as yellow solid (4.2 g, 49%): LCMS RT: 3.47 min; MH+: 402.6.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH3:9])(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[C:14]([O:13][C:11](=[O:12])[NH:10][C@@H:7]([CH2:8][CH3:9])[CH2:6][N:18]=[N+:19]=[N-:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)butyl methanesulfonate (13.4 g, 50 mmol) in DMF (100 mL) was added sodium azide (6.5 g, 100 mmol). The reaction mixture was heated at 70° C. for 18 h. After cooling to rt, water was added, and the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (SiO2; 0-50% EtOAc/hexanes) provided the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.87 (d, J=8.6 Hz, 1H), 3.54-3.37 (m, 1H), 3.27-3.20 (m, 2H), 1.45-1.25 (m, 2H), 1.39 (s, 9H), 0.82 (t, J=7.4 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:16]2=[CH:17][N:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+].C(Cl)[Cl:36]>>[ClH:36].[ClH:36].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:16]2=[CH:17][N:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ccncc2o1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1cc2cc([C@@H]3CCCN3)oc2cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 700 mg sample of the compound from step 9c above in 5 mL of CH2Cl2 at 0° C. was added 5 mL of TFA. The reaction mixture was stirred for 1 hour at 0° C. then poured into saturated Na2CO3, and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated, and the residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :MeOH. The product was converted to the salt by treatment with HCl/ether, which was recrystallized from ethanol/EtOAc: 1H NMR (D2O, 300 MHz) δ 2.19-2.52 (m, 3H), 2.64 (m, 1H), 3.53-3.58 (m, 2H), 5.13 (t, 1H, J=8 Hz), 7.34 (s, 1H), 8.05 (dd, 1H, J=0.8, 5.8 Hz), 8.49 (d, 1H, J=5.8 Hz), 9.07 (s, 1H); MS m/z: 189 (M+H)+, 206 (M+NH4)+ ; Anal. Calcd for C11H12N2O·2.0 HCl.H2O: C, 47.33; H, 5.78; N, 10.03. Found: C, 47.32; H, 5.83; N, 9.90.
Reaction SMILES: [O:1]=[C:2]1[CH2:15][CH:14]2[C:9](C(O)=O)([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:26])C=CC=CC=1.C([N:38]([CH2:41]C)CC)C>C1(C)C=CC=CC=1>[N:38]([C:9]12[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2](=[O:1])[CH2:15][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:41]=[O:26]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C1CC2CCCCC2(C(=O)O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C=NC12CCCCC1CC(=O)c1ccccc12
Yield: 65.7 %

Procedure:
A solution of the compound from Example 52 (1 g, 4.1 mmol) and diphenylphosphorylazide (1.25 g, 4.5 mmol) in triethylamine (0.6 g) and 30 ml toluene was heated at 110° C. for 30 minutes. Workup and silica gel chromatography gave the title compound (0.65 g, 66%) as a yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:21])[N:13]=[C:14](S(C)(=O)=O)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1>[NH2:21][C:12]1[N:13]=[C:14]([N:43]2[CH2:44][CH2:45][N:40]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:46]=[CH:47][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:41][CH2:42]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 70 °C
Yield: 86.7 %

Procedure:
To a solution of 2-(4-fluorophenethyl)-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.14 mmol) and triethylamine (30 μl, 0.21 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (51 mg, 0.21 mmol). The reaction mixture was heated at 70° C. for 3 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 70:1) to yield the title compound as a light yellow solid (64 mg, 85%).
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:35])[CH:27](Cl)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][CH2:21]1>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:35])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[CH2:24][CH2:25]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COc1ccccc1N1CCN(C(=O)C(Cl)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)C(c2ccccc2)n2cnc3ccccc32)CC1
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
A mixture of sodium hydride (0.47 g of 80% dispersion) in dry dimethyl formamide (10 ml) at 0°-5° C. was treated with benzimidazole (1.584 g) and the mixture stirred for 30 mins. A solution of 1-(2-methoxyphenyl)-4-(2-chloro-1-oxo-2-phenylethyl) piperazine (4.624 g) in dry DMF (20 ml) was added and the mixture was stirred at 90° C. for 5 hrs then at ambient temperature overnight. The suspension was filtered and the solvent evaporated under vacuum. The residue, in dichloromethane was washed well with water and dried over magnesium sulphate, to give 6 g of an oil. The crude product was purified by dry column flash chromatography to give the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)([O-:26])=[O:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 mg (0.37 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 17 mg (0.44 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 76 mg (0.44 mmol) of 4-nitrobenzyl chloride was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.CN([C:23]([CH:25]=[CH2:26])=O)C.FC(F)(F)C(O)=O>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]2=[N:1][CH:23]=[CH:25][CH:26]=[C:3]2[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5]1
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Reactant: C=CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Reaction time: 72 h

Procedure:
The above solution from Example 20A is admixed with 61.25 ml (60.77 g, 0.613 mol) of dimethylaminoacrolein and 56.28 ml (83.88 g, 0.736 mol) of trifluoroacetic acid, and the mixture is boiled under argon for 3 days. The solvent is subsequently evaporated under reduced pressure and the residue is added to 2 l of water, and the mixture is extracted three times with 1 l of ethyl acetate in each case. The combined organic phases are dried with magnesium sulphate and concentrated using a rotary evaporator. The mixture is chromatographed over 2.5 kg of silica gel and eluted using a toluene/toluene-ethyl acetate=4:1 gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[C@@H:29]([OH:30])[C:28](=[O:31])[N:27]([CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH3:36])[C:26]3[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=3[S:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.[C:49]([O-:54])(=[O:53])[C:50]([O-:52])=[O:51]>C(Cl)Cl>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C@H:23]2[C@@H:29]([O:30][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[N+:11]([O-:13])=[O:12])[C:28](=[O:31])[N:27]([CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH3:36])[C:26]3[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=3[S:24]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C([O-])C(=O)[O-]
Reactant: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C)CCN1C(=O)[C@H](OC(=O)c2ccc(Cl)cc2[N+](=O)[O-])[C@H](c2ccc(OC)cc2)Sc2ccccc21
Product: O=C(O)C(=O)O
Yield: 86.4 %

Procedure:
A solution of 0.88 g of 4-chloro-2-nitrobenzoyl chloride in 3 ml of methylene chloride is added to a mixture of 1.41 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 15 ml of methylene chloride and 1 ml of triethylamine. The mixture is treated in the same manner as described in Example 28-(2). The crude product is converted to its oxalate and then recrystallized from methanol. 1.9 g of (+)-cis-2-(4-methoxyphenyl)-3-(4-chloro-2-nitrobenzoyloxy)-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate are thereby obtained as colorless prisms. Yield: 86.4%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:14])[CH:11]=2)[CH2:6]1)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[S-:25][C:26]#[N:27].[K+]>C(O)C>[CH2:17]([N:24]1[C:3]([C:5]2([CH2:15][CH3:16])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:14])[CH:11]=3)[CH2:6]2)=[CH:2][N:27]=[C:26]1[SH:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC1(C(=O)CBr)Cc2ccc(F)cc2C1
Reactant: NCc1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: CCC1(c2cnc(S)n2Cc2ccccc2)Cc2ccc(F)cc2C1
Yield: 94.4 %

Procedure:
1.62 g of 2-bromo-1-(2-ethyl-5-fluoro-indan-2-yl)-ethanone was dissolved in 25 ml of ethanol in a glass round-bottomed flask equipped with a mechanical stirrer, a thermometer and a dropping funnel. The reaction mixture was heated to reflux temperature while stirring. 0.366 g of benzylamine dissolved in 5 ml ethanol was added slowly in a drop-wise fashion to the solution. After the addition of benzylamine the mixture was refluxed for one hour. 0.330 g of potassium thiocyanate was added portionwise during 30 minutes and the reaction mixture was refluxed for 2 hours. The reaction mixture was evaporated to dryness before 150 ml ethyl acetate was added and the solution was washed with water. The organic phase was dried over Na2SO4, filtered and evaporated providing 1.13 g of 1-benzyl-5-(2-ethyl-5-fluro-indan-2-yl)-imidazole-2-thiol (yield 31%). The analytical sample was purified using TLC-plates. The purity was measured by HPLC: 62%. Normally the crude product was used in the following step.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1>C(Cl)Cl.C1COCC1.O=[Mn]=O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: OCc1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
4-(Benzimidazol-2-yl)-benzyl alcohol from above (0.175 g, 0.78 mmol) was dissolved in CH2Cl2 (5 mL) and THF (8 mL), treated with activated MnO2 (0.68 g, 7.8 mmol) and stirred at room temperature for 1.5 h. The mixture was filtered through celite, the cake washed with CH2Cl2 and the solvent from the eluent removed under reduced pressure to afford 4-(benzimidazol-2-yl)-benzaldehyde (92 mg, 42%). 1H NMR (CD4OD) δ 7.28 (m, 2H), 7.60 (br, 1H (NH)), 7.65 (d, 2H, J=7.8 Hz), 8.09 (d, 2H, J=7.8 Hz), 8.30 (d, 2H, J=9.0 Hz), 10.08 (s, 1H (CHO)).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:15])[N:6]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:34]=[N+:35]=[N-:36])(C)C.C(O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]2[NH:36][N:35]=[N:34][N:15]=2)[N:6]=1
Reactant: N#Cc1nc(Cc2ccccc2F)n2ccccc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccccc1Cc1nc(-c2nnn[nH]2)c2ccccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 188 mg (0.75 mmol) of 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carbonitrile from example 18A, 18.6 mg (0.075 mmol) of dibutyltin oxide and 172 mg (1.50 mmol) of trimethylsilyl azide in 5 ml of toluene is heated under reflux for 20 h. Cooling is followed by addition of 5 ml of ethanol and stirring at RT for 15 h. The mixture is then concentrated, mixed with water and extracted with ethyl acetate. The organic phase is concentrated in vacuo, and the residue is purified by preparative HPLC. The product is taken up in ethyl acetate and clarified with activated carbon. The solid obtained after concentration is crystallized from dichloromethane. 40 mg (18% of theory) of the title compound are obtained as pale reddish crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19](I)[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH2:25]([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])[CH3:26].O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH2:25]([O:27][C:28](=[O:29])[C:30]1[CH:35]=[CH:34][C:33]([C:19]2[CH:18]=[C:17]([C:11]([OH:16])([C:12]([F:15])([F:14])[F:13])[CH:10]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])[CH3:24])[CH:22]=[CH:21][N:20]=2)=[CH:32][CH:31]=1)[CH3:26]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(C(C)C(O)(c2ccnc(I)c2)C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2cc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)ccn2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-(2-iodo-pyridin-4-yl)-butan-2-ol (Example 139, 92 mg), 4-ethoxycarbonylphenylboronic acid (42 mg) and 1,1,bis(diphenylphosphino)ferrocenpalladium(II)dichloromethane in dioxane (0.7 mL) was treated with water (0.4 mL) and 2N—Na2CO3 (0.351 mL) and stirred at 80° C. under argon for 16 h. The reaction mixture was cooled down to r.t., diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 1:2) to give the title compound as light yellow amorphous material (78 mg). MS (m/e)=494.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH2:12][CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[C:4](=[O:20])[C:3]=1[C:21](OC)=[O:22].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CCO>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:21]([C:3]2[C:4](=[O:20])[N:5]([CH2:12][CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])[C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[CH:8][CH:7]=3)=[O:22])=[CH:28][CH:27]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1c(O)c2ncccc2n(CCN(C)S(C)(=O)=O)c1=O
Solvent: CCO
Product: CN(CCn1c(=O)c(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc21)S(C)(=O)=O

Procedure:
In a manner similar to that described in Example 2, methyl 4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate was dissolved in EtOH and treated with 4-fluorobenzylamine at reflux. After cooling the product fell out of solution and was collected. The crude was dissolved in CHCl3, washed with 10% KHSO4 solution, the organic was dried over MgSO4, filtered and evaporated to give the product as a white foam.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][N:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C[OH:18].[OH-].[Na+].OO>C1COCC1.CCOCC.O>[OH:18][CH:7]1[CH2:6][CH2:5][CH:4]2[CH:9]([CH2:1][N:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]2)[CH2:8]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CC2CC=CCC2C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CCC(O)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (48.18 g, 215.8 mmol) in THF (500 mL) was added a solution of BH3-DMS in THF (2 M in THF, 130 mL, 260.0 mmol) dropwise at 0° C. The reaction mixture was warmed slowly to rt and stirred overnight, then cooled down to 0° C. again. Methanol (120 mL) was added dropwise to the above mixture, and followed by a mixture of NaOH aqueous solution (3 M, 75 mL, 225 mmol) and H2O2 (30% in water, 75 mL). The resulting mixture was stirred at 60° C. for 1.5 h, then cooled down to rt, and diluted with Et2O (500 mL) and water (450 mL), then extracted with EtOAc (450 mL×3). The combined organic phases were washed with brine (500 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as orange oil (49.04 g, 94.2%), which was used in the next step without further purification.