Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH:34]=O)=[CH:28]3)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[CH:34][C:29]4[NH:30][C:31]5[C:27]([CH:28]=4)=[CH:26][C:25]([O:24][CH2:23][CH2:22][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:33][CH:32]=5)[C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: O=C1Nc2cc(-c3cccnc3)ccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
6-Pyridin-3-yl-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][CH:56]([S:58](Cl)(=[O:60])=[O:59])[CH3:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:58]([CH:56]([CH3:57])[CH3:55])(=[O:60])=[O:59])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 25 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and propane-2-sulfonyl chloride as starting materials in 25% yield. LCMS for C27H33ClN7O3S (M+H)+: m/z=570.2.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]([CH3:16])[CH3:15])=[C:2]=[O:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:29][C:28](=[O:30])[CH:27]=[CH:26][NH:25]2)=[CH:20][CH:19]=1>>[CH:14]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[NH:1][C:2]([N:25]1[CH:26]=[CH:27][C:28](=[O:30])[CH2:29][C@H:24]1[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)=[O:3])([CH3:16])[CH3:15]
Reactant: COc1cc(N=C=O)c(C(C)C)cc1OC
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Product: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(C(C)C)cc1OC

Procedure:
1-Isocyanato-2-isopropyl-4,5-dimethoxy-benzene was reacted with (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one following the procedure of step 3 of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14].[CH3:16][C@@:17]1([CH2:20]OS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)[CH2:19][O:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:16][C@@:17]1([CH2:20][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=2[NH:12][C:13](=[O:15])[CH3:14])[CH2:19][O:18]1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1OC[C@]1(C)CO1
Yield: 79.5 %

Procedure:
A mixture of 2-nitro-4-(trifluoromethyl)phenol (310 mg, 1.5 mmol), palladium on carbon (10%, 125 mg) and acetic anhydride (306.3 mg, 3.0 mmol) in methanol was hydrogenated for 2 h at atmospheric pressure. The catalyst was filtered off, the filtrate was concentrated in vacuo to give crude N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide (331 mg). A part (219.16 mg, 1.0 mmol) of N-[2-hydroxy-5-(trifluoromethyl)phenyl]acetamide was treated with [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (273.27 mg, 1.0 mmol) in the presence of Cs2CO3 (406.25 mg, 1.25 mmol) in DMF (5 mL) at room temperature for 5 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (230 mg).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH:27][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@H](N)CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
p-Toluoyl chloride (0.48 ml, 3.63 mmol) was added to a solution of 1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (1 g, 3.0 mmol) and triethylamine (0.633 ml, 4.54 mmol) in methylene chloride under nitrogen atmosphere. After 1 h, the product was extracted into ethyl acetate and the organic layer was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography with hexanes/ethyl acetate (1:2) gave N-{1(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (1.2 g) as an oil. The free amine was dissolved in ether and 3.5 equivalents of 1N ethereal HCl solution (10.7 ml) was added. Filtration of the resulting solid provided N-{(S)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (1.2 g) as the bis hydrochloride salt, mp 227.8-228.9° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([CH2:19][NH:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])=[CH:17][CH:18]=3)[CH:12]=[C:6]2[C:5]=1[NH:26][C@H:27]1[C@@H:31]([CH2:32][CH3:33])[CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28]1)(=[O:3])[NH2:2].[Si](I)(C)(C)C>C(#N)C>[CH2:32]([C@H:31]1[CH2:30][NH:29][CH2:28][C@H:27]1[NH:26][C:5]1[C:6]2[N:7]([CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([CH2:19][NH:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])=[CH:17][CH:18]=3)[CH:12]=2)[N:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3])[CH3:33]
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (203 mg, 0.347 mmol) in acetonitrile (8 mL) at 0° C. was added TMS-I (0.189 mL, 1.386 mmol) and after stirring 15 minutes at 0° C., the cooling bath was removed. After stirring 4 hr at rt, the reaction mixture was re-cooled to 0° C. and 2 ml of MeOH were added. The mixture was allowed to warm to rt with stirring over 2 hr. At this time, the volatiles were removed in vacuo and the residue was triturated with ethyl ether. Filtration afforded a dark brown solid. Attempts to triturate with EtOAc were unsuccessful, so the mother liquor from the EtOAc trituration was recombined with the filter cake. The material was taken up in MeOH and was filtered. The filtrate was concentrated and was triturated with DCM. Filtration and drying afforded 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (277 mg, 0.392 mmol, 113% yield) as a dark brown solid. The material will be used as is in the next step. MS (ES+) m/z: 452.4 (M+H); LC retention time: 1.453 min (analytical HPLC Method O).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(I)cc1F
Solvent: ClCCl
Solvent: CO
Product: O=C(NOCCO)c1ccn2cncc2c1Nc1ccc(I)cc1F
Yield: 81.3 %

Procedure:
8-(2-Fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (151 mg, 0.31 mmol) was dissolved in methanol and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. Appropriate fractions were combined and concentrated to give a residue that was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) to afford the title compound as a pale yellow solid (115 mg, 81%). LCMS (method A): RT=6.36 min, [M+H]+=457. 1H NMR (CD3OD): 8.27 (1H, d, J=0.85 Hz), 7.80-7.77 (1H, m), 7.57-7.53 (1H, m), 7.49-7.46 (1H, m), 6.95 (1H, t, J=8.48 Hz), 6.76 (1 H, d, J=7.37 Hz), 6.68 (1H, s), 4.00-3.94 (2 H, m), 3.75-3.71 (2 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[CH3:12][C:13]([O-])(C)[CH3:14].[K+].C(Br)C=C>C1COCC1>[CH2:14]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)[CH:13]=[CH2:12]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCn1ccc2cc(OC)ccc21
Reaction time: 1 h

Procedure:
5-Methoxyindole (294 mg, 2.0 mmol) was dissolved in THF (10 mL) and treated with 1M KOtBu in THF (2.2 mL, 2.2 mmol). After stirring for 1 hour, allyl bromide (190 μL, 2.2 mmol) was added and the reaction mixture was stirred for an additional 2 hrs. Standard aqueous workup provided N-Allyl-5-methoxyindole as an off white solid, which was used without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=1.S(Cl)([Cl:23])=O>>[Cl:23][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[N:18][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2ccc3ccccc3n2)nc1
Product: ClCc1ccc(OCc2ccc3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 6-(2-quinolylmethoxy)-3-pyridylmethanol (2.66 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-(5-chloromethyl-2-pyridyloxymethyl)quinoline (2.50 g, yield 88%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 118–119° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=O)[CH2:14]1)([O-:3])=[O:2].CC(O)=O.[CH2:23]([NH2:25])[CH3:24].Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:23]([NH:25][CH:15]1[CH2:16][CH2:17][CH:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:14]1)[CH3:24]
Reactant: O=C1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCNC1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-nitro-1H-indol-3-yl)cyclopentanone (1.6 g, 6.55 mmol) in 1,2-dichloroethane (50 mL) was added AcOH (0.40 mL, 6.55 mmol), EtNH2.HCl (0.53 g, 6.55 mmol) and NaBH(OAc)3 (2.1 g, 9.83 mmol) and the mixture left to stir overnight at room temperature. The reaction mixture was extracted with 2N NaOH (10 mL) and washed with dichloromethane (2×10 mL). The dichloromethane layer was separated and evaporated. The crude material was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain the product as a yellow solid as a mixture of diastereomers (1.2 g, 67%). 1H-NMR (CDCl3) δ 1.10-1.16 (m, 6H), 1.45-1.92 (m, 10H), 1.96-2.13 (m, 3H), 2.13-2.36 (m, 3H), 2.50-2.58 (m, 1H), 2.65-2.76 (m, 4H), 3.28-3.43 (m, 3H), 3.49-3.60 (m, 1H), 7.11 (d, 1H, J=1.8 Hz), 7.15 (d, 1H, J=1.5 Hz), 7.35 (s, 1H), 7.38 (s, 1H), 8.08 (d, 1H, J=2.1 Hz), 8.11 (d, 1H, J=2.1 Hz), 8.32 (brs, 1H, NH), 8.41 (brs, 1H, NH), 8.61 (d, 1H, J=2.1 Hz), 8.63 (d, 1H, J=2.1 Hz); EI-MS (m/z, %) 273 (M+, 90).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].Br[CH2:15][CH2:16][Cl:17].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6]
Reactant: ClCCBr
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCCCl)c1
Temperature: 55 °C
Reaction time: 15 h
Yield: 84.9 %

Procedure:
A mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (77 g, 409 mmol), 1-bromo-2-chloroethane (176 g, 1.23 mol) and Cs2CO3 (146 g, 449 mmol) in DMF (2 L) was stirred at 70° C. for 3 h and at 55° C. for 15 h. The mixture was cooled to room temperature and partitioned between ethyl acetate (1 L) and water (2 L). The aqueous layer was extracted with ethyl acetate (2×) and the combined organics were washed with water, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 4:1 to 7:3) provided the 3-(2-Chloro)ethoxy-4-difluoromethoxybenzaldehyde compound (87 g).
Reaction SMILES: BrB(Br)Br.[Cl:5][C:6]1[C:16]([O:17]C)=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]=1[O:19]C.O>C(Cl)Cl>[Cl:5][C:6]1[C:16]([OH:17])=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[OH:19]
Reactant: CCOC(=O)c1cc(OC)c(Cl)c(OC)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc(O)c(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
Tribromoborane (318 μL, 3.29 mmol) was added dropwise to a solution of ethyl 4-chloro-3,5-dimethoxybenzoate (2) (115 mg, 0.470 mmol) in DCM (1.5 mL) at 0° C. and the mixture was stirred at the same temperature for 4 h. The reaction mixture was allowed to warm to RT and then poured cautiously in to iced water (5 mL). The mixture was extracted with EtOAc (3×5 mL), and the combined organic extracts were washed with brine (2×5 mL), dried over MgSO4 and evaporated in vacuo to give 4-chloro-3,5-dihydroxybenzoic acid (3) (72 mg, 78%) as a brown solid: m/z 187 [M−H]− (ES−).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:41]1[CH:42]=[CH:43][C:38]([CH2:37][NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])=[CH:39][CH:40]=1
Reactant: Nc1cccc(S(=O)(=O)NCc2ccncc2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccncc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-pyridin-4-ylmethyl-benzenesulfonamide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 601.2 [(M−H)−]; mp 221° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 86 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.52-3.58 (m, 4H), 3.82 (s, 3H), 4.09-4.13 (m, 4H), 6.85 (d, 7=9.2 Hz, 2H), 7.03-7.15 (m, 1H), 7.41 (m, 1H), 7.52-7.58 (m, 2H), 8.16 (d, 1=9.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[OH:24])=[CH:4][CH:3]=1.I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[O:24][CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-ol (I-(4A-7)b; 50 mg, 0.14 mmol), 2-iodopropane (26 mg, 0.15 mmol), and cesium carbonate (50 mg, 0.15 mmol) were combined in dimethylformamide (0.7 ml) and stirred overnight. Additional 2-iodopropane (13 mg, 0.76 mmol), and cesium carbonate (25 mg, 0.76 mmol) were added and stirred an addional day. The reaction mixture was diluted with ethyl ether and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), evaporated to dryness, and then purified on a Biotage™ Flash 12S column using 0–70% ethyl acetate in hexanes as eluant to afford title compound 31A-1 (34 mg, 56%); 1H NMR: +ESI MS (M+1) 399.4; (400 MHz, CD2Cl2) δ 8.51 (s, 1H), 7.56 (dd, J=7.5, 1.7 Hz, 1H), 7.47–7.34 (m, 5H), 7.23 (d, J=9.1 Hz, 2H), 5.71 (septuplet, J=6.2 Hz, 1H), 1.50 (d, J=6.2 Hz, 6H).
Reaction SMILES: [OH:1]O.[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[CH:18][N:17]=[N:16][CH:15]=3)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH3:4]>C(O)C>[CH2:3]([S:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:14]([N:13]=2)=[CH:15][N:16]=[N:17][CH:18]=3)=[C:8]([O:21][CH3:22])[CH:7]=1)=[O:1])[CH3:4]
Reactant: OO
Reactant: CCSc1ccc(-c2nc3cnncc3[nH]2)c(OC)c1
Solvent: CCO
Product: CCS(=O)c1ccc(-c2nc3cnncc3[nH]2)c(OC)c1
Reaction time: 3 h

Procedure:
10 ml of 30% strength H2O2 are added to a boiling solution of 2.84 g of 2-(4-ethylthio-2-methoxyphenyl)-1,3,5,6-tetraazaindene in 50 ml of ethanol, and the mixture is then boiled for 3 hours. Cooling down and customary working up gives 2-(4-ethylsulfinyl-2-methoxyphenyl)-1,3,5,6-tetraazaindene.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]2[CH:14]=[C:13]([CH:15]([NH2:17])[CH3:16])[O:12][N:11]=2)=[CH:8][N:9]=1
Reactant: CC(c1cc(-c2cnc(Oc3ccc(OCC4CC4)cc3Cl)s2)no1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1cc(-c2cnc(Oc3ccc(OCC4CC4)cc3Cl)s2)no1
Temperature: 60 °C
Yield: 96.8 %

Procedure:
To a solution of Example 30G (276 mg, 0.53 mmol) in ethanol (6 mL) was added hydrazine monohydrate (0.16 mL, 3.2 mmol). The reaction was heated at 60° C. for 45 minutes and filtered. The filtrate was concentrated and purified on silica gel eluting with 90:8:2 dichloromethane/methanol/concentrated ammonium hydroxide to provide 201 mg of the title compound (97%) as an amber liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.29-0.38 (m, 2H) 0.53-0.65 (m, 2H) 1.12-1.23 (m, 1H) 1.34 (d, J=7.35 Hz, 3 H) 3.88 (d, J=7.35 Hz, 2H) 3.97-4.15 (m, 1H) 6.84 (s, 1H) 7.03 (dd, J=9.19, 2.94 Hz, 1H) 7.24 (d, J=2.94 Hz, 1H) 7.53 (d, J=9.19 Hz, 1H) 7.91 (s, 1H); MS (ESI) m/z 392.0 (M+H)+.
Reaction SMILES: BrCCC[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[S:6]1(=[O:22])=[O:21].[Cl:23][CH2:24][CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([N:7]2[S:6](=[O:21])(=[O:22])[N:5]([CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:24][Cl:23])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=3)=[CH:19][CH:18]=1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(c2ccc(Cl)cc2)c2ccccc2N1C(CCCl)c1ccccc1
Reaction time: 16 h
Yield: 39.2 %

Procedure:
To a mixture of 1-(3-bromopropyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.28 g, 1.0 mmol), (S)-(−)-3-chloro-1-phenyl-1-propanol (0.17 g, 1.0 mmol), and triphenylphosphine (314 mg, 1.2 mmol) in anhydrous THF (15 mL) was added DIAD (0.23 mL, 1.2 mmol) under nitrogen at 25° C. The mixture was stirred for 16 hours followed by concentration of the mixture in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-40% ethyl acetate in hexane) to afford 0.17 g of 1-(4-Chloro-phenyl)-3-(3-chloro-1-phenyl-propyl)-1,3-dihydro-benzo[1,2,5]-thiadiazole 2,2-dioxide that was immediately carried on to the next step. MS (ESI) m/z [M−H]− 431;
Reaction SMILES: [C:1]([CH:3]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]1=2)#[N:2].[CH3:17]I.[H-].[Na+].O>CN(C)C=O>[C:1]([C:3]1([CH3:17])[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]1=2)#[N:2]
Reactant: N#CC1Sc2ccccc2-c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C#N)Sc2ccccc2-c2ccccc21
Yield: 75 %

Procedure:
To a stirred solution of 6-cyano-6H-dibenzo[b,d]thiopyran (4.5 g; 0.02 mol) and CH3I (28.4 g; 0.2 mol) in 100 ml of dimethylformamide, 50% NaH (1.5 g; 0.03 mol) was added in small portions. After 16 hours at room temperature the mixture was poured into water and extracted with diethyl ether. The organic phase was washed with water and dried over Na2SO4. Evaporation of the solvent gave 6-cyano-6-methyl-6H-dibenzo[b,d]thiopyran (3.58 g; 0.015 mol; yield 75%).