Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:18][CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:18][CH:19]([CH3:20])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: CC(N)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(NC1CCC(Nc2ccc3[nH]ncc3c2)CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.2 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and (2-amino-3,3-dimethylbutane (51 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (8 mg) and a syn-form compound (5 mg).
Reaction SMILES: C([N:3](CC)[CH:4]=[CH:5][C:6]([C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])=O)C.[NH2:30]N>CO.C(O)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:17]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:6]2[NH:30][N:3]=[CH:4][CH:5]=2)[CH:9]=1)=[O:18]
Reactant: NN
Reactant: CCN(C=CC(=O)c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OC)CC
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccn[nH]1
Yield: 78.1 %

Procedure:
To a solution of 1-[3-(3-Diethylamino-acryloyl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (1.5 g, 3.72 mmole) in methanol/acetic acid (50 mL/2.0 mL) mixture was added hydrazine (0.82 g, 37.22 mmole). The reaction mixture was refluxed at 55 C for 20 hrs. The methanol/acetic acid was evaporated from the reaction mixture and the solid was triturated with ether/methanol. The solid was filtered and washed with ether. Next, the solid was dried in vacuo to furnish a colorless solid (1.0 g, 76%). LCMS m/z (%)=345 (M+H, 100), 1H NMR (Bruker, 400 MHz, DMSO-d6) δ: 13.0 (bs, 1H), 8.89 (bs, 1H), 8.37 (bs, 1H), 8.09-810 (d, J=6.05 Hz, 1H), 7.74-7.97 (bs, 1H), 7.52-7.64 (bs, 1H), 7.39-7.40 (d, J=5.94 Hz, 1H), 7.27-7.32 (m, 2H), 7.01-7.09 (m, 2H), 6.73 (s, 1H), 3.82 (s, 3H) (major tautomer).
Reaction SMILES: [SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][SH:7].Cl[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:11]1[CH2:10][CH2:9][S:7][CH2:6][CH2:5][S:4][CH2:3][CH2:2][S:1][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: SCCSCCS
Reactant: ClCCOCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C1COCCSCCSCCSCCO1

Procedure:
This compound is obtained by reacting 1,5-dimercapto-3-thiapentane with 1,8-dichloro-3,6-dioxaoctane in the presence of cesium carbonate in dimethylformamide (DMF): ##STR2##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[N:15]([CH3:16])/[C:14](=[N:17]\[H])/[N:13]([CH3:19])[C:12]2=[O:20])=[CH:2]1.[CH3:21]I>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[N:15]([CH3:16])/[C:14](=[N:17]\[CH3:21])/[N:13]([CH3:19])[C:12]2=[O:20])=[CH:2]1
Reactant: [H]/N=C1/N(C)C(=O)C(=Cc2c[nH]c3ccccc23)N1C
Reactant: CI
Solvent: CO
Product: C/N=C1/N(C)C(=O)C(=Cc2c[nH]c3ccccc23)N1C
Yield: 20.3 %

Procedure:
500 mg of (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone are refluxed in methanol for 24 hours with 425 mg of methyl iodide. The product is chromatographed on silica gel and alumina. There are obtained 107 mg of (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=2)[C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:17]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)=[N:27]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCOCC3)c2)n1
Yield: 47.8 %

Procedure:
3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (3.14 g, 9.5 mmol), 1-methyl-1H-pyrazol-3-amine (1.85 g, 19.0 mmol) and HATU (4.70 g, 12.35 mmol) were dissolved in DMF (12.5 mL) and DIPEA (3.31 mL, 19.0 mmol) added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL), extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a pale yellow gum (1.85 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:36])C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(=O)OCC>C1COCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][Br:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1CO)Cc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1CBr)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.7 %

Procedure:
To a solution of compound 3h (4.15 g, 9.2 mmol) in dry THF (50 mL) was added NBS (4.1 g, 23 mmol) and PPh3 (6 g, 23 mmol) at 0° C. The mixture was stirred at 0° C. for 20 min. Then the mixture was stirred at rt for 2 hr. The solvent was evaporated in vacuo and purified by CC eluting with PE:EA=4:1 to give 3i as a white solid (2.3 g, 50% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].Cl.O1CCO[CH2:15][CH2:14]1>C(O)C>[CH2:14]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: C1COCCO1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid (5.0 g, 21 mmol) in 150 mL absolute ethanol was added 15 mL of 4N HCl/dioxane. The mixture was heated to reflux for 24 hours then cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and H2O, and the separated organic phase was washed sequentially with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO-d6) δ 8.22 (d, 1H), 7.94 (dd, 1H), 7.80 (d, 1H), 4.33 (q, 2H), 1.33 (t, 3H); MS (DCI+) m/z 263 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]3[N:11]([CH2:14][C:15]4[CH:26]=[CH:25][C:18]5[N:19]=[C:20](S(C)=O)[S:21][C:17]=5[CH:16]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)=[N:3]1.Cl.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([OH:37])[C@H:32]1[OH:38].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]3[N:11]([CH2:14][C:15]4[CH:26]=[CH:25][C:18]5[N:19]=[C:20]([NH:30][C@@H:31]6[CH2:36][CH2:35][CH2:34][C@@H:33]([OH:37])[C@H:32]6[OH:38])[S:21][C:17]=5[CH:16]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)=[N:3]1
Reactant: N[C@@H]1CCC[C@@H](O)[C@H]1O
Reactant: Cn1nnc(-c2ccc3c(c2)ncn3Cc2ccc3nc(S(C)=O)sc3c2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1nnc(-c2ccc3c(c2)ncn3Cc2ccc3nc(N[C@@H]4CCC[C@@H](O)[C@H]4O)sc3c2)n1
Temperature: 120 °C
Yield: 9.7 %

Procedure:
To a suspension of 6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (330 mg, 0.8 mmol) and (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride (391 mg, 2.4 mmol), prepared as described in Gauthier Errasti, et al, Org. Lett. 2009, 13, 2912-2915, in anhydrous NMP (3.0 mL) was added DIEA (703 μL, 4.0 mmol). The mixture was heated in a sealed tube at 120° C. for 15 h. Additional (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride (258 mg, 1.6 mmol) and DIEA (703 μL, 4.0 mmol) were added, and the mixture was heated at 140° C. for a further 15 h. The mixture was cooled to rt and was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2S,3R)-3-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (37 mg, 10%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.29 (s, 1H), 7.90-7.98 (m, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.31 (m, 1H), 7.23 (dd, J=1.5, 8.4 Hz, 1H), 5.52 (s, 2H), 4.41 (s, 3H), 3.93 (m, 1H), 3.79 (m, 1H), 3.25 (m, 1H), 1.91 (m, 1H), 1.52-1.69 (m, 3H), 1.32-1.44 (m, 2H), 1.15-1.25 (m, 2H); LCMS (ESI) m/z 477 (M+H)+.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].Cl>ClCCl.C1C=CC=CC=1>[OH:25][C:19]1[CH:18]=[C:17]([O:16][CH3:15])[C:22]([O:23][CH3:24])=[CH:21][C:20]=1[C:10]([C:9]1[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=1)=[O:11]
Reactant: COc1ccc(O)cc1OC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1cc(O)c(C(=O)c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.0M solution of boron trichloride(142 ml) in dichioromethane was added to 4-fluorobenzoyl chloride(16.8 ml) in benzene (200 ml). Next, 3,4-dimethoxyphenol(20.0 g) in benzene (100 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then poured onto ice water and allowed to stir for 15 minutes, then 1N HCl (500 ml) was added and stirred at room temperature for 17 hours. The reaction mixture was extracted with EtOAc, the EtOAc was separated, concentrated and dried to give the title product(41.7 g) as an orange solid. 1H NMR consistent with desired structures.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:8][CH:9]=1
Reactant: Cc1nccn1-c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Product: Cc1nccn1-c1ccc(CCl)cc1

Procedure:
To 4-(2-methyl-1H-imidazole-1-yl)benzenemethanol add thionyl chloride. Monitor the progress of the reaction by thin-layer chromatography. Upon completion remove the excess thionyl chloride in vacuo. Partition the residue between 1N NaOH and CH2Cl2. Separate and dry the organic layer. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].CS([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=1)(=O)=O>C(O)C>[NH:2]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=1)[NH2:3]
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 15 °C

Procedure:
1.7 ml (1.7 g, 34.0 mmol) of hydrazine hydrate are added to 2.0 g (8.5 mmol) of 2,5-bis(methylsulfonyl)pyridine [Woods et al., J. Heterocycl. Chem. 1984, 21, 97-101] in 15 ml of ethanol, and the mixture is stirred under reflux for 4 h. For work-up, the reaction solution is cooled to 15° C., the precipitated solid is filtered off, the filter residue is washed with ethanol and diethyl ether and the product is dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1O.CCN=C=NCCCN(C)C.CS(O)(=O)=O>O.C(Cl)(Cl)Cl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]2[O:8][C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=3)=[N:14][C:15]=2[CH:20]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cc(Cl)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(-c2nc3cc(Cl)ccc3o2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (25.0 g, 135 mmol), 2-amino-4-chlorophenol (21.3 g, 149 mmol), CHCl3 (500 mL), and WSC (28.5 g, 149 mmol) were added together and stirred at room temperature for 2 hours. The reaction mass was concentrated, and then the residue was washed with water and ethanol. To a dioxane (500 mL) solution of the solid obtained was added methanesulfonic acid (81.9 g, 811 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (31.0 g, 78% yield) as reddish-brown crystals.
Reaction SMILES: Br.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=3)[N:11]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.42 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted twice with 40 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.23 g of 4-methyl-N-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[CH:13]1([N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[NH:22][CH:19]1[CH2:20][CH2:21][N:16]([CH:13]2[CH2:15][CH2:14]2)[CH2:17][CH2:18]1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: NC1CCN(C2CC2)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cnc(NC2CCN(C3CC3)CC2)c(Cl)c1

Procedure:
A mixture of EXAMPLE 387A (0.4 g), 1-cyclopropylpiperidin-4-amine (0.3 g) and N,N-diisopropylethylamine (0.37 mL) in dioxane (3 mL) was heated at 100° C. for 18 hours. The crude product was isolated by concentration and was purified on silica gel, which was eluted with ethyl acetate to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([Br:13])[CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:14]I>CN(C=O)C>[CH3:14][N:9]1[C:10]2[C:6](=[CH:5][C:4]([F:3])=[CH:12][C:11]=2[Br:13])[CH:7]=[CH:8]1
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)cc(Br)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60%, 1.75 g, 43.8 mmol) in DMF (134 mL) was added a solution of 5-fluoro-7-bromoindole (7.8 g, 36.4 mmol) in DMF (10 mL). After 1 h at room temperature, the mixture was treated with methyl iodide (3.4 mL, 54.6 mmol) with cooling in an ice-water bath. The reaction mixture was allowed to warm up room temperature and stirred overnight. The reaction was quenched with water, extracted with ethyl acetate, and the organic layer was washed with water and brine, dried (sodium sulfate) and concentrated to give a crude product, which was used without further purification. 1H NMR (400 MHz, CDCl3) 4.06 (s, 3H), 6.34 (d, J=3.13 Hz, 1H), 6.96 (d, J=3.13 Hz, 1H), 7.07 (dd, J1=2.34 Hz, J2=8.60 Hz, 1H), 7.12 (dd, J1=2.34 Hz, J2=9.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([N+:33]([O-:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([N+:33]([O-:35])=[O:34])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction was carried out under argon. (rac)-Allyl 4-(4-cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (15.0 g, 30.8 mmol) and morpholine (1.5 eq., 4.03 g, 46.3 mmol) were initially charged in dry THF (300 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 1.78 g, 1.54 mmol) was added, and the reaction mixture was stirred at RT for 2 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (700 ml). The organic phase was washed with 0.5 N hydrochloric acid (500 ml) and with saturated sodium chloride solution (300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate and dried under high vacuum. The title compound was obtained as a solid (12.87 g, 93% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O>[CH2:19]([NH:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc2c(c1F)CCC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C1CCc2c1ccc(NCc1ccccc1)c2F
Yield: 10.4 %

Procedure:
As presented in the following reaction formula, a mixture of 5-amino-4-fluoro-2,3-dihydro-1H-inden-1-one (2.3 g, 14 mmol), cesium carbonate (Cs2CO3; 12 g, 28 mmol) and benzyl bromide (0.17 g, 72 mmol) in acetonitrile (CH3CN; 20 mL) was stirred under reflux for 48 hours. The mixture was concentrated to obtain the residue, which was dissolved in water (20 mL). The resulting solution was extracted three times with 20 mL of ethyl acetate. The combined organic phase was washed with saturated brine (50 mL), and dried and concentrated with anhydrous sodium sulfate to thereby give a crude product, which was purified by pre-TLC to give 5-(benzylamino)-4-fluoro-2,3-dihydro-1H-inden-1-one (370 mg, yield: 10%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[CH2:27](Br)[C:28]#[CH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]=[C:2]1[N:8]([CH2:29][C:28]#[CH:27])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (160 mg, 0.451 mmol) in DMF (2 mL) was added propargyl bromide (80 mg, 0.672 mmol) and powdered cesium carbonate (219 mg, 0.672 mmol). The mixture was stirred under nitrogen at ambient temperature for 18 h. The reaction was diluted with water and extracted twice with ethyl acetate. The residue obtained from the combined organic extracts was purified by flash chromatography on silica gel eluting with 5:1 (v/v) hexane:ethyl acetate to afford the title compound (143 mg, 80%) as a white solid. TLC Rf=0.19 (6:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.38 (s, 9H), 2.30 (m, 1H), 4.69 (m, 2H), 4.96 (m, 2H), 5.66 (m, 1H), 7.28 (m, 3H), 7.39 (s, 5H), 7.48 (m, 1H). MS APCI, m/z=293 (M+1). LC/MS: 2.86 min.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.[F:18][C:19]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:20]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+]>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:20]=1[CH2:21][N:17]([CH2:21][C:20]1[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:19]=1[F:18])[C:15]1[CH:14]=[CH:13][C:12]2[NH:8][CH:9]=[N:10][C:11]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)n1cnc2cc(N)ccc21
Reactant: Fc1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(F)c(CN(Cc2cc(F)c(F)cc2F)c2ccc3[nH]cnc3c2)cc1F

Procedure:
The compound was synthesized starting from N1-Boc-benzimidazol-5-amine (233 mg; 1 mmol; 1 eq.), 2,4,5-trifluorbenzylbromide (563 mg; 2.5 mmol; 2.5 eq.) and K2CO3 (345 mg; 2.5 mmol; 2.5 eq.) according to method 4; Yield: 0.172 (40.9%); MS m/z: 422.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.68 (s, 4H); 6.74 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.78 (br s, 1H); 7.23-7.29 (m, 2H); 7.39 (d, 1H, 3J=8.9 Hz); 7.51-7.56 (m, 2H); 7.97 (s, 1H); 12.03 (br s, 1H); HPLC (METHOD [A]): rt 16.46 min (100%)