Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:33])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3C)c2cc1OC
Yield: 58 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methyl-aniline (50 mg) was dissolved in chloroform (3 ml), and p-fluorophenyl isocyanate (22 μl ) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to give 42 mg (yield 58%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O>O>[CH2:9]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1)[C:10]1[CH:12]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=c1ccocc1O
Reactant: CC(C)=O
Solvent: O
Product: O=c1ccocc1OCc1ccccc1
Yield: 34 %

Procedure:
3-Benzyloxy-4-pyrone is prepared from 3-hydroxy-4-pyrone as described by Spenser et al, Canadian Journal of Chemistry, 1962, 40, 1377 and has m.p. 82°-85° C. A mixture of this compound (1 g) and ethylenediamime (0.37 g) in water (12 ml) is heated under reflux for 1 hour. The reaction mixture is evaporated to dryness and the residue is treated with concentrated hydrochloric acid (12 ml) and the mixture is heated on a steam bath for 30 minutes. The excess acid and water are evaporated under reduced pressure to give a solid brown residue. This is slurried in acetone, then filtered off and recrystallised from ethanol containing a little concentrated hydrochloric acid to give 1-(2'-aminoethyl-3-hydroxypyrid-4-one in 34% yield as colourless needles, m.p. 264°-266° C., νmax (nujol) 1050, 1540, 1600, 1635 cm-1, δ(d6DMSO), 2.85 (t, 2H), 4.35 (t, 2H), 7.1 (d, 1H), 8.1 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: NCCCO
Product: NCc1ccc(Cl)cc1NCCCO

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 3-amino-propanol analogously to the preparation of Intermediate 113.1. colorless oil; ES-MS: M−=213.1; HPLC: AtRet=2.27 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[O:30])=[C:4]([OH:32])[CH:3]=1.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[O:30])=[C:4]([OH:32])[CH:3]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(Br)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2ccc(Br)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 79.2 %

Procedure:
To an ice cold stirred solution of 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (13.1 g, 27.1 mmol) in triethylsilane (25.0 mL) was added trifluoroacetic acid (25.0 mL). The solution was stirred at ambient temperature for 64 h, then concentrated in vacuo to dryness. Recrystallization from diethyl ether (25.0 mL) in a Branson ultrasonic bench top water bath afforded 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (10.1 g, 79%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.17 (s, 1H), 7.40-7.03 (m, 13H), 6.99-6.92 (m, 2H), 6.79-6.74 (m, 2H), 6.58-6.50 (m, 1H), 5.10 (s, 1H); MS (ES−) m/z 468.2 (M−1), 470.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5][CH2:6]S(C)=O>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH:5]=[CH2:6]
Reactant: COC(=O)[C@H](CCS(C)=O)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: C=C[C@H](NC(=O)OCc1ccccc1)C(=O)OC

Procedure:
Sulfoxide 60 (5.69 g, 18.2 mmol) was placed in a round bottomed flask in a kugelrohr. This was directly connected to a low vacuum diaphragm pump and heated/distilled at 140° C. The distillate was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a colourless oil, 0.905 g, 20%. Rf=0.24 (1/7 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24]([N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[C:25]#[CH:26].C(N(CC)CC)C>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:26]#[C:25][CH:24]([N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])[CH3:23])=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1
Reactant: C#CC(C)N1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Benzyloxy-5-(4-bromophenoxy)pyridine (826 mg, 2.32 mmol) and 2-(1-methylprop-2-ynyl)isoindole-1,3-dione (693 mg, 3.48 mmol) were dissolved in anhydrous acetonitrile under argon and admixed with triethylamine (2.78 ml, 19.94 mmol), copper iodide (22.1 mg, 0.116 mmol) and bis(triphenylphosphine)palladium(II) chloride (81.4 mg, 0.116 mmol). The reaction mixture was stirred at 100° C. in a microwave reactor for 30 min. A further 0.75 equivalent of the reactants were added and the stirring was continued at 100° C. for a further 60 min. The batch was concentrated, admixed with ethyl acetate and water and filtered, and the organic phase was separated off and concentrated. The crude product was further reacted without purification.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].O.[NH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>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.COCCOC>[NH2:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Temperature: 100 °C
Yield: 91.3 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (500 mg, 1.49 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (1.49 mL, 2.98 mmol), (Ph3P)4Pd (86 mg, 0.074 mmol) (Aldrich), and 3-aminophenylboronic acid monohydrate (253 mg, 1.63 mmol) (Lancaster) in 10 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 96 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 35% ethyl acetate-hexanes elution) to yield pure (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (410 mg, 91%) as a yellow solid (mp 92-94° C.) (solid to gel).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[NH:13][CH:12]=[CH:11]2.Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH:12]=[CH:11]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=c1c2ccc(Br)cc2ccn1CC1CC1
Temperature: 50 °C

Procedure:
Cesium carbonate (2.62 g), intermediate 1 (1.5 g) and (bromomethyl)cyclopropane (0.8 mL) were stirred and heated at 50° C. for 4 hours. The mixture was allowed to cool then poured into water and extracted with ethyl acetate. The organic extracts were combined dried and evaporated under reduced pressure. The residue was triturated with ether and the sub-titled compound isolated by filtration (1.0 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[C:14]([F:17])([F:16])[F:15].C1(C)C=CC=CC=1.[P:25]([O:30]C)([O:28][CH3:29])[O:26][CH3:27]>>[CH3:27][O:26][P:25]([CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[C:14]([F:17])([F:16])[F:15])([O:28][CH3:29])=[O:30]
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CP(=O)(OC)OC)c(C(F)(F)F)c1

Procedure:
6.20 g of ethyl 4-(bromomethyl)-3-trifluoromethylbenzoate (Reference Example 2 (step 2)) was dissolved in 12 ml of trimethyl phosphite and the mixture was heated at reflux for 4 hours under an argon atmosphere. After the completion of the reaction, the operation of adding of toluene to the residue, followed by azeotropic removal of trimethyl phosphite was repeated three times. The residue was purified by silica gel column chromatography to obtain 4.96 g of the objective compound as a yellow oily product.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:31][C:28]([F:29])([F:30])[O:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=3)[CH2:19][CH2:18]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 94.2 %

Procedure:
A mixture of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine (30.1 g, 68.8 mmol) prepared in Reference Example 191 and pyridinium p-toluene sulfonate (5.2 g, 20.6 mmol) in ethanol (450 ml) was stirred at 70° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a saturated sodium hydrogencarbonate aqueous solution were added to the residue, which was stirred for a while. The mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) to afford 4-[4-(4-trifluoromethoxyphenoxy)-piperidin-1-yl]phenol (22.9 g, yield 94%) as a a pale brown powder.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH:16]1[CH3:44])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][CH:32]1[CH2:31][CH2:30][N:29]([C:19]2[N:18]=[C:17]3[CH:16]([CH3:44])[NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:34][CH2:33]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)C(C)N(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)C(C)NCC2

Procedure:
A solution of 6-benzyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (150 mg, 0.241 mmol) and Pd(OH)2 on carbon (16.9 mg, 0.024 mmol) in THF (1.21 mL) was purged and placed under hydrogen atmosphere (balloon) overnight. The mixture was then filtered through Celite™ and concentrated to give the title compound as its TFA salt (132 mg).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:37]1([CH:42]2[CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:44]4[CH2:45][CH2:46][CH:42]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:43]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.59 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 494 [M+H]
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)[OH:4].[Cl:15][CH2:16][C:17](Cl)=[O:18].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:15][CH2:16][C:17]([NH:1][CH2:2][CH:3]([OH:4])[C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:18]
Reactant: Cn1ncc2ccc(C(O)CN)cc21
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2ccc(C(O)CNC(=O)CCl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the crude material 2-amino-1-(1-methyl-1H-indazol-6-yl)ethanol (390.8 mg, ˜50%, ˜1 mmol)in DMF was then added 2-chloroacetyl chloride (138.7 mg, 1.2 mmol) and iPr2NEt (0.347 mL, 2 mmol). The resulting mixture was stirred at room temperature for 2 hr. The mixture was then taken into partition between EtOAc and brine. The organic layer was separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried dried (Na2SO4), filtered and evaporated to dryness. The residue was purified on CombiFlash (50% EtOAc/Hex) to give 2-chloro-N-(2-hydroxy-2-(1-methyl-1H-indazol-6-yl)ethyl)acetamide. LCMS-ESI+: calc'd for C12H14ClN3O2: 268.1, 270.1 (M+H+); found: 268.2, 270.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:14]=[N:15][N:16]([CH3:22])[C:17]=3[NH:18]C(=O)C)[CH:8]=2)[C:5]2[CH:23]=[CH:24][CH:25]=[CH:26][C:4]=2[N:3]=1.[ClH:27]>>[ClH:27].[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:14]=[N:15][N:16]([CH3:22])[C:17]=3[NH2:18])[CH:8]=2)[C:5]2[CH:23]=[CH:24][CH:25]=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)Nc1c(-c2cccc(-n3c(N)nc4ccccc43)c2)cnn1C
Agent: Cl
Product: Cn1ncc(-c2cccc(-n3c(N)nc4ccccc43)c2)c1N

Procedure:
2-Amino-1-[3-(5-amino-1-methyl-4-pyrazolyl)phenyl]benzimidazole hydrochloride was prepared from 2-amino-1-[3-(5-acetamido-1-methyl-4-pyrazolyl)phenyl]benzimidazole by hydrolysis with 25% refluxing hydrochloric acid. mp 190°-193° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][S:10][C:11](=[O:13])[CH3:12])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].C([O-])(=O)C.[NH2+]1CCCCC1.O>C1C=CC=CC=1>[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][S:10][C:11](=[O:13])[CH3:12])=[O:6])([O-:16])=[O:15]
Reactant: CC(=O)CC(=O)OCCSC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)SCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Yield: 85.7 %

Procedure:
A solution of 7.0 g of 2-acetylthioethyl acetoacetate, 5.14 g of 3-nitrobenzaldehyde and 0.99 g of piperidinium acetate in 100 ml of benzene was heated at reflux under azeotropic dehydration conditions for 2 hours. The reaction mixture was poured into water and extracted with benzene, and the extract was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 9.83 g of 2-acetylthioethyl 2-(3-nitrobenzilidene)acetoacetate.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 216 h
Yield: 21.7 %

Procedure:
4-BROMO-2,5-DIFLUOROBENZENESULFONYL CHLORIDE (10.0 g, 0.0345 mol) and 2-AMINOTHIAZOLE (3.80 g, 0.0379 mol) were mixed in Pyridine (40 mL, 0.5 mol). The reaction was allowed to stir at room temperature for 9 days. The reaction was concentrated in vacuo to a total volume of approximately 40 mL. The residue was triturated with 1N HCl (aq). Acetonitrile was added until the precipitate became free-flowing. The solid was collected by filtration and rinsed with acetonitrile then ethyl ether. The solid was dissolved in boiling acetonitrile and treated with activated carbon then filtered through a celite pad. The filtrate was reduced to ⅓ its original volume by distillation. The mixture was cooled to room temperature. The crystals were collected by filtration and rinsed with ethyl ether. Vacuum drying gave 2.66 g of off-white solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH3:35])[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH3:35])[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CCCOc1ccc2cc(C3(O)CCNCC3)ccc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Product: CCCOc1ccc2cc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)ccc2c1
Yield: 55.4 %

Procedure:
Beginning with 0.199 gm (1.1 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.300 gm (1.1 mMol) 4-hydroxy-4-(6-propoxynaphth-2-yl)piperidine, 0.289 gm (60%) of the title compound were recovered as an off-white solid by the procedure described in Example 9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:13](=[O:16])(=[O:15])[NH2:14])=[C:6]([CH:12]=1)[CH2:7][NH:8]C(=O)C.[ClH:17]>C(O)C>[ClH:17].[NH2:8][CH2:7][C:6]1[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: CC(=O)NCc1cc(F)ccc1S(N)(=O)=O
Agent: Cl
Solvent: CCO
Product: NCc1cc(F)ccc1S(N)(=O)=O

Procedure:
(Step 3) To a solution of N-(5-fluoro-2-sulfamoylbenzyl)acetamide obtained in Step 2 (2.7 g) in ethanol (20 ml) was added hydrochloric acid (10 ml) at room temperature, and the mixture was stirred with heating under reflux for 3 hr, and then overnight at 80° C. The solvent was evaporated under reduced pressure. The residue was collected by filtration, and washed with diethyl ether to give 2-(aminomethyl)-4-fluorobenzenesulfonamide hydrochloride (1.49 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1([CH3:17])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH3:17][C:4]1([C:2]([NH2:1])=[O:3])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC1(C(N)=O)CCNCC1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
A 500-mL three-neck round bottom flask was equipped with an overhead mechanical paddle stirrer, thermocouple with N2-inlet, and reflux condenser that was vented to the atmosphere. The reactor was charged with the product of Example 9 (45.68 g, 188.5 mmol), p-toluenesulfonic acid monohydrate (46.67 g, 2453 mmol, 1.3 equiv) and isopropanol (179.2 g). The mixture was warmed to 80±10° C. After 45 minutes, the reaction solution was allowed to slowly cool; at about 78° C. the p-toluenesulfonate salt of the title compound began to precipitate from the reaction mixture. When the mixture had reached 70° C., heptane (40.2 g) was added to the mixture, which was then stirred for about 30 minutes. The mixture was then allowed to cool to ambient temperature over about 3 hours. The suspension was filtered and the reactor and cake were rinsed with a mixture of isopropanol (90.2 g) and heptane (78.7 g). The cake was dried under vacuum (˜100 mmHg w/N2 bleed) at a temperature of about 55-60° C. to give the p-toluenesulfonate salt of the title compound 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (s, 3H) 1.39-1.55 (m, 2H) 2.08 (d, J=14.55 Hz, 2H) 2.28 (s, 3H) 276-2.89 (m, 2H) 3.07-3.19 (m, 2H) 7.04 (s, 1H) 7.09-7.14 (m, 2H) 7.33 (s, 1H) 7.45-7.51 (m, 2H) 8.30 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[C:5]([NH:8][C:21](=[O:23])[CH3:22])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(Br)nc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.3 %

Procedure:
To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (5.0 g, 19 mmol) and pyridine (3.8 mL, 46 mmol) in anhydrous THF (75 mL) was added acetyl chloride (1.6 mL, 23 mmol) in a drop-wise manner. After stirring for 48 hr at rt, additional acetyl chloride (0.4 mL, 6 mmol) was added and the mixture was stirred for an additional 48 hr at rt. The solvent was removed in vacuo, and the residue was diluted with 30% EtOAc in hexanes. The mixture was filtered, and the filtrate was purified via silica gel chromatography eluting with 30% EtOAc in hexanes to give a yellow-brown solid (1.8 g, 31%). 1H NMR (CDCl3, 300 MHz): δ 8.34 (s, 1H), 8.08 (s, 1 H), 2.46 (s, 3 H), 0.32 (s, 9H). HPLC retention time: 2.29 minutes. MS ESI (m/z): 312.2, 314.2 (M+H)+, calc. 311.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C@@H:11]([CH3:17])[CH2:12][C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>O>[CH2:3]([O:10][C@@H:11]([CH3:17])[CH2:12][C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C[C@H](C)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](CC(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.73 g of potassium hydroxide in 140 mL of cold water was dissolved methyl (S)-3-benzyloxybutyrate (18) (24.21 g). The solution was stirred in an ice bath for one hour and at room temperature for one hour. Methanol was added to give a clear solution and the reaction was stirred overnight.