Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(OP([CH:14]1[S:18][CH2:17][CH2:16][S:15]1)(OCC)=O)C.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=O>CCCCCC.O1CCCC1>[S:18]1[CH2:17][CH2:16][S:15][C:14]1=[C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH3:19]
Reactant: CCOP(=O)(OCC)C1SCCS1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=C1SCCS1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.3M solution of n-butyllithium in hexane (28 ml) is added at -78° to a solution of 2-diethoxyphosphoryl-1,3-dithiolane (8.1 g) in dry tetrahydrofuran (70 ml). The mixture is stirred for one hour at -78° and 4-fluoroacetophenone is added (4.3 g). The mixture is stirred for one more hour at the same temperature and slowly warmed to room temperature. After removal of the solvents, the residue is dissolved in dichloromethane (200 ml). The solution is washed with a 10% aqueous solution of ammonium chloride (3×100 ml) and with water (2×100 ml), dried over magnesium sulphate and evaporated in vacuo. The oily residue is purified by column chromatography on silica gel using hexane/toluene 1:1 as eluant. The product is dried in vacuo to constant weight to yield 1-(1,3-dithiolan-2-ylidene)-1-(4-fluorophenyl)-ethane, m.p. 27°-31°.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11](C#N)=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:16].[OH-].[Na+].Cl.[C:25](=[O:28])([O-])[OH:26].[Na+]>C(O)C>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:25]([OH:26])=[O:28])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:16]
Reactant: Cc1nc2ccc(C#N)nc2n1Cc1ccc(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)nc2n1Cc1ccc(Cl)cc1Cl
Reaction time: 12 h

Procedure:
To a suspension of 3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (113 mg) in ethanol (0.6 ml) was added a 30% aqueous sodium hydroxide solution (0.3 ml), and the mixture was refluxed under heating for 12 hr. After 12 hr, a 30% aqueous sodium hydroxide solution (0.5 ml) was added and the mixture was refluxed under heating 3 hr. The reaction mixture was cooled, adjusted to pH 1 with 6N hydrochloric acid, stirred for 1 hr and adjusted to pH 4 with a saturated aqueous sodium hydrogencarbonate solution. The precipitated crystals were collected by filtration to give the objective compound (144 mg) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.CN(C=O)C.[N+:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([O-:24])=[O:23].N>O=S(Cl)Cl.O.CCN(CC)CC.N1C=CC=CC=1>[N+:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:16][CH:15]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=C(O)c1ccc(Nc2ccncc2)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(Nc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.8 %

Procedure:
Compound D2 (172 mg, 0.80 mmol) was refluxed in SOCl2 (5 mL) containing a catalytic amount of DMF for 1 h (until a clear solution was obtained). The reaction mixture was cooled to room temperature and excess SOCl2 was removed under vacuum. Dioxane (10 mL) was added to the residue, and then removed under vacuum. The residue was cooled in a dry ice-acetone bath, p-nitroaniline (112 mg, 0.81 mmol) and pyridine (1.3 mL) were added, followed by Et3N (0.3 mL), and the mixture was stirred at room temperature for 20 min, and then refluxed for 1 h. The reaction mixture was cooled to room temperature and diluted with H2O, and then basified with aqueous NH3 and stirred for 30 min. The resulting precipitate was filtered, and washed sequentially with water, hexane and CH2Cl2. The crude product was dissolved in MeOH and then adsorbed onto silica gel, and the resulting adsorbate chromatographed on silica gel, eluting with 0-10% MeOH:CH2Cl2, to give D3 (85 mg, 32%); mp 298-302° C. (MeOH); 1H NMR [(CD3)2SO] δ 10.64 (s, 1 H, NH), 9.21 (s, 1 H, NH), 8.30-8.24 (m, 4 H, ArH), 8.09-8.05 (m, 2 H, ArH), 8.00-7.98 (m, 2 H, ArH), 7.34-7.31 (m, 2 H, ArH), 7.07-7.05 (d, m, 2 H, ArH);LCMS 235+ve.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[N:3]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[N:3][N:4]2[CH2:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C:18]([N:20]([CH3:22])[CH3:21])=[O:19]
Reactant: CN(C)C(=O)c1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CN(C)C(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A solution of 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide (0.400 g, 0.888 mmol) and MeOH (8.8 mL) was cooled to 0° C. Zinc dust (0.290 g, 4.44 mmol) was added and the mixture was stirred vigorously for 15 minutes, followed by the dropwise addition of saturated aqueous NH4Cl (9 mL). The mixture was stirred vigorously for 15 minutes at 0° C. and then warmed to ambient temperature and stirred for an additional 1 hour. The mixture was diluted with MeOH and filtered. To the filtrate was added saturated aqueous NH4OAc and the mixture was concentrated to remove bulk MeOH. The mixture was extracted with EtOAc and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (2 to 20% IPA/CHCl3) to afford 0.160 g (61%) of the title compound as a yellow/orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[CH3:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Br:11])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N)c(Br)c1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide is added in portions over 0.5 hours at below 40° C. After 15 minutes, the mixture is washed with H2O (4×100 ml). The solution is dried (MgSO4) and evaporated to dryness to afford 70.53 g of 4-amino-3-bromoacetophenone, mp 59°-62° C. A 35 g sample of this material in 180 ml of dry dimethylformamide is stirred and heated at reflux with 17.57 g of Cu2 (CN)2 for 6 hours under N2 atmosphere. Subsequently, 180 ml of FeCl3 /HCl solution (40 g FeCl3.6H2O/10 ml concentrated HCl/60 ml H2) is added and the mixture is heated for 20 minutes at 60°-70° C. and poured into 350 ml of H2O. The aqueous mixture is extracted with CH2Cl2 and the extracts are washed with H2O, saturated NaHCO3 solution and H2O, respectively. The CH2Cl2 solution is evaporated to dryness in vacuo and the residue is recrystallized from 95% EtOH to afford 14.25 g, mp 155°-159° C., of 4-amino-3-cyanoacetophenone. A 4.8 g sample of this product in 100 ml of EtOAc and 100 ml of CHCl3 containing 13.32 g of CuBr2 is heated at reflux temperature for 20 minutes. The mixture is further heated after 20 ml of EtOH is added and then filtered while still hot. The filter cake is washed with 50 ml of hot 20% MeOH/CH2Cl2 and the combined organic solutions are evaporated to dryness in vacuo. The residue is stirred in 25 ml of CH2Cl2 and the solid is collected and washed with CH2Cl2 to give 8.08 g of the phenacyl bromide. This material is added to 50 ml of t-BuNH2 in 100 ml of EtOH at 5° under N2 atmosphere. After 10 minutes of stirring, the mixture is allowed to warm to 30° C. to give a solution. This solution is cooled to 10° and 4 g of NaBH4 is added in portions. After 45 minutes, the mixture is allowed to warm (42° C.) and kept at 20° C. until the exotherm subsides. The mixture is then evaporated to dryness and the residue is washed with H2O. The residue is dried and treated with 200 ml of boiling MeOH and the hot MeOH solution is filtered. The filter cake is further washed with hot MeOH and the combined filtrates are concentrated to afford crystals. This solid is recrystallized from MeOH/2-PrOH to afford 2.08 g, mp 184°-186° C., of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([F:30])([F:31])[F:17])=[N:12]1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccccc2C(F)(F)F)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: C[O:2][C:3]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1)(OC)[CH3:4]>C(O)=O>[NH2:13][C:9]1[N:8]=[C:7]([C:3](=[O:2])[CH3:4])[CH:12]=[CH:11][N:10]=1
Reactant: COC(C)(OC)c1ccnc(N)n1
Solvent: O=CO
Product: CC(=O)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4-(1,1-dimethoxy-ethyl)-pyrimidin-2-ylamine (Step A, 15 g, 81.87 mmol) was added HCOOH (70.0 mL). The resulting mixture was stirred at RT under argon for 3 h. The mixture was evaporated to dryness. The solid was recrystallized from EtOH to give a brown solid. MS m/z:138.2(M+H). Calc'd for C6H8N3O: 138.14.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH:27]1([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]3[S:38][C:39]([C:43]([OH:45])=O)=[C:40]([CH3:42])[N:41]=3)[C:32]2=[O:46])[CH2:29][CH2:28]1.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][NH2:54])[CH:48]=1>>[CH:27]1([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]3[S:38][C:39]([C:43]([NH:54][CH2:53][C:49]4[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=4)=[O:45])=[C:40]([CH3:42])[N:41]=3)[C:32]2=[O:46])[CH2:28][CH2:29]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCCN(CC3CC3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxotetrahydro pyrimidin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 22% yield: nip 142-145° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.52-8.51 (m, 1H), 7.68-7.65 (m, 1H), 7.28-7.23 (m, 1H), 6.07 (m, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.15 (t, J=5.9 Hz, 2H), 3.48 (t, J=5.9 Hz, 2H), 3.31 (d, J=7.0 Hz, 2H), 2.61 (s, 3H), 2.16-2.09 (m, 2H), 1.05-0.98 (m, 1H), 0.55-0.49 (m, 2H), 0.28-0.23 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.0, 159.2, 152.9, 152.7, 149.0, 148.6, 135.6, 133.9, 123.6, 117.6, 52.8, 45.6, 45.5, 41.2, 21.3, 17.3, 9.3, 3.4; MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].[CH3:11][Si](C=[N+]=[N-])(C)C.[O-][Mn](=O)(=O)=O.[K+].[BH4-].[Na+]>C1C=CC=CC=1.O.C(Cl)(Cl)Cl.CO.CO>[OH:2][CH2:1][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CO)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-formyl-2-furan carboxylic acid (1 g, 7.14 mmoles) was stirred in benzene (18 mL)/methanol (4 mL) in a 3-neck 50 mL round bottom flask with one neck connected to a funnel that was previously flushed with nitrogen gas. Trimethylsilyl diazomethane 2M in hexanes (3.6 mL, 7.2 mmoles) was added dropwise over a period of 15 min. After addition, the medium was a green limpid solution, which was stirred for 2 h at r.t. The reaction advancement is monitored by TLC 8:2 Hexanes/AcOEt followed by 95:5 CHCl3/MeOH, and stained with KMnO4. Solvents were evaporated under vacuum, and 14 mL of methanol was added. The flask was placed in an ice-water bath and sodium borohydride (600 mg, 15.8 mmoles) was added. The reaction mixture was stirred for 3 h at r.t. Water was poured off and the mixture extracted with AcOEt. The organic phase was dried over MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography (7×3.5 cm) with 100 mL of 90:10, then 200 mL of 80:20, and finally 400 mL of a 75:25 mixture of Hexane/AcOEt to yield a yellow powder after extraction (780 mg, 70%). NMR 1H 300 MHz, CDCl3, (δ, ppm): 7.13 (d, J=3.4 Hz, 1H), 6.41 (d, J=3.3 Hz, 1H), 4.67 (d, J=6.2 Hz, 2H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:22][CH2:23][C:24](Cl)=O>C(O)(=O)C>[Cl:22][CH2:23][C:24]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([O:18][CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N)c(C(=O)Nc2ccccc2Cl)cc1OC
Solvent: CC(=O)O
Product: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 45.8 %

Procedure:
Prepared according to Procedure B with 1a (2.95 g, 9.63 mmol) and chloroacetyl chloride (2.3 mL, 28.9 mmol) in acetic acid (30 mL). Purified by extraction from aq. K2CO3 and recrystallization from isopropanol to afford 1.61 g of a brown crystalline solid (46%). 1H NMR (CDCl3) δ: 7.59-7.66 (m, 2H); 7.45-7.56 (m, 3H); 7.20 (s, 1H); 4.37 (d, J=12 Hz, 1H), 4.08 (d, J=12 Hz, 1H); 4.04 (s, 3H); 4.00 (s, 3H). MS (ES): m/z 365.0 (M+).
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][C:21]([OH:24])([CH3:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[CH3:28][C:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[N:31](C2CCCCO2)[N:30]=1>>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16]([C:32]3[NH:31][N:30]=[C:29]([CH3:28])[CH:33]=3)[C:15]([N:19]3[CH2:22][C:21]([OH:24])([CH3:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2I)C1
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC(C)(O)C2)[nH]n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 89 using N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxy-3-methyl azetidin-1-yl)-5-iodonicotinamide (Stage 90.1) and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give the title product as a white solid. HPLC (Condition 7) tR=5.72 min, UPLC-MS (Condition 8) tR=0.99 min, m/z=464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 3H) 2.28 (br. s, 3H) 3.66 (s, 4H) 5.42 (br. s, 1H) 6.16 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.84-7.91 (m, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.71 (s, 1H) 10.21 (s, 1H) 12.63 (br. s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][C@H:34]1[CH2:38][NH:37][C@H:36]([C:39]([OH:41])=[O:40])[CH2:35]1>>[OH:33][CH:34]1[CH2:38][N:37]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[O:21][CH3:22])=[C:10]([C:23]([F:25])([F:24])[F:26])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:36]([C:39]([OH:41])=[O:40])[CH2:35]1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CC(O)CC3C(=O)O)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with trans-4-hydroxy-L-proline. A yellow solid 110 was obtained (0.031 g, 65%). MS (APCI) m/z 491 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][CH2:33][CH3:34])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:38](C1CCCN1)CC>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH2:32][CH:33]([CH3:38])[CH3:34])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCCC1CCCN1
Reactant: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5CC(C)C)c4)cc23)CC1
Yield: 21.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 2-(2-methylpropyl)pyrrolidine (127 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 12.0 mg of the title compound (21.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][C:10]=1[CH3:17])([CH3:7])[CH3:6])[CH3:2].[CH3:19][O:20][CH2:21][C:22]1[C:27]([C:28](O)=[O:29])=[CH:26][N:25]=[C:24]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:23]=1.COC(=O)CC(=O)COC>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:28]([C:27]2[C:22]([CH2:21][O:20][CH3:19])=[N:23][C:24]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[N:25][CH:26]=2)=[O:29])=[CH:11][C:10]=1[CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1C
Agent: COCC(=O)CC(=O)OC
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2COC)cc1C

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 97B]) was reacted with 4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 4-methoxy-3-oxo-butyric acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N:23]1([CH2:22][CH2:21][CH2:20][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCCN1CCCCC1
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1OCCCN1CCCCC1

Procedure:
Salicylaldehyde (27 g) is treated first with 11 g of 50% sodium hydride in 175 ml of dimethylformamide and then with 150 ml of a 2 N toluene solution of N-(3-chloropropyl)-piperidine following the procedure described in Example 31A, yielding 47.7 g of the title compound as an oil, boiling point 155°-160° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[N:6]1([C:15]2[O:16][C:17]([CH2:27][CH2:28][C:29](O)=[O:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:19]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[N:6]1([C:15]2[O:16][C:17]([CH2:27][CH2:28][C:29]([N:3]3[CH2:4][CH2:5][S:1][CH2:2]3)=[O:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:19]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: C1CSCN1
Reactant: O=C(O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: O=C(CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1)N1CCSC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
A mixture of thiazolidine (145 mg), 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl}-5-oxazolyl]propionic acid (300 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (222 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (253 mg) and N,N-dimethylformamide (1 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (16 ml) and the reaction mixture was extracted with ethyl acetate (5 ml). The organic layer was concentrated, introduced into preparative HPLC and purified to give 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propanoyl}thiazolidine (165 mg, 46%). Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 125–126° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]5([CH3:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:23]=4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12.Br[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]5([CH3:31])[CH2:30][CH2:29][N:28]([CH2:33][CH2:34][N:35]6[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]6)[CH2:27][CH2:26]5)[CH:23]=4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reactant: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(Cn2cc(-c3ccc(C(=O)NCc4ccn5ccnc5c4)s3)cn2)CCN(CCN2CCNCC2)CC1
Reaction time: 8 h

Procedure:
A solution of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.100 g, 0.197 mmol) in N,N-dimethylformamide (2 ml) was added tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (0.058 g, 0.197 mmol) followed by N,N-diisopropylethylamine (0.138 ml, 0.788 mmol) and the reaction was stirred overnight. The reaction mixture was purified directly using normal phase chromatography and the resulting material was treated with HCl in dioxane (4M) for 2 hours then concentrated to give the title compound as a hydrochloride salt. 1H NMR (500 MHz, DMSO-d6) δ 14.64 (s, 1H), 10.40 (s, 1H), 9.72 (s, 1H), 9.54 (t, J=6.0 Hz, 1H), 8.89 (d, J=6.9 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.22 (s, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.91 (d, J=3.9 Hz, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.50 (dd, J=7.0, 1.4 Hz, 1H), 7.28 (d, J=3.8 Hz, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.23-3.54 (m, 10H), 3.35 (d, J=38.3 Hz, 8H), 1.72 (d, J=77.7 Hz, 4H), 0.98 (s, 3H); MS (ESI(+)) m/e 547 (M+H)+.