Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15]>C(Cl)Cl>[Cl:19][C:18]([Cl:21])([Cl:20])[CH2:17][O:16][C:14](=[O:15])[NH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[O:7])[N:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN(C)C(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a 250 mL round bottom flask, 4-amino-N,N-dimethyl-benzamide (20 g, 0.1219 mol; prepared as described in Preparation 1) and 2,2,2-trichloroethyl chloroformate (30 g, 0.1463 mol), TEA (34 mL, 0.2438 mol) and DCM (100 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude product was washed with diethyl ether and dried under reduced pressure to afford the title compound [30 g, 73%]. LC-MS (ESI): Calculated mass: 338.0; Observed mass: 341.0 (RT: 1.38 min). The compound was directly taken to the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([CH:8]([C:18](=O)[CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)#[N:2].[CH2:24]([C:26]1[N:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)[CH3:25]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[C:28]3[N:27]([C:26]([CH2:24][CH3:25])=[CH:30][CH:29]=3)[N:31]=[C:18]([CH3:19])[C:8]=2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:21]=[CH:22][CH:23]=1)#[N:2]
Reactant: CCc1cccn1N
Reactant: CCOC(=O)CCCCC(C(C)=O)C(=O)c1cccc(C#N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cccc(C#N)c1
Yield: 83.8 %

Procedure:
To a solution of ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.18 g) in toluene (30 mL) was added 2-ethyl-1H-pyrrol-1-amine (1.17 g) and p-toluenesulfonic acid monohydrate (96 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The mixture was evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 200 mL) eluting with hexane-ethyl acetate=20-1, 15-1, and 10-1 to give ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (3.29 g, 83.8%) as an yellow oil.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1)[CH2:12][CH3:13]>>[CH2:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[S:6]([Cl:10])(=[O:8])=[O:7])[CH2:12][CH3:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCc1cc2ccccc2s1
Solvent: CN(C)C=O
Product: CCCc1sc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-Propylbenzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (3.6 mmoles, 0.28 ml), sulfuryl chloride (3.1 mmoles, 0.25 ml) and 2-propylbenzo[b]thiophene (1.8 mmoles, 0.32 g). Flash chromatography (3% ethyl acetate/hexanes) provided 0.28 g (56%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:41]([CH:38]3[CH2:40][CH2:39]3)=[O:42])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(Cc1c(C(=O)C2CC2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using cyclopropanecarbonyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Clc1nc2ccccc2[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2nc(Cl)[nH]c2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
2-Chlorobenzimidazole (1.05 g) was dissolved in DMF (10 mL), and N-chlorosuccinimide (1.01 g) was added thereto. The mixture was stirred at 60° C. for 30 min and the reaction mixture was added to water. The precipitated solid was collected by filtration to give 2,5-dichlorobenzimidazole (0.480 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[CH:15](SC1C=CC=CC=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Ni].C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1oc(-c2ccccc2)cc(O)c1C(CCc1ccccc1)Sc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: O=c1oc(-c2ccccc2)cc(O)c1CCCc1ccccc1

Procedure:
The title compound was prepared by Method F using Raney-Nickel (Grace 3100), ethanol (15 mL), 4-hydroxy-6-phenyl-3-[3-phenyl-1-(phenylthio)propyl]-2H-pyran-2-one (0.150 g, 0.362 mmol). m.p. 195-196° C.; 1H NMR (400 MHz, DMSO-d6) δ1.73 (m, 2 H), 2.40 (t, 2 H), 2.60 (t, 2 H), 6.68 (s, 1 H), 7.23 (m, 5 H), 7.52 (m, 3 H), 7.74 (m, 2 H).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH2:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([NH:30][CH3:29])=[O:20])[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CN
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)NC)C1(C)C

Procedure:
The product from Example 205 and methylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.13 (s, 3H), 1.23 (s, 3H), 1.26-1.42 (m, 3H), 1.57 (s, 9H), 1.57-1.66 (m, 2H), 1.72-1.82 (m, 1H), 2.24-2.45 (m, 2H), 2.54-2.56 (m, 3H), 2.61-2.67 (m, 2H), 2.96-3.02 (m, 1H), 7.24-7.28 (m, 1H), 8.50 (s, 1H). (ESI+) m/z 408 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[C:10]1=[O:30])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[C:10]1=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Yield: 64.7 %

Procedure:
A solution of (S)-benzyl 4-(3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (7 g, 17 mmol) in 50% TFA/CH2Cl2 (50 mL) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated sodium carbonate (200 mL) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to yield (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (3.4 g, 11 mmol, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[OH:19].Cl[CH:21]([CH3:25])[C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3[CH2:17][CH2:16][CH2:15][CH2:14][C:11]=3[C:12]2=[O:13])=[CH:4][C:3]=1[O:19][CH:21]([CH3:25])[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)C(C)Cl
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Reaction time: 3 h

Procedure:
A mixture of 4.0 g. of N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 2.0 g. of 3-chloro-2-butanone, 2.1 g. of potassium carbonate, 1.0 g. of potassium iodide and 30 ml. of acetone was refluxed with stirring for 3 hours. The precipitate was separated by a filtration and the filtrate was concentrated under a reduced pressure and the residue was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 2:3) to obtain 4.2 g. of Compound No. 24 shown in Table 1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH2:9][C:10]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Br:20])[CH:14]=1)([OH:12])[CH3:11])=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([CH2:9][C:10]([O:12][S:2]([CH3:1])(=[O:4])=[O:3])([C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Br:20])[CH:14]=1)[CH3:11])=[N+:7]=[N-:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(CN=[N+]=[N-])c1cc(Br)ncc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CN=[N+]=[N-])(OS(C)(=O)=O)c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., methanesulfonyl chloride (2.04 ml, 3.00 g, 26.20 mmol) was dropwise added to a solution of 1-azido-2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (6.00 g, 21.81 mmol) and NEt3 (3.65 ml, 2.65 g, 26.2 mmol) in DCM (200 ml). The reaction mixture was stirred at 0° C. for 1 h, then for another 1 h at 0° C. to rt. The reaction mixture was quenched with 1M aq. NaHCO3 soln. and diluted with DCM. The phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were dried over Na2SO4, filtered and concentrated. HPLC purification (Alltech Grom Saphir 65 Si 10 μM column, 250×50 mm, gradient n-heptane:EtOAc 0-1.6 min 85:15, 1.6-16 min 0:100, 16-21.2 min 0:100, flow 100 ml/min, detection 254 nm) yielded the title compound as well as recovered starting material that could be reacted again according to the above procedure. HPLC RtH4=0.96 min; ESIMS: 353, 355 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.28 (d, 1H), 7.56 (d, 1H), 4.08 (d, 1H), 3.82 (d, 1H), 3.22 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9]/[C:10]/2=[CH:13]\[C:14](Cl)=[O:15])=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9]/[C:10]/2=[CH:13]\[C:14]([NH2:2])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)/C=C1\CCc2ccc(F)cc21
Yield: 90.6 %

Procedure:
A 29.6% aqueous ammonium hydroxide solution (17.6 mL, 134 mmol) was added dropwise to a stirred, chilled (ice bath) solution of (E)-2-(6-fluoro-1-indanylidene)acetyl chloride (14.1 g, 67 mmol) in dichloromethane (165 mL). After an hour, the resulting white precipitate was collected by filtration, dissolved in ethyl acetate (600 mL) and washed with water (3×300 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated in vacuo. The resulting off-white solid was washed with hexane, giving 11.6 g (91%) of (E)-2-(6-fluoro-1-indanylidene)acetamide, m.p., 180-183° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)([O-])=O.NN>C(O)C.[Pd]>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1-c1ccco1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccccc1-c1ccco1
Reaction time: 20 h

Procedure:
113 mg (0.6 mmol) 2-(2-nitro-phenyl)-furan are dissolved in 2 ml of ethanol and combined with 6 mg palladium on activated charcoal (10% Pd). 110 μl of a 35% aqueous hydrazine solution are added to this suspension and the reaction mixture is stirred for 20 h under reflux conditions. The catalyst is suction filtered, the filtrate is combined with 25 ml of water and adjusted to pH 5. This mixture is extracted three times with 10 ml of ethyl acetate. The combined organic phases are dried and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4(O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([O:30][Si](C)(C)C)=[C:27]([CH3:29])[CH3:28]>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:27]([CH3:29])([CH3:28])[C:26]([O:25][CH3:24])=[O:30])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: OC1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)C(C)(C)C1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Yield: 97.7 %

Procedure:
To 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-ol (125 mg, 0.40 mmol) in 5 mL of DCE was added TiCl4 (0.44 mmol; 0.44 mL of 1 M solution in DCM). A precipitate immediately formed. The reaction was concentrated in vacuo to approx 1 mL volume and treated with 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.23 mL, 1.2 mmol) and the reaction became homogeneous and was complete. The reaction was quenched with NaHCO3, extracted 4× EtOAc, and combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography using 25% EtOAc in hexanes to give methyl 2-(4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-yl)-2-methylpropanoate (155 mg, 99%). MS found: (M+H)+=397.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C)c1
Product: COC(=O)c1nc(N)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-m-tolyl-propionic acid methyl ester with thiourea. LC-MS: tR=0.78 min; [M+H]+=249.0.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:20][CH:21]=3)[C:8]=2[CH:9]=1)=O.[Br:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1.ClCCl.C([O-])(O)=O.[Na+]>CC(O)C>[Br:28][C:29]1[S:33][C:32]2=[N:34][C:3]([C:5]3[O:6][C:7]4[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]5[N:18]=[C:19]([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[S:20][CH:21]=5)[C:8]=4[CH:9]=3)=[CH:2][N:31]2[N:30]=1
Reactant: Nc1nnc(Br)s1
Reactant: O=C(CBr)c1cc2c(OCc3csc(-c4ccccc4)n3)cc(F)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: Fc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Temperature: 150 °C
Yield: 43.8 %

Procedure:
In a 2-5 mL microwave pressure vial was added 2-bromo-1-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone (Example 36E, 35 mgs, 0.078 mmol) in propan-2-ol (2 mL) followed by 5-bromo-1,3,4-thiadiazol-2-amine (16.2 mgs, 0.09 mmol). The reaction was heated to 80° C. overnight and to 150° C. for 1 h in microwave oven. The reaction mixture was then poured into a mixture of dichloromethane (8 mL) and saturated NaHCO3 (2 mL) and this was extracted twice with dichloromethane. The organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (ISCO 12 g gold column using 100% dichloromethane, then 1% ethyl acetate and then 2% ethyl acetate in dichloromethane) to give the title material (18 mgs, 43%) as a yellowish solid. LC (Method B): 2.754 min. LCMS (APCI) calcd for C22H13BrFN4O2S2 [M+H]+ m/z 526.96, found 527.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2.CCN(C(C)C)C(C)C>C(O)CCC>[N:35]1[C:27]([NH:25][C@H:23]([C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH3:24])=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester from Example 6 (202 mg), 6-chloro-9H-purine (91 mg, 0.586 mmol) and DIPEA (0.2 mL, 1.17 mmol) in n-butanol (1 mL) was stirred in a sealed tube for 3 h at 120° C. After cooling to RT, the crude reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with diethyl ether affording 112 as a pale brown solid (113 mg, 38% over two steps). LCMS: RT 3.24 min [M+H]+ 463.2. 1H NMR (CDCl3, 400 MHz): δ 8.54 (1H, s), 7.98 (1H, s), 7.78 (1H, d, J=7.55 Hz), 7.49 (1H, d, J=7.36 Hz), 7.28-7.07 (3H, m), 6.13 (1H, br), 4.89-4.78 (1H, m), 4.47-4.04 (2H, m), 2.97-2.78 (1H, m), 2.60-2.26 (3H, m), 1.99-1.62 (6H, m), 1.49 (9H, s)
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3ccnc23)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)n3ccnc23)CC1
Temperature: 90 °C
Yield: 69.3 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(5-bromoimidazo[1,2-a]pyrazin-8-yl)piperazine-1-carboxylate (1.0 g, 2.62 mmol), thiophen-2-ylboronic acid (0.50 g, 3.93 mmol), Pd(PPh3)2Cl2 (200 mg, 0.26 mmol), Cs2CO3 (0.60 g, 3.93 mmol) and DMF (30 mL). After air was purged by bubbling N2 into the reaction solution, the reaction mixture was heated at 90° C. for 30 h. Work-up: the reaction mixture was poured into water (150 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 0.70 g (72%) of the product as a yellow solid. MS m/z: 386 (M+H+).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:21][C@H:22]([CH2:27][OH:28])[C@H:23]([CH2:25][CH3:26])[CH3:24])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:21][C@H:22]([CH:27]=[O:28])[C@@H:23]([CH3:24])[CH2:25][CH3:26])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Molecular sieves (15 g, 4 Å) were stirred in dry CH2Cl2 (175 mL) for 10 min. Then a mixture of pyridinium chlorochromate (8.6 g, 39.9 mmol) and silica gel (9 g) 15 was added and the mixture was stirred an additional 10 min. To the suspension was added 5-chlorothiophene-2-sulfonyl isoleucinol (4 g, 13.4 mmol) dissolved in CH2Cl2 (15 mL) and the resulting slurry was stirred for 2 h. The reaction mixture was filtered and the solvent was removed. The residue was subjected to a Biotage™ eluting with 20% EtOAc/hexane to give 3.22 g (81%) of the aldehyde (LCMS=294.21 (M−H), rt=1.10 min).
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:23][CH3:24])[CH:15]2[N:10]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:14]=32)[CH2:9][CH2:8][CH2:7]1)(=O)C.CO.[OH-].[Na+]>O>[OH:4][CH2:5][C:6]1([CH2:23][CH3:24])[CH:15]2[N:10]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:14]=32)[CH2:9][CH2:8][CH2:7]1
Reactant: CCC1(COC(C)=O)CCCN2CCc3c([nH]c4ccccc34)C21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1(CO)CCCN2CCc3c([nH]c4ccccc34)C21

Procedure:
1.50 g. (4.6 mmoles) of 1-acetoxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine are dissolved in 15 ml. of methanol, and a solution of 0.40 g. (10 mmoles) of sodium hydroxide in 4 ml. of distilled water is added. The mixture is refluxed for 45 minutes, then diluted with 30 ml. of distilled water. The separated crystals are filtered off and washed with distilled water. 1.05 g. of the title compound are obtained; m.p.; 230°-233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:23]([O-])=O>[Pd].C(OCC)(=O)C.CO>[CH3:22][O:21][CH2:20][CH2:19][N:17]([CH3:18])[C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:5]3[CH:4]=[C:3]([NH2:23])[C:2]([NH2:1])=[CH:7][CH:6]=3)=[N:9][C:10]=2[CH:16]=1
Reactant: COCCN(C)c1ccc2[nH]c(-c3ccc(N)c([N+](=O)[O-])c3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCN(C)c1ccc2[nH]c(-c3ccc(N)c(N)c3)nc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-(2-methoxy-ethyl)-methyl-amine (0.65 g, 1.9 mmol) in 4:1 ethyl acetate/methanol (50 ml) under nitrogen, was added 5% palladium on carbon (100 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-{5-[(2-methoxy-ethyl)-methyl-amino]-1H-benzoimidazol-2-yl}-benzene-1,2-diamine as a thick oil that was used in the next step without any purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=3[C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=2)[CH:3]=1.[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][C:5]1[N:6]([C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=[C:8]2[C:4]=1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9]2
Reactant: CCOC(=O)c1ccccc1-n1cc2cc(C)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-n1nc2ccc(C)cc2c1Br
Yield: 80.2 %

Procedure:
Carbon tetrachloride (26 ml) was added to ethyl 2-(5-methyl-2H-indazol-2-yl)benzoate (1.43 g, 5.10 mmol) as obtained in Reference Example 3 and the mixture was stirred. Thereto were added N-bromosuccinimide (0.908 g, 5.10 mmol) and azobisisobutyronitrile (78 mg, 0.48 mmol), and the mixture was refluxed under heating for 3 hours. After cooling, the mixture was filtered, and the cake was washed twice with carbon tetrachloride (5 ml). The filtrate was concentrated, and subjected to flash chromatography on silica gel using a mixed solvent of hexane/ethyl acetate (8:1-3:1), whereby 1.47 g of ethyl 2-(3-bromo-5-methyl-2H-indazol-2-yl)benzoate was obtained.