Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][C:12]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]1([C:12]2([NH:11][C:9]3[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=[C:2]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:23]=4)[CH:10]=3)[CH2:14][CH2:13]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1cnc(Cl)cc1NC1(c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cnc(Nc2cccc(N3CCNCC3)c2)cc1NC1(c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a mixture of 6-chloro-4-(1-phenylcyclopropylamino)nicotinamide (150 mg, 0.522 mmol) in p-Dioxane (4.5 mL) was added tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (174 mg, 0.626 mmol), Pd(OAc)2 (23 mg, 0.104 mmol), BINAP (65 mg, 0.104 mmol) and Cs2CO3 (510 mg, 1.566 mmol). After stirred at 80° C. for 15 h, it was concentrated to give crude residue, which was then treated with TFA in DCM, 30 min later, the solution was concentrated, the residue was purified by preparative HPLC to give 4-(1-phenylcyclopropylamino)-6-(3-(piperazin-1-yl)phenylamino)nicotinamide. MS found for C25H28N6O as (M+H)+ 429.4. UV: λ=254.6 nm. 1H NMR: (CD3OD) δ 8.17 (s, 1H), 7.31-7.20 (m, 4H), 7.13 (m, 2H), 6.95 (dd, J=8.0, 2.0 Hz, 1H), 6.79 (t, J=2.0 Hz, 1H), 6.60 (dd, J=7.2, 2.0 Hz, 1H), 6.12 (s, 1H), 3.34 (m, 8H), 1.36 (m, 4H) ppm.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([N:22]1[C:26]2[CH:27]=[C:28]([NH:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38][CH2:37]3)[C:29]3[N:30]([C:31]([CH3:34])=[N:32][N:33]=3)[C:25]=2[CH:24]=[C:23]1[CH3:43])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C=O>C(Cl)Cl>[CH2:15]([N:22]1[C:26]2[CH:27]=[C:28]([NH:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([NH:42][CH3:1])[CH2:38][CH2:37]3)[C:29]3[N:30]([C:31]([CH3:34])=[N:32][N:33]=3)[C:25]=2[CH:24]=[C:23]1[CH3:43])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(cc(N[C@H]3CC[C@H](N)CC3)c3nnc(C)n32)n1Cc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN[C@H]1CC[C@H](Nc2cc3c(cc(C)n3Cc3ccccc3)n3c(C)nnc23)CC1
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (11 mg, 0.053 mmol) was added to a mixture of trans-N-(6-benzyl-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-yl)cyclohexane-1,4-diamine (10. mg, 0.027 mmol, from Example 217) and formaldehyde solution (37 wt % in water, 3.2 mg, 0.040 mmol, Aldrich) in DCM (0.5 mL). After 30 minutes, both monomethylated and dimethylated products were observed by LCMS. Purification via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded monomethylated product. (Yield: 0.8 mg, 7%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]=[C:7]([CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)[O:6][N:5]=1.Cl.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32](Cl)=[O:33])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([NH:3][C:4]2[N:8]=[C:7]([CH:9]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10]3)[O:6][N:5]=2)=[O:33])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)CC1CCN(Cc2ccccc2)CC1
Reactant: Nc1noc(C2CN3CCC2CC3)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1CCN(Cc2ccccc2)CC1)Nc1noc(C2CN3CCC2CC3)n1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a suspension of sodium hydride (0.4 g) in N,N-dimethylformamide was added 3-amino-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.2 g) at 0° C. and the mixture was stirred for 1 hour. To the mixture was added (1-benzylpiperidin-4-yl)acetyl chloride hydrochloride (2.53 g) during 30 minutes at 0° C. After stirred for additional 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The extract was washed with water, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on alumina with chloroform to give 3-{(1-benzylpiperidin-4-yl)acetylamino}-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.11 g).
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:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[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:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([NH:30][CH3:29])=[O:20])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Reactant: CN
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)NC)C1(C)C

Procedure:
The product from Example 96 and methylamine hydrochloride (Aldrich) were processed using the method described in Example 99 to afford the title compound. 1H NMR (DMSO-d6) δ 0.47 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.22 (s, 3H), 1.26-1.33 (m, 2H), 1.36-1.45 (m, 1H), 1.57 (s, 9H), 1.57-1.68 (m, 3H), 1.95-2.07 (m, 1H), 2.57 (d, J=4.7 Hz, 3H), 2.60-2.67 (m, 3H), 2.72-2.83 (m, 1H), 4.78 (q, J=4.5 Hz, 1H), 8.49 (s, 1H). MS (ESI+) m/z 408 (M+H)+. Anal. calcd. for C22H37N3O2S: C, 64.83; H, 9.15; N, 10.31. Found: C, 64.55; H, 9.02; N, 10.29.
Reaction SMILES: CCOP(S)(OCC)=S.[Br:10][C:11]1[CH:12]=[C:13]([C:17](=O)[CH:18]=[CH:19][C:20]([OH:22])=O)[CH:14]=[CH:15][CH:16]=1.BrC1C=C(C(=O)CC(SP(OCC)(OCC)=S)C(O)=O)C=CC=1.O.[NH2:48][NH2:49]>C(O)C>[Br:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20](=[O:22])[NH:48][N:49]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C=CC(=O)c1cccc(Br)c1
Reactant: NN
Agent: CCOP(=S)(OCC)SC(CC(=O)c1cccc(Br)c1)C(=O)O
Agent: CCOP(=S)(S)OCC
Solvent: O
Solvent: CCO
Product: O=c1ccc(-c2cccc(Br)c2)n[nH]1
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
1.12 g (0.006 mole) of O,O-diethyldithiophosphoric acid were added, at room temperature, to a suspension of 1.28 g of 4-(3-bromophenyl)-4-oxo-2-butenoic acid in 10 ml of ethanol, and then the mixture was stirred for 10 minutes. Formation of 4-(3-bromophenyl)-2-diethoxyphosphinothioylthio-4-oxobutanoic acid was confirmed by thin layer chromatography but the compound was not separated from the reaction mixture. 0.3 g (0.006 mole) of hydrazine monohydrate was added to the reaction mixture, which was then stirred overnight at room temperature. At the end of this time, the crystals which had precipitated were collected by filtration and washed with ethanol to give 0.48 g of the desired 6-(3-bromophenyl)-3(2H)pyridazinone. The filtrate was concentrated and then subjected to column chromatography through silica gel eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give a further 0.48 g of the product, a total of 0.96 g (yield 76%) of the product, melting at 202°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Nc1cc(Cl)ccc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-chlorophenol (705 mg, 4.9 mmol) and 2-fluoro-5-nitrobenzoyl chloride (1.00 g, 5.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: N([O-])=O.[Na+].[ClH:5].[CH3:6][S:7][C:8]1[N:9]=[CH:10][C:11](N)=[N:12][CH:13]=1>O>[Cl:5][C:11]1[CH:10]=[N:9][C:8]([S:7][CH3:6])=[CH:13][N:12]=1
Reactant: CSc1cnc(N)cn1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cnc(Cl)cn1
Reaction time: 1 h
Yield: 26 %

Procedure:
Sodium nitrite (50.9 g, 0.74 Mop was dissolved in water (150 mL), followed by dropwise addition into a 5N aqueous hydrochloric acid solution (1.0 L) at 0° C. over 1 hour. Subsequently, 5-(methylsulfanyl)pyrazine-2-amine (40.4 g, 0.28 mol) synthesized in Example (97a) was added at 0° C. over 40 minutes, and stirring was carried out at 0° C. for 1 hour. The reaction solution was brought back to room temperature, and water (500 mL) was added, followed by extraction with ethyl acetate (1.0 L). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (11.9 g, yield 26%) as a white solid.
Reaction SMILES: Cl.Br[CH:3]([CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]([N:16]([CH3:18])[CH3:17])[CH3:15])=[CH:9][CH:8]=1)=[O:5].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>>[CH2:20]([N:22]([CH2:23][CH3:24])[CH:3]([CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]([N:16]([CH3:18])[CH3:17])[CH3:15])=[CH:9][CH:8]=1)=[O:5])[CH3:21]
Reactant: CC(=Nc1ccc(NC(=O)C(C)Br)cc1)N(C)C
Reactant: CCNCC
Agent: Cl
Product: CCN(CC)C(C)C(=O)Nc1ccc(N=C(C)N(C)C)cc1

Procedure:
Following the procedure described in Example 3, reaction of 27.5 g of N'[4-(α-bromopropionyl)aminophenyl]-N,N-dimethylacetamidine hydrochloride with 40 g of diethylamine gives N'-[4-(α-diethylaminopropionyl)aminophenyl]-N,N-dimethylacetamidine, which is converted, in the crude form, into the naphthalenedisulphonate by means of one equivalent of naphthalenedisulphonic acid. Yield 16 g, melting point >260° C (decomposition) (recrystallized from ethanol/H2O).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:30]3[CH2:34][O:33]C(C)(C)[O:31]3)[CH:29]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:29]=[C:28]([CH:30]([OH:31])[CH2:34][OH:33])[CH:27]=[N:26][CH:25]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(c2cncc(-c3nc(NCc4ccccc4)c4c(-c5ccccc5)ccn4n3)c2)O1
Solvent: O=C(O)C(F)(F)F
Product: OCC(O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
N-Benzyl-2-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.150 g, 0.314 mmol) was dissolved in TFA (10 mL) and stirred for 1 h at 60° C. TFA was removed under reduced pressure and the reaction mixture was diluted with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to a residue which was purified by preparative HPLC (Condition B-53 as described in general methods) to get 1-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)ethane-1,2-diol (90.0 mg, 65.5%). The enantiomers of 1-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)ethane-1,2-diol were separated by SFC (Condition B-52 as described in general methods).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[C:26]([O:27][CH3:28])=[CH:25][C:23]([NH2:24])=[C:22]([CH3:29])[CH:21]=1>>[CH3:18][O:19][C:20]1[C:26]([O:27][CH3:28])=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[C:22]([CH3:29])[CH:21]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(C)c(N)cc1OC
Product: COc1cc(C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4,5-dimethoxy-2-methylaniline (48 mg, 0.290 mmol) similar to Example 117 and isolated as a red solid (8 mg, 11%). 1H NMR (CDCl3): 9.69 (s, 1H), 8.74-8.68 (m, 2H), 7.56 (s, 1H), 7.43-7.39 (m, 1H), 6.84 (s, 1H), 6.83 (s, 1H), 6.46 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C(OC(C)(C)C)(C)(C)C.[K].O.[C:22]([O:26][C:27](=[O:30])[CH:28]=[CH2:29])([CH3:25])([CH3:24])[CH3:23]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(C)(C)C
Agent: [K]
Solvent: O
Product: CC(C)c1ccccc1OCCC(=O)OC(C)(C)C
Temperature: 130 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
2-Isopropylphenol (6 g) was dissolved in acrylic acid tert-butyl ester (6.2 g), and to the mixture was added potassium tert-butyloxide (0.3 g). The reaction mixture was stirred at 130° C. for 6 h. To the reaction mixture was added water, the reaction mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain the compound (10) 4.3 g.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.[C:15]1([C:21]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:22]2[CH:26]=[C:25]([CH:27]=[O:28])[N:24]=[CH:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:12][C:9]1([CH3:13])[O:8][C:7]2[C:2]([CH:27]([C:25]3[N:24]=[CH:23][N:22]([C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:26]=3)[OH:28])=[CH:3][C:4]([CH3:14])=[CH:5][C:6]=2[CH2:11][O:10]1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1cc(Br)c2c(c1)COC(C)(C)O2
Product: Cc1cc2c(c(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c1)OC(C)(C)OC2
Yield: 31 %

Procedure:
Starting from 8-bromo-2,2,6-trimethyl-4H-1,3-benzodioxin and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The organomagnesium compound is added at ambient temperature. The reaction product is purified by chromatography on silica (15 μm) (eluent: 98:2 v/v dichloromethanemethanol). Yield: 31% of theory; M.P.: 205°-215° C. (recrystallized from acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:22])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])C>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][S:28]([CH3:26])(=[O:30])=[O:29])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine (0.15 g, 0.42 mmol) obtained in Example 25 is dissolved in methylene chloride (5 ml) and pyridine (0.34 ml), and thereto is added ethylsulfonyl chloride (0.04 ml, 0.50 mmol) under ice-cooling, and the mixture is stirred for 3 hours. To the mixture is added ice-water (20 ml), and the mixture is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution (20 ml×2) and a saturated brine (20 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent: chloroform/methanol), and further recrystallized from diethyl ether to give the title compound (0.07 g) as colorless crystals, m.p. 131-133° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1C=C[C:16](=[O:23])[NH:17]2)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C(NC=O)C=1)O[Si](C(C)(C)C)(C)C)=[N+]=[N-]>>[NH2:1][CH2:2][C@@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:17][CH:16]=[O:23])[CH:13]=1)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NC=O)c1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 2, using Intermediate 11 in place of Intermediate 1. ES/MS calcd. C15H27N2O3Si+ 311.2. found m/z=311 (M+H)+
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:17])(=[O:11])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2cccc(S(=O)(=O)N3CCc4ccccc43)c2)c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 3-methoxyaniline (68 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(3-methoxyphenyl)benzamide as an off-white solid. Yield: 94 mg (42%). 1H-NMR: 8.34 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.42 (t, J=2.0 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 6.71 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 3.98 (t, J=8.5 Hz, 2H), 3.32 (s, 3H), 2.92 (t, J=8.5 Hz, 2H)
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([O:20]CC)=O)[CH:3]=1.Cl.[NH3:24]>>[OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([NH2:24])=[O:20])[CH:3]=1
Reactant: N
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(=O)OCC)n1
Agent: Cl
Product: CCCOc1ccccc1-c1nc(O)cc(C(N)=O)n1
Reaction time: 72 h

Procedure:
A solution of ethyl 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxylate (0.44 g) in aqueous ammonia solution (20 ml) was stirred in a stoppered flask at ambient temperature for 4 hours and then allowed to stand for 3 days. The reaction mixture was acidified with concentrated hydrochloric acid to precipitate the title compound, 0.46 g, m.p. 232°-4° C. This was recrystallized from ethanol:methanol to yield the pure title compound, 0.32 g, m.p. 233.5°-234.5° C.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16](=[O:36])[CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[N:10]=[N:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16](=[O:36])[CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[N:10]=[N:9]1
Reactant: O=C(CC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCCc1cn(Cc2ccccc2)nn1
Reactant: [H][H]
Solvent: CCO
Product: O=C(CC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCCc1c[nH]nn1

Procedure:
3,5-dichlorobenzyl 4-(2-((2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethyl)amino)-2-oxoethyl)piperidine-1-carboxylate (81.5 mg, 0.154 mmol) was dissolved in ethanol (4 ml). The solution was then submitted to continuous flow hydrogenation using H-cube hydrogenation apparatus, at 70° C. and 30 bar hydrogen pressure for 2 hours. The resultant solution was concentrated under reduced pressure. Purification was carried out using preparative LC-MS. Product fractions were collected, concentrated under reduced pressure, diluted with ethyl acetate, and washed with water. The organic portion was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: CO[C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[C:7]([OH:28])=[CH:8][C:9]3[C:10]([CH3:27])([CH3:26])[C:11]4[CH:12]=[C:13]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:24][CH3:25])[CH:14]=[CH:15][C:16]=4[C:17]=3[C:5]=2[CH:4]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([Li])CCC.Cl>CCCCCC.O1CCCC1>[N:33]1([C:3]2[C:30]([O:31][CH3:32])=[CH:29][C:6]3[C:7]([OH:28])=[CH:8][C:9]4[C:10]([CH3:27])([CH3:26])[C:11]5[CH:12]=[C:13]([C:18]6[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=6[O:24][CH3:25])[CH:14]=[CH:15][C:16]=5[C:17]=4[C:5]=3[CH:4]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNCC1
Reactant: COc1cc2c(O)cc3c(c2cc1OC)-c1ccc(-c2ccccc2OC)cc1C3(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccccc1-c1ccc2c(c1)C(C)(C)c1cc(O)c3cc(OC)c(N4CCCCC4)cc3c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 500 mL one-neck flask was added the product from Step 1(10 g), piperidine (5.2 mL and anhydrous tetrahydrofuran (150 mL). n-Butyl lithium in hexane solution (2.5M, 35 mL) was dropped to the mixture through addition funnel slowly. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into cold aqueous hydrochloric acid (10%, 60 mL). The resulting mixture was extracted with ethyl acetate (200 mL) and the recovered top layer was filtered through a silica gel plug using ethyl acetate and hexane mixture as eluent. All silica gel plug and chromatography mentioned herein was carried out using ethyl acetate and hexanesmixture as eluent if not specified. Solid 2-(piperidin-1-yl)-3-methoxy-7,7-dimethyl-9-(2-methoxyphenyl)-7H-benzo[C]fluoren-5-ol (10 g) was obtained by re-crystallization from solution in ethyl acetate/hexanes.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:26])=[C:6]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH:7][C:8]([C:10]1[N:14](CC2C=CC=CC=2)[N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[C:5]([OH:26])=[C:6]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH:7][C:8]([C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)c1cc(C)cc(NC(=O)c2nnn[nH]2)c1O
Reaction time: 12 h
Yield: 16.8 %

Procedure:
A solution of 3'-acetyl-1-benzyl-2'-hydroxy-5'-methyl-1H-tetrazole-5-carboxanilide (1.6 g) in glacial acetic acid (73 ml) was hydrogenated at 55° C. and 4.1 kg/cm2 for 12 hours, using a catalyst of palladium on charcoal (5% w/w). The mixture was filtered and the filtrate was evaporated in vacuo to give a solid residue, which was purified by chromatography on a column of silica gel, using a mixture of chloroform, methanol and formic acid (86:10:4 by volume) is eluant. The fastest moving fraction (pale yellow) was collected and further purified by thin layer chromatography on silica gel, using a mixture of chloroform, methanol and formic acid (86:10:4 by volume) as eluant, and the product was recrystallised from aqueous dimethylformamide to give 3'-acetyl-2'-hydroxy-5'-methyltetrazole-5-carboxanilide (0.2 g), m.p. 245°-247° C. (with decomposition).