Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14]Cl)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([N:12]([CH2:16][CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:13][CH3:14])[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(C=O)cc1
Yield: 60.3 %

Procedure:
To the solution of 18.4 g (0.15 mol) of 4-hydroxybenzaldehyde in 100 ml acetone, 27.5 g (0.16 mol) of N,N-diethyl-N-(2-chlorethyl)-amine IX and 22.1 g (0.16 mol) potassium carbonate was added at the room temperature under stirring. The mixture was then intensively stirred at the boiling temperature for 12 hours. The mixture was cooled, potassium chloride was separated, washed with acetone. The solvent was distilled off from the solution on the vacuum rotatory evaporator. Afforded 20 g (60.6%) of 4-diethylaminoethoxybenzaldehyde X. Colourless fluid boiling point 120-123° C./0.5 torr, n20D=1.536. Lit. [5] reports boiling point 123-125° C./0.8 torr, n20D=1.530.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:8]1[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]1
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccccc2Cl)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 3.3 mL of 2-chlorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then stirred for 2 hours at room temperature. The crude product was triturated from diethyl ether to afford a solid (m.p. 124°-125° C.). 1H NMR (CDCl3) δ2.63 (dd, 1H), 3.10 (dd, 1H), 3.68 (dd, 2H), 6.07 (dd, 1H), 7.3-7.65 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[C:18]1([CH3:29])[CH:23]=[CH:22][C:21]([S:24]([O:27]C)(=[O:26])=[O:25])=[CH:20][CH:19]=1>CO>[C:18]1([CH3:29])[CH:19]=[CH:20][C:21]([S:24]([O-:27])(=[O:25])=[O:26])=[CH:22][CH:23]=1.[CH2:13]([O:12][C:10]([C:9]1[CH:15]=[CH:16][C:6]([O:5][CH2:4][CH2:3][N+:2]([CH3:18])([CH3:1])[CH3:17])=[CH:7][CH:8]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1ccc(OCCN(C)C)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CO
Product: CCOC(=O)c1ccc(OCC[N+](C)(C)C)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
25.0 g (0.11 mol) of the ethyl 4-(2-dimethylaminoethoxy)benzoate obtained in Comparative Example 1 were dissolved in 250 mL of methanol in a nitrogen atmosphere. After adding 23.6 g (0.13 mol) of methyl p-toluenesulfonate while stirring at room temperature, the solution was stirred for 2 hours while heating to 50° C. After distilling off the solvent, the resulting residue was recrystallized from a mixed solvent of 100 mL of methanol and 500 mL of ethyl acetate to obtain 35.9 g of the target substance (yield: 81%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.[O:24]1[CH2:29][CH2:28]O[CH2:26][CH2:25]1.O1C=CC=C1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C>[O:24]1[CH:29]=[CH:28][CH:26]=[C:25]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(Oc1ccc(-c2cc3nccnc3[nH]2)cc1)C(F)(F)F
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccco1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1coc(-c2ccc(-c3cc4nccnc4[nH]3)cc2)c1
Temperature: 180 °C

Procedure:
A mixture of 6-(4-trifluoromethanesulfonyloxyphenyl)-5H-pyrrolo[2,3-b]pyrazine [20 mg, Reference Example 18(e)], dioxane (2.5 mL), furan-2-boronic acid (9.8 mg), sodium carbonate solution (0.06 mL, 2N), and tetrakis(triphenylphosphine)palladium[0] (4 mg) was heated at 180° C. in a microwave oven for 40 minutes. The reaction mixture was then evaporated and the residue was subjected to chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give, after trituration with a mixture of ethyl acetate and methanol, the title compound (7 mg) as a yellow solid. MS: 262.1 (MH+). RT=3.05 minutes.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[CH:23][C:22]=3[O:34][CH3:35])=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:43]CC)C.CCCCCC>CC(C)=O>[CH3:35][O:34][C:22]1[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:25]=[CH:26][C:21]=1[C:19]([N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][N:14]2[C:5]([C:3]([OH:4])=[O:43])=[CH:6][CH:7]=[C:8]2[CH2:9]1)=[O:20]
Reactant: CCOCC
Reactant: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step E (1.6 g, 2.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (2.3 mL, 5.8 mmol). After stirring overnight, the reaction was acidified with 2 N hydrochloric acid (3.2 mL, 6.4 mmol) then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided 1.2 g of desired product as an off-white solid, m.p. 201–204° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:25])=[O:24])[CH:3]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)N3CCOCC3)cc1CS2(=O)=O

Procedure:
A mixture of Example 49j (0.2 g, 0.45 mm) and morpholine (0.08 mL, 0.9 mmol) in dry ethyl acetate (25 mL) was stirred overnight at room temperature, treated with water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous HCl (50 mL), water, brine, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.19 g, (86%); 1H NMR (DMSO-d6): δ 2.80 (s, 3H, CH3), 3.0 (t, 4H, 2CH2), 3.7 (s, 4H, 2CH2), 5.5 (s, 2H, CH2), 8.0 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.2 (s, 2H, Ar). MS: m/e (EI+) 487 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.CC(C)([O-:11])C.[K+].CS(C)=O.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:22][CH2:18][CH2:19][C:20]([OH:11])=[O:21])=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CCC=Cc1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a suspension in DMSO/THF 1:1 volume/volume (26 mL) of 3-thiophencarboxaldehyde (2.0 g; 18 mmoles) and 2-(carboxyethyl) (triphenyl)phosphonium bromide (8.9 g; 21 mmoles) 5.3 g of potassium t-butoxide are added. The reaction mixture is left under stirring for 2 hours at room temperature. Then the organic phase is washed with water (20 mL) and extracted with chloroform (2×20 mL). The solvent is removed and the aqueous phase is acidified with concentrated HCl and extracted with chloroform (2×20 mL). The organic phase is recovered and washed with water and dried with sodium sulphate. After filtration, the organic phase is concentrated under vacuum. The obtained residue is purified by chromatography on silica gel by using as eluent a ligroin/ethyl acetate 1:1 volume/volume mixture. 2.3 g of a mixture of the two cis and trans diastereoisomers of the 5-(thiophen-3-il)-pent-4-enoic acid are obtained (yield 70%). Rf=0.35 (ligroin/ethyl acetate 6/4 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.29 (m, 1H, ArH), 7.23 (m, 1H, ArH), 7.18 (m, 2H, ArH), 7.09 (m, 2H, ArH), 6.44 (m, 2H, CH), 6.06 (m, 1H, CH), 5.57 (m, 2H, CH), 2.68 (m, 2H, CH2), 2.52 (m, 6H, CH2); 13C NMR (CDCl3) δ (ppm): 179.2, 179.1, 139.9, 138.2, 128.9, 128.5, 127.9, 125.9, 125.5, 125.2, 124.9, 124.5, 123.1, 121.2, 33.9, 33.8, 27.8, 24.2; FT-IR (film) νmax: 3098.1, 2923.5, 1693.2, 1410.6, 1267.7, 1242.6, 1206.6, 1155.3, 966.1, 755.4 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].[CH:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]2[C:30]([O:32][C:33](=O)[C:23]=2[CH:22]=1)=[O:31]>>[CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:30](=[O:31])[C:24]5[C:23](=[CH:22][CH:21]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=5)[C:33]4=[O:32])[CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COC(=O)c1ccc2nc(-c3cccc(N)c3)oc2c1
Product: COC(=O)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)O)cc5C4=O)c3)oc2c1

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)benzoxazole-6-carboxylic acid methyl ester (100 mg, 0.37 mmol) and 1,2,4-benzenetricarboxylic anhydride (72 mg, 0.37 mmol) the title compound was obtained (148 mg, 90%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.39(m, 1H), 8.32(m, 3H), 8.13(d, 1H), 8.05(dd, 1H), 7.96(d, 1H), 7.80(m, 2H), 3.91(s, 3H). MS 443 m/z (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=O)[O:37]CC)[N:30]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:24][CH2:25][N:26]([C:36]([NH:35][C:31]3[N:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[O:37])[CH2:27][CH2:28]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)Nc1cccnn1
Reactant: Brc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Temperature: 180 °C
Yield: 36 %

Procedure:
5-Bromo-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (1 mmol, from Step 5), in acetonitrile (3 mL) was treated with ethyl pyridazin-3-ylcarbamate (184 mg, 1.10 mmol) and diisopropylethylamine (0.52 mL, 3.00 mmol) and was heated to 180° C. in a microwave for 40 min. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (0-6% ethanol (containing 11% aq NH4OH):dichloromethane) to afford a light yellow foam (168 mg, 36% yield). MS (APCI) M+1=466.0; 1H NMR (400 MHz, CDCl3) δ ppm 2.48 (t, J=5.46 Hz, 2H) 2.58-2.65 (m, 2H) 3.60 (t, J=5.75 Hz, 2H) 3.65-3.74 (m, 2H) 6.42 (s, 1H) 6.86 (dd, J=8.67, 0.49 Hz, 1H) 6.96-7.03 (m, 2H) 7.07 (d, J=7.60 Hz, 1H) 7.38 (t, J=7.80 Hz, 1H) 7.44 (dd, J=9.16, 4.48 Hz, 1H) 7.79 (dd, J=8.77, 2.53 Hz, 1H) 8.24 (dd, J=2.53, 0.39 Hz, 1H) 8.26-8.37 (m, 1H) 8.79 (br. s, 1H).
Reaction SMILES: C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[CH2:21]([O:23][CH2:24]Cl)[CH3:22].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[C:35]([CH:44]=[O:45])=[CH:36][C:37]3[NH:41][CH:40]=[N:39][C:38]=3[C:42]=2[F:43])=[C:29]([Cl:46])[CH:28]=1>C1COCC1>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[C:35]([CH:44]([OH:45])[CH2:24][O:23][CH2:21][CH3:22])=[CH:36][C:37]3[NH:41][CH:40]=[N:39][C:38]=3[C:42]=2[F:43])=[C:29]([Cl:46])[CH:28]=1
Reactant: CCOCCl
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Solvent: C1CCOC1
Product: CCOCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of lithiomethyl ethyl in THF (6 mL) (prepared from 4,4′-di-tert-butylbiphenyl (5.85 mg, 2.20 mmol). Li (18 mg, 2.59 mmol), and EtOCH2Cl (0.20 mL, 2.05 mmol) by the procedure reported in Tetrahedron 1996, 52, 1943) is added a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (29 mg, 0.080 mmol) in THF (1 mL) at −78° C. The resulting solution is stirred for 1 hour and then quenched with saturated aqueous NH4Cl at −78° C., warmed to room temperature, and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromotography (100% CH2Cl2 to 3% to 5% MeOH in CH2 Cl2) to give the desired product (15 mg, 44%): MS APCI (+) m/z 428, 430 (M+, Br pattern) detected.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[C:17]1([N:23]2[C:27](B(O)O)=[CH:26][CH:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:10]1([N:7]2[C:6]3[CH:16]=[C:2]([C:27]4[N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:24]=[CH:25][CH:26]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccnn1-c1ccccc1
Reactant: Brc1ccc2ncn(-c3ccccc3)c2c1
Product: c1ccc(-n2nccc2-c2ccc3ncn(-c4ccccc4)c3c2)cc1

Procedure:
The title compound, off-white solid (36 mg, 29%), MS (ISP) m/z=337.3 [(M+H)+], mp 194° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-phenyl-1H-benzo[d]imidazole (intermediate E) (100 mg, 366 μmol) and commercially available 1-phenyl-1H-pyrazol-5-ylboronic acid [CAS No. 1238702-56-1] (89.5 mg, 476 μmol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC.C([Li])CCC.[CH3:30][C:31]12[CH2:40][CH2:39][CH:34]([CH2:35][CH:36]1[CH:37]=O)[C:33]([CH3:42])([CH3:41])[C:32]2=[O:43].[CH2:44](Cl)[Cl:45]>O>[CH3:30][C:31]12[CH2:40][CH2:39][CH:34]([CH2:35][CH:36]1[CH:37]=[CH:44][Cl:45])[C:33]([CH3:42])([CH3:41])[C:32]2=[O:43]
Reactant: ClCCl
Reactant: CC1(C)C(=O)C2(C)CCC1CC2C=O
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: CC1(C)C(=O)C2(C)CCC1CC2C=CCl

Procedure:
A mixture of 30 g of triphenylphosphine, 200 ml of anhydrous ether and 11 g of methylene chloride is cooled to -30° and 77 ml of 1.3M n-butyl lithium solution is added over one hour. To the stirred solution is added 11 g of crude 1,3,3-trimethyl-bicyclo-(2.2.2)-octan-2-one-6-carboxaldehyde. The mixture is slowly heated to reflux and held at reflux for 2 hours. The mixture is poured into 100 ml of water and the organic layer is separated and dried over Mg 804 and the solvent is stripped off the product. Structure: ##SPC43##
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=1)(=[O:4])=[O:3]>[OH-].[OH-].[Pd+2].CO.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(N)cn1
Reaction time: 3 h
Yield: 86.3 %

Procedure:
A suspension of 241 mg (0.34 mmol) of 20% of Pearlman's catalyst on carbon and 693 mg (3.43 mmol) of the 2-methanesulfonyl-5-nitropyridine in 15 mL of MeOH and 3 mL of ethyl acetate was stirred under an atmosphere of hydrogen for 3 hours. The solution was filtered and concentrated. The crude mixture was further purified by filtration through a silica column with ethyl acetate to afford 510 mg (86%) of 6-methanesulfonylpyridin-3-ylamine.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].BrC1C=CC=C([N+]([O-])=O)C=1[NH:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][NH:23][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Reactant: O=[N+]([O-])c1cccc(Br)c1NCCO
Product: N#Cc1cccc([N+](=O)[O-])c1NCCO

Procedure:
2-[(2-hydroxyethyl)amino]-3-nitrobenzonitrile was prepared starting from 2-chloro-3-nitrobenzonitrile [prepared as described in WO 97/38983] (0.89 g) according to the procedure described for the synthesis of 2-[(2-bromo-6-nitrophenyl)amino]ethanol. Yield 1.06 g (99 %). 1H NMR (400 MHz, CD3CN) δ ppm: 3.00 (t, J=4.8 Hz, 1H), 3.68 (q, J=4.7 Hz, 2H), 3.81 (m, 2H), 6.70 (dd, J=8.6, 7.6 Hz, 1H), 7.75 (dd, J=7.6, 1.5 Hz, 1H), 8.28 (dd, J=8.6, 2.0 Hz, 1H), 8.41 (bs, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([OH:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27].Cl>ClCCl>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([O:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)=[O:27]
Reactant: COc1ccc(O)cc1OC1CCCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC(=O)c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyphenol (0.2 g) and triethylamine (1.35 mL) in dichloromethane (5 mL) is treated portionwise at 0-5° C. with 2,6-dichlorobenzoyl chloride (0.28 g), and the solution is warmed to room temperature and stirred for a further 2 hours. The reaction mixture is poured into hydrochloric acid (50 ml; 2N) and is extracted with diethyl ether (3×50 mL). The combined organic extracts are then washed with water (100 mL), and brine (100 mL), dried over magnesium sulfate and concentrated. The residual oil is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (4:1 v/v), to give (3-cyclopentyloxy-4-methoxyphenyl) 2,6-dichlorobenzoate (0.28 g), m.p. 100-101° C. [Elemental analysis: C,59.7; H,4.7%; calculated: C,59.9; H,4.8%].
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][C:11](O)=[O:12])[N:5]=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[C:44]1([CH:50]([NH2:52])[CH3:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][C:11]([NH:52][CH:50]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:51])=[O:12])[N:5]=[CH:4][C:3]=1[NH:14][C@@H:15]1[CH2:20][C@@H:19]2[CH2:21][C@@H:17]([C:18]2([CH3:23])[CH3:22])[C@H:16]1[CH3:24]
Reactant: CC(N)c1ccccc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCC(=O)O)c(=O)c1Br)C2(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)CCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O)c1ccccc1
Yield: 94.7 %

Procedure:
3-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoic acid (32 mg, 0.080 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.160 mmol), 1-hydroxybenzotriazole anhydride (11 mg, 0.080 mmol) and triethylamine (22 μL, 0.160 mmol) in N,N-dimethylformamide (1 mL) were stirred with 1-phenylethylamine (20 μL, 0.160 mmol) at room temperature for 24 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=15/1) to give the desired product (38 mg, 95% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:19][N:18]=1.Cl>C1COCC1.CO>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccnc(Br)c1)c1cccc(F)c1C#N
Reactant: FC(F)c1cc(Br)ccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
n-Butyllithium (2.5 M in hexane) (0.353 mL, 0.88 mmol) was added to 4-bromo-2-(difluoromethyl)pyridine (183 mg, 0.88 mmol) in THF (7 mL) at −78° C. under argon atmosphere. The reaction was stirred for 30 min before N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 0.73 mmol) in THF (2 mL) was added. The reaction was kept at −78° C. for 1 hour and then allowed to reach room temperature. Methanol (5 mL) was added followed by hydrochloric acid (1 M in diethylether) (2.204 mL, 2.20 mmol) and the reaction was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate. The aqueous phase was extracted with EtOAc (×3). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (64 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([NH2:12])[S:8][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)C.Cl.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][N:30]=1.C[OH:38]>C1COCC1.ClCCl>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([NH:12][C:33](=[O:38])[C:32]3[CH:35]=[CH:36][C:29]([CH3:28])=[N:30][CH:31]=3)[S:8][C:7]=2[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)cc12
Reactant: CO
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)nc3)cc12
Temperature: 20 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-amine (100 mg, 0.392 mmol) in THF (8 ml) and diethylisopropyl amine (0.147 ml, 2.2 eq.) was stirred together at −10° C. under an argon atmosphere. To this was slowly added 6-methyl-nicotinyl chloride hydrochloride (83 mg, 0.431 mmol, 1.1 eq) in dichloromethane (5 ml) and the mixture stirred to 20° C. overnight. The reaction was again cooled to 0° C. and Methanol was then added (1.2 ml) and the mixture stirred for 30 min to 20° C. The mixture was then evaporated to dryness and chromatographed over silica gel eluting with a gradient of heptane/EtOAc (1:1 to 1:8). The product fractions were pooled and evaporated to afford the title compound (83 mg, 57% yield) as a yellow solid MS: m/e=375.4 (M+H+).
Reaction SMILES: Cl.[NH2:2]N.[OH-].[Na+].C[N:7]([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>CO>[NH:2]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:10]=2[CH:9]=[N:7]1
Reactant: NN
Reactant: CN(C)C=C1C(=O)CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCc2[nH]ncc21
Yield: 87.6 %

Procedure:
According to Scheme 1 Step 2: A solution of hydrazine hydrochloride (41.9 mmol, 2.87 g), NaOH (6 M, 42 mmol, 7.0 mL) in MeOH (100 mL) was added, at 0° C., to a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (41.9 mmol, 7.00 g) and the reaction mixture was stirred under reflux for 3 hours. After evaporation, water was added and the aqueous phase was extracted with AcOEt at 50° C. The organic phase was dried over Na2SO4, was filtered and was concentrated under reduced pressure to yield 6,7-dihydro-1H-indazol-4(5H)-one (36.7 mmol, 5.00 g, 88%) as a yellow powder.