Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14]([N:16]3[CH:20]=[CH:19]N=C3)=[O:15])=[N:10][C:9]=2[CH3:21])[CH:5]=[C:4]([CH3:22])[N:3]=1.NCC[C:26]([N:28]([CH3:30])[CH3:29])=[O:27]>CN(C=O)C>[CH3:22][C:4]1[CH:5]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:15])[NH:16][CH2:20][CH2:19][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[N:10][C:9]=2[CH3:21])[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: CN(C)C(=O)CCN
Reactant: Cc1cc(-c2sc(NC(=O)n3ccnc3)nc2C)cc(C)n1
Solvent: CN(C)C=O
Product: Cc1cc(-c2sc(NC(=O)NCCC(=O)N(C)C)nc2C)cc(C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of imidazole-1-carboxylic acid [5-(2,6-dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide (Intermediate BA) (0.05 g, 0.16 mmol) in DMF (1.5 ml) under an inert atmosphere is added 3-amino-N,N-dimethyl-propionamide (Amine) (0.018 g, 0.16 mmol). The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the resulting crude residue is dissolved in THF and passed through a plug of polymer supported isocyanate resin (0.5 g, pre-washed with THF). The solution is concentrated in vacuo and the crude residue is trituated with ether-ethyl acetate to afford the titled compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:11].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl.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>[CH:19]1([N:12]([CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])[C:10](=[O:11])[CH2:9][CH2:8][O:7][CH2:6][CH2:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(CN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1)OC
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: ClCCl
Solvent: CO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Temperature: 100 °C
Yield: 108.3 %

Procedure:
To 3-(3-bromophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide (1.4 g), prepared as in Preparation 3 Step iii), within a 35 mL microwave tube with stirrer were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.92 g), potassium carbonate (0.88 g) and Pd(Ph3P)4 (0.18 g) followed by methanol (8 mL). The vial was sealed and heated within a CEM Discover microwave at 100° C. for 15 min. The mixture was diluted with DCM and washed once with water, once with brine, dried over sodium sulphate and the solvent evaporated to afford crude material as an orange oil. This was purified on silica using ethyl acetate as the eluent to afford the product (1.52 g). MS [M+H-MeOH]+=412 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.78 and 7.77 (2×s, 1H), 7.40-7.32 (m, 2H), 7.23 and 7.22 (2×t, J=7.6 Hz, 1H), 7.07-7.03 (m, 1H), 4.52 and 4.36 (2×t, J=5.3 Hz, 1H), 4.05-3.95 and 3.69-3.60 (2×m, 1H), 3.901 and 3.898 (2×s, 3H), 3.75-3.64 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.34 and 3.25 (2×d, J=5.1 Hz, 2H), 2.84 and 2.83 (2×t, J=6.6 Hz, 2H), 2.65 and 2.63 (2×t, J=6.1 Hz, 2H), 1.79-1.04 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C@H:15]2[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[CH2:17][CH2:16]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](COc3ccc(F)cc3)CC[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1ccc(OC[C@@H]2CC[C@@H]3CNCCN3C2)cc1
Yield: 102.5 %

Procedure:
A solution of 0.20 g (0.55 mmol) of (7R,9aR)-2-BOC-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 10 mL of trifluoroacetic acid and 3 mL of water was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo and the residue diluted with water. The solution was adjusted to pH 12 with 15% NaOH, and extracted with ethyl acetate (2×). The organic phase was dried (magnesium sulfate), filtered and evaporated to give 0.149 g of the title compound which was used without further purification for subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH2:10][C:11]([CH2:22][C:23]#[C:24][C:25](=[O:27])[CH3:26])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[Au].ClC1C=CC=CC=1Cl>[C:25]([C:24]1[C:4]2[C:3](=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=2)[CH:8]=[C:9]2[CH2:10][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:22][C:23]=12)(=[O:27])[CH3:26]
Reactant: CCOC(=O)C(CC#CC(C)=O)(CC=Cc1ccccc1Cl)C(=O)OCC
Agent: [Au]
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)C1(C(=O)OCC)Cc2cc3c(Cl)cccc3c(C(C)=O)c2C1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
A microwave irradiation vial (10-20 mL) was equipped with a sir bar (1.5 cm) and was charged with compound 5m (0.3 g, 0.77 mmol) and 1,2-dichlorobenzene (12.8 mL). The reaction was irradiated with stirring at 180° C. for 30 min, turning gold in color. The reaction was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2:8 to collect the pure product. The title compound was isolated as a yellow oil in quant. yield (0.298 g). Small traces of contaminants were observed.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[N:11][C:10]=2[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=1)=[O:5])[CH3:2].B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.C([O-])(=O)C.[K+].B([O-])[O-].[CH2:53]([O:55][C:56]([C:58]1([CH2:71]C)[CH2:63][CH2:62][N:61]([C:64]2[N:69]=[CH:68][C:67](Br)=[CH:66][N:65]=2)[CH2:60][CH2:59]1)=[O:57])[CH3:54].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH2:1]([NH:3][C:4]([C:6]1[C:14]2[S:13][C:12]([NH:15][C:16](=[O:20])[NH:17][CH2:18][CH3:19])=[N:11][C:10]=2[CH:9]=[C:8]([C:67]2[CH:66]=[N:65][C:64]([N:61]3[CH2:62][CH2:63][C:58]([CH3:71])([C:56]([O:55][CH2:53][CH3:54])=[O:57])[CH2:59][CH2:60]3)=[N:69][CH:68]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(Br)cn2)CC1
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)NCC)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C(=O)NCC)c2s1
Temperature: 80 °C
Yield: 42 %

Procedure:
[7-(Ethylcarbamoyl)-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]trifluoromethanesulfonate (150 mg, 0.344 mmol), bis-(neopentyl glycolato)diboron (155 mg, 0.688 mmol) and potassium acetate (100 mg, 0.89 mmol) were weighed into a Kymax tube. DMF (4 mL) was added and the mixture degassed by bubbling N2 through for 15 min. Pd(dppf)Cl2 (28 mg, 0.0344 mmol) was added and the reaction sealed and heated to 80° C. for 3 h at the end of which time LCMS indicated clean boronate formation. The reaction was allowed to cool to ambient temperature then 1-(5-bromo-pyrimidin-2-yl)-4-ethyl-piperidine-4-carboxylic acid ethyl ester (169 mg, 0.516 mmol), cesium carbonate solution (185 μl, 0.688 mmol, 3.7M aq. soln.) and Pd(dppf)Cl2 (28 mg, 0.0344 mmol) were added and the reaction sealed and heated to 90° C. for 3 h at the end of which time LCMS indicated formation of the desired product. The reaction mixture was diluted with EtOAc, washed with water then brine and the organic layer dried (MgSO4), filtered and the solvent was removed in vacuo. The crude material obtained was purified by flash chromatography on silica gel using DCM:MeOH 96:4 as eluent. The product was obtained as a pale brown solid, 78 mg, 42% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH:11]1[CH2:27][CH2:26][C:14]2([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:10]([CH3:9])[CH:11]2[CH2:27][CH2:26][C:14]3([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (596 mg, 4.0 mmol) and tert-butyl 8-(methylamino)-2-azaspiro[4.5]decane-2-carboxylate (1.29 g, 4.8 mmol) in EtOH (10 mL) was added Et3N (0.92 g, 9.1 mmol) and the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the product as a pale yellow solid (580 mg, 38.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@H:4]([CH2:35][CH2:36][S:37][CH3:38])[NH:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]2[CH2:20][S:19][CH2:18][N:17]2C(OC(C)(C)C)=O)=[O:15])=[CH:9][C:8]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(S)C=CC=CC=1.[ClH:47].O1CCOCC1>>[ClH:47].[CH3:1][O:2][C:3](=[O:39])[C@H:4]([CH2:35][CH2:36][S:37][CH3:38])[NH:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]2[CH2:20][S:19][CH2:18][NH:17]2)=[O:15])=[CH:9][C:8]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CSCN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Agent: Cl
Agent: Sc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CSCN2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of [4-(N-tert-butoxycarbonyl-(R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methionine methyl ester (270 mg, 0.47 mmol) and thiophenol (0.1 mL, 0.97 mmol) was added 4N HCl-dioxane (10 mL) and the reaction mixture was stirred for 45 minutes at ambient temperature. The reaction mixture was partitioned between water and ether. The aqueous phase was extracted with ether. The organic extracts were discarded and the aqueous phase was lyophilized to give [4-((R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methionine methyl ester hydrochloride (150 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([OH:14])[C:10]=1[O:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH2:18](I)[CH3:19].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([O:14][CH2:18][CH3:19])[C:10]=1[O:11][CH2:12][CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CCOc1c(O)cc(C(C)=O)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(C)=O)cc(C(C)(C)C)c1OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(3-tert-Butyl-4-ethoxy-5-hydroxyphenyl)ethanone (O3.010; 470 mg) and ethyl iodide (193 μl) were dissolved in DMF (6.2 ml), and sodium hydride (57 mg) was added. After stirring at RT for 0.5 h, the DMF was drawn off and the residue was taken up in EA, washed with water, dried and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient 0-30% within 60 min). 420 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8](C(OC(C)(C)C)=O)[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)C.Cl>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[CH:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)c[nH]c1C
Temperature: 54 °C
Yield: 87.2 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (2600 g) and ethanol (7800 mL) were stirred vigorously while 10 N hydrochloric acid (3650 mL) was slowly added. The temperature increased from 25° C. to 35° C. and gas evolution began. The mixture was warmed to 54° C. and stirred with further heating for one hour at which time the temperature was 67° C. The mixture was cooled to 5° C. and 32 L of ice and water were slowly added with stirring. The solid was collected by vacuum filtration and washed three times with water. The solid was air dried to constant weight to give of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (1418 g, 87% yield) as a pinkish solid. 1H-NMR (dimethylsulfoxide-d6) δ2.10, 2.35 (2×s, 2×3H, 2×CH3), 4.13 (q, 2H, CH2), 6.37 (s, 1H, CH), 10.85 (s, 1H, NH). MS m/z 167 [M+1].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](OC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].C(OC(C)C)(C)C>[Zn]>[C:1]1([CH2:7][CH2:8][C:9]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)O
Reactant: COC(=O)CCc1ccccc1
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)CCc1ccccc1

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 3-phenylpropionate (3.0 mmol), t-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 5 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, t-butyl 3-phenylpropionate was obtained quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[CH:14][CH2:15][CH2:16][CH2:17][C:12]3([CH2:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:11]1[C:12]2([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=3)[CH2:17][CH2:16][CH2:15][CH:14]=[C:13]2[N:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:10]1=[O:27])(=[O:30])[CH3:29]
Reactant: N#Cc1ccc(CC23CCCC=C2N(c2cc(Cl)cc(Cl)c2)C(=O)N3)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)N(c2cc(Cl)cc(Cl)c2)C2=CCCCC21Cc1ccc(C#N)cc1

Procedure:
4-[1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (150 mg) (0.38 mmol) in acetic anhydride (5 ml) was refluxed 3 days. After cooling, the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (DCM/acetone, 97.5/2.5), then HPLC to give 4-[3-Acetyl-1-(3,5-Dichlorophenyl)-2-oxo-1,2,3,4,5,6-hexahydro-benzimidazol-3a-ylmethyl]benzonitrile (13.5 mg) as a white solid. 1H NMR (CDCl3): 7.55 (2H, d), 7.3-7.2 (3H, m), 6.70 (2H, m), 4.95 (1H, m), 3.70 (1H, d), 3.05 (1H, m), 2.50 (3H, s), 2.45-2.1 (2H, m), 2.1-1.6 (3H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.C(O[C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=2)[CH:27]=1)=O)(C)(C)C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=4)[CH:27]=3)[CH2:23][C:22](=[O:39])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1nccc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (121 mg, 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (49 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:30][N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37](Cl)=[O:38])=[N:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:30][N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37]([NH:23][C:14]2[CH:15]=[C:16]([Sn:19]([CH3:20])([CH3:22])[CH3:21])[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:38])=[N:32]1
Reactant: Cc1cn(C)nc1C(=O)Cl
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(Phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (250 mg) was dissolved in DCM (10 ml) and pyridine (0.051 ml) was added. 1,4-Dimethyl-1H-pyrazole-3-carbonyl chloride (100 mg) in DCM (5 ml) was added dropwise. The reaction was stirred at RT for 2 h. After this time saturated sodium bicarbonate aq (25 ml) was added and the reaction was stirred vigorously for 5 min before the DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DCM, and then applied to the top of a 20 g silica cartridge preconditioned with cyclohexane. The column was washed with 50% cyclohexane:ether (100 ml), before the compound was eluted with ether, then 5% methanol in ether. The product containing fractions were evaporated to dryness to afford the title compound, 310 mg.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br.O>C(O)(=O)C>[Br:19][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:18])=[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=1
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Oc1c(Cc2ccccc2)cc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
A solution of 2-(phenylmethyl)-1-naphthol (1.00 g, 4.3 mmole) in acetic acid (20 mL) was stirred at room temperature. A solution of bromine (0.7 g, 4.3 mmole) in acetic acid (6 mL) was added dropwise over 10 minutes. The mixture was stirred for another 5 minutes, then poured into water. The resulting solid was collected by filtration and recrystallized (cyclohexane) to provide the title compound (1.21 g, 88%) as off-white needles, mp 123°-125°.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:23](=[O:25])[CH3:24])[CH3:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1.[I-].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(=O)([O-])O.[Na+].CN(C)C=O>[C:31]1([CH2:30][CH2:29][N:5]2[CH2:6][CH2:7][CH:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([C:23](=[O:25])[CH3:24])[CH3:22])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH2:9][CH2:10]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCNCC2)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCN(CCc3ccccc3)CC2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
The N-(4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide acetate (3.71 g, 10.6 mmol) prepared in Preparative Example 17 was dissolved in a suspension of sodium hydrogencarbonate (2.52 g) and potassium iodide (3.32 g) in dimethylformamide (50 ml), followed by the addition of 2-bromoethylbenzene (1.49 ml, 11.0 mmol). The obtained mixture was stirred at 70° C. for 3 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-[1-(2-phenylethyl)-4-piperidyl]-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless oil (3.19 g, yield: 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[C:11]([NH:14][C:15](=[O:26])[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][CH2:18][CH3:19])([CH3:13])[CH3:12].[C:28](=O)([O-])[O-].[K+].[K+].C=O.O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[C:11]([N:14]1[C:15](=[O:26])[CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([CH2:18][CH3:19])[CH2:28]1)([CH3:12])[CH3:13]
Reactant: CCNC(C(=O)NC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCN1CN(C(C)(C)C(=O)Nc2cc(Cl)ccc2Cl)C(=O)C1c1ccccc1
Yield: 43.2 %

Procedure:
To a solution of N-(2,5-dichlorophenyl)-2-(α-ethylaminophenylacetylamino)isobutyramide (0.9 g) in ethanol (15 mL) were added potassium carbonate (0.5 g) and paraformaldehyde (0.5 g), and the mixture was heated at reflux for 4 hours. After the reaction solution was added to water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting crude product was purified by thin-layer chromatography (silica gel, diethyl ether/n-hexane=1/1) to give 0.4 g of the title compound.
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.Cl.[CH3:13][C:14]1([CH3:39])[C:23]2[C:18](=[CH:19][C:20]([N+:35]([O-])=O)=[C:21]([NH:24][C:25](=O)[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:22]=2)[NH:17][C:16](=[O:38])[CH2:15]1>N1C=CC=CC=1>[CH3:13][C:14]1([CH3:39])[C:23]2[CH:22]=[C:21]3[NH:24][C:25]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[N:35][C:20]3=[CH:19][C:18]=2[NH:17][C:16](=[O:38])[CH2:15]1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)CC3(C)C)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)CC(=O)N4)cc1
Reaction time: 2 h

Procedure:
4.7 g. (20 mmole) of the above compound were mixed in 50 ml. pyridine, while cooling with ice, with 3.7 g. (22 mmole) 4-methoxybenzoyl chloride. After 2 hours at 25° C., the reaction mixture was poured on to ice, acidified with 2N hydrochloric acid, extracted with methylene chloride, dried and evaporated to give 6.9 g. (93% of theory) 4,4-dimethyl-6-(4-methoxybenzoylamino)-7-nitro- 1,2,3,4-tetrahydroquinolin-2-one; m.p. 288°-290° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:12])[N:11]=1)[C:5](OC)=[O:6].[BH4-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([Br:12])[N:11]=1
Reactant: COC(=O)c1cc(Br)nc(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Br)nc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 2,6-dibromoisonicotinate (10.0 g, 33.91 mmol) in ethanol (200.0 ml) was slowly added NaBH4 (6.4 g, 169.18 mmol) at room temperature under stirring. The reaction was heated to reflux and kept at reflux for 2 hours. The reaction solution was cooled to room temperature, and 2 M HCl (35.0 ml) was added slowly with stirring until the bubbling stopped. The ethanol was removed by rotary evaporation. Solid NaOH was added under stirring until the solution became basic. The solution continued to be stirred, and during stirring the product was precipitated. A white solid product was collected by filtration. After drying, the product was obtained in an amount of 5.0 g (55.6%).