Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)/[CH:3]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C.C(OCC)(=O)C>[F:18][C:14]1[CH:13]=[C:12]2[C:17](/[C:9](=[C:4]3\[O:5][C:6]([CH3:8])([CH3:7])[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]4)=[CH:3]\3)/[C:10](=[O:19])[NH:11]2)=[CH:16][CH:15]=1
Reactant: OCCN1CCNCC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1N1CCN(CCO)CC1
Temperature: 100 °C

Procedure:
A mixture of (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (95 mg, 0.29 mmol) and 1-(2-hydroxyethyl)piperazine (0.40 mL, 3.3 mmol) in 6 mL of DMF was heated in 100° C. bath for 2 hours. The mixture was cooled, diluted with ethyl acetate (60 mL), washed with brine (3×50 mL), and concentrated to give the crude product, which was purified by silica gel chromatography with 5-20% methanol in chloroform to give (3E)-6-fluoro-3-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a grey solid. Yield: 73 mg, 67%.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][C:54]=1[C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([N:65]2[CH2:66][CH2:67][N:62]([C:60](=[O:61])[C:54]3[CH:55]=[C:56]([Cl:59])[CH:57]=[CH:58][C:53]=3[Cl:52])[CH2:63][CH2:64]2)=[O:31])=[CH:24][CH:25]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1cc(Cl)ccc1Cl)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
HOBt (25 mg, 0.185 mmol) and DIPEA (22 mg, 0.175 mmol) were added to a stirred solution of N-biphenyl-4-yl-malonamic acid (50 mg, 0.175 mmol) in DMF (3 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (50 mg, 0.26 mmol) was added followed by the addition of (2,5-dichloro-phenyl)-piperazin-1-yl-methanone hydrochloride (55 mg, 0.187 mmol). The reaction mixture was stirred at room temperature overnight. Water was then added and the resulting precipitate was filtered and purified by column chromatography using silica gel 60-120 mesh and 50% ethyl acetate in hexane as eluant to afford 35 mg (41%) of N-biphenyl-4-yl-3-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 497.11 M+1)+, 95.5%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.64 (m, 2H), 7.58 (m, 4H), 7.44 (m, 3H), 7.38 (d, 2H), 7.32 (m, 2H), 3.95 (m, 2H), 3.8 (m, 1H), 3.75 (m, 4H), 3.65 (m, 1H), 3.52 (d, 3H), 3.34 (m, 3H).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](Cl)=[N:9][OH:10])[CH:2]=1.O1CCCC1.[C:23]([C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:24]=[C:23]([C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=3)[O:10][N:9]=2)[CH:2]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1cccc(-c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3cccc(-c4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of biphenyl-3-yl-acetohydroximoyl chloride (60 mg) described in Manufacturing Example 85-1-3 and tetrahydrofuran (3 mL) were added 3-ethynyl-pyridin-2,6-diamine (15 mg, 0.11 mmol) described in Manufacturing Example 13-1-3 and triethylamine (94 μL, 0.68 mmol), which was stirred for 2 hours at room temperature. Water was added to the reaction mixture at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound in a crude product. Then, the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (32 mg, 62%) as a trifluoroacetic acid salt.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:21])[NH:15]2)[CH:3]([NH:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH3:5].C[O-:23].[Na+].N1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=CC1=O>CO>[CH:30]1([C:29]([O:20][C:17]2[CH:18]=[CH:19][C:10]([CH:2]([OH:1])[CH:3]([NH:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH3:5])=[C:11]3[C:16]=2[NH:15][C:14](=[O:21])[CH:13]=[CH:12]3)=[O:23])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: C[O-]
Reactant: O=c1ccc2ccccc2[nH]1
Agent: [Na+]
Solvent: CO
Product: CCC(NC(C)C)C(O)c1ccc(OC(=O)C2CCCCC2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.8 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril was dissolved in 100 ml of methanol, and a methanolic solution of 10% sodium methylate was added to the resulting solution in an equimolar amount relative to the starting carbostyril compound. The mixture was concentrated to dryness and the resulting residue was dissolved in 100 ml of dimethylformamide. 2.9 g of cyclohexanecarboxylic acid chloride was then added while cooling with ice-water and the mixture was stirred for one hour at a temperature of 0° C. The precipitate formed was separated by filtration and washed successively with dimethylformamide and diethyl ether to obtain 4.0 g of 8-cyclohexylcarbonyloxy-5-(1-hydroxy-2-isopropylaminobutyl)carbostyril having a melting point of 186.5°-187.5° C. (after recrystallization from chloroform-diethyl ether).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[CH:3]=1.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:8])=[C:4]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[CH:3]=1
Reactant: Cc1cc(C(=O)O)c(-n2nccn2)cc1F
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: Cc1cc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c(-n2nccn2)cc1F

Procedure:
The title compound was prepared following the same general protocol as described in Example A318, using 4-fluoro-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[CH3:26][I:27]>C1(C)C=CC=CC=1>[I-:27].[CH3:26][N+:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7][C:6]3[CH:25]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21]3)[C:10]=12
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: CI
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc[n+](C)c32)CC1
Product: [I-]
Temperature: 100 °C
Yield: 61.5 %

Procedure:
A mixture of 500 mg (1.42 mmole) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 175 μl (2.81 mmole) of methyl iodide in 30 mL of toluene was heated at 100° C. for about 19 hours. The reaction mixture was cooled to room temperature and the solvent decanted off. The remaining residue was recrystallized twice from CH2Cl2 /isopropyl ether/hexanes to give 432 mg of the title compound as tan crystals. (m.p. 245°-247° C.).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[SH:18][CH2:19][C:20]([NH2:22])=[O:21].[OH-].[K+]>CN(C)C=O.O>[NH2:13][C:12]1[C:11]2[C:2](=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=3)[S:18][C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: COc1cc2cc(C#N)c(Cl)nc2cc1OC
Reactant: NC(=O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cc3c(N)c(C(N)=O)sc3nc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 20 g of 2-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 500 ml of dimethylformamide was added 20 g of 2-mercaptoacetamide. To the resultant mixture was added dropwise a solution of 15 g of potassium hydroxide in 100 ml of water. The mixture was stirred at room temperature for 30 minutes and enough additional water was added to give a homogeneous solution. The mixture was stirred at room temperature for 16 hours and then poured into 4 liters of water. The yellow precipitate which formed was separated by filtration and dried to give 3-amino-6,7-dimethoxy thieno[2,3-b]quinoline-2-carboxamide melting at about 278.5°-279.5° C. with decomposition.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].ClC1C=C(Cl)C(Cl)=CC=1[O:17][C:18](=O)[C@@H:19]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1>CN(C)C=O>[CH2:1]([NH:7][C:18](=[O:17])[C@@H:19]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: O=C1CC[C@@H](C(=O)Oc2cc(Cl)c(Cl)cc2Cl)N1
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)[C@@H]1CCC(=O)N1
Reaction time: 20 h

Procedure:
4 ml of n-hexyl amine were added at 0° C. to a solution of 3.1 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester in 10 ml of dimethyl formamide and the solution was left at room temperature for 20 hours. The solvent was removed by distillation in vacuo at room temperature. The residue was taken up in 90% aqueous methanol, and the solution was filtered successively through 200 ml each of Levatit S 100(H+ -form)and Serdolit Blau (OH- -form). The ion exchanger columns were washed with 200 ml of 90% methanol and the combined eluate and washing solution were concentrated in vacuo. The L-pyroglutamic acid n-hexyl amide obtained as a colorless solid was recrystallized from ethyl acetate.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].CCN(C(C)C)[CH:21]([CH3:23])[CH3:22].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH:21]([CH3:23])[CH3:22])=[CH:30][CH:29]=3)=[O:17])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: Nc1ccccc1
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 41 %

Procedure:
To the suspension of theophylline-7-acetic acid (101, 32.5 g, 0.136 mol) in anhydrous DMF (400 mL), was added DIPEA (54 mL, 0.31 mol) at 0° C. The neat aniline (102, 20.4 mL, 0.143 mol) was added followed by addition of DMAP (19.2 g, 0.16 mol) and EDCI (30.1 g, 0.16 mol). The reaction mixture was warmed to room temperature over 18 h, then stirred at 40-43° C. for 1.5 days. The reaction mixture was diluted with CH2Cl2 (1.8 L), washed with H2O (0.7 L), 10% citric acid (0.5 L), NaHCO3 (saturated, 0.6 L), brine, dried over Na2SO4 and concentrated in vacuo and crystallized from ethyl acetate/hexanes to yield compound 200 (41%, 19.8 g): MS (APCI) m/z: 356.2 [M+H]+. Anal. Calcd. for C18H21N5O3: C, 60.83; H, 5.96; N, 19.71. Found: C, 60.53; H, 5.97; N, 19.76.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:61])[CH2:59][CH3:60])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:61][CH:58]([C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][CH:56]=2)[CH2:59][CH3:60])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.209 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g), 1-(4-chlorophenyl)propan-1-amine (0.085 g) and DIPEA (0.262 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.138 g, 66.8
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>ClCCl>[C:9]1([CH:2]([NH:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([N+:26]([O-:28])=[O:27])[CH:18]=2)(=[O:23])=[O:24])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC(c2ccccc2)c2ccccc2)ccc1Cl
Reaction time: 16 h
Yield: 74 %

Procedure:
To a stirred solution of aminodiphenylmethane (1.9 g, 11 mmol) and 4-chloro-3-nitrobenzenesulfonyl chloride (2.56 g, 10 mmol) in 75 mL of dichloromethane was added triethylamine (2 mL, 14.4 mmol). The solution was stirred for 16 h. The reaction mixture was washed successively with 1M HCl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The resulting yellow solid was recrystallized from ethyl acetate/hexane to give 2.98 g of product in (74%) yield as pale yellow crystals: 1H NMR (400 MHz, CDCl3) δ5.34 (d, 1H, J=7.0 Hz), 5.73 (d, 1H, J=7.0 Hz), 7.11-7.14 (m, 4H), 7.23-7.26 (m, 6H), 7.43 (d, 1H, J=8.5 Hz), 7.67 (dd, 1H, J=2.0, 8.5 Hz), 7.93 (d, 1H, J=2.0 Hz).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)nc2)C2CCCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
To a mixture of ethyl 3-{[(5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}pyridin-2-yl)carbonyl]amino}propanoate (274 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (235 mg, 91%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]3)[CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21]>>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=4)[CH:3]=3)[CH:10]=[CH:11][CH:12]=2)[N:17]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Nc1ccc2cccc(Oc3cc(Cl)ncn3)c2n1
Product: N#Cc1ccc(-c2cc(Oc3cccc4ccc(N)nc34)ncn2)cc1

Procedure:
According to the procedure described for Example 124(b), 8-(6-chloro-pyrimidin-4-yloxy)-quinolin-2-ylamine, (Example 124(a)), (0.20 g, 0.73 mmol) and 4-cyanophenylboronic acid (0.16 g, 1.1 mmol, Aldrich) provided the title compound as a white solid. Mp: 234–236° C. MS (ESI, pos. ion.) m/z:340 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].[ClH:11].[CH3:12][CH2:13]O>>[NH2:1][CH:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([O:6][CH2:12][CH3:13])=[O:5].[ClH:11]
Reactant: CC(C)C(N)C(O)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)C(N)C(C)C

Procedure:
Treat 3-Amino-2-hydroxy-4-methylpentanoic acid (0.89 g, 6.05 mmol) (Peet, N. P. et al., J. Med. Chem., 33, 394 (1990)) in CH3CH2OH (25 mL and then 20 mL) with gaseous HCl. Concentrate and dry over KOH pellets to give the title compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:41]([NH:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][C:32]([F:31])([F:43])[F:44])[CH:35]=4)=[O:42])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(OC(F)(F)F)c1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 43.4 mg (0.21 mmol) of 3-trifluoromethoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 8.5 mg (14.7% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([S:39]([NH:42][CH3:43])(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:31][C:32]1[CH:33]=[C:34]([S:39]([NH:42][CH3:43])(=[O:40])=[O:41])[CH:35]=[CH:36][C:37]=1[O:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: CNS(=O)(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(-c4nccs4)[nH]3)c2)c(F)c1
Temperature: 100 °C
Reaction time: 19 h
Yield: 29.3 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (60.0 mg, 0.139 mmol) synthesized in Example (38d) and 3,4-difluoro-N-methylbenzenesulfonamide (47.4 mg, 0.229 mmol) synthesized in Example (58a) were dissolved in N,N-dimethylformamide (5.0 mL), and potassium carbonate (77.0 mg, 0.557 mmol) was added, followed by stirring at 100° C. for 19 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out with ethyl acetate (30 mL). 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=0%-25%) to afford the desired compound (21.1 mg, yield 30%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=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>>[ClH: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:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[N:3]=2)=[C:22]([CH3:29])[CH:21]=1
Reactant: COc1cc(C)c(N)cc1OC
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1cc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)cc1OC
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-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 brown solid. (23 mg, 30%). 1H NMR (CDCl3): 9.54 (dd, J=1.5, 4.5 Hz, 2H), 9.05 (dd, J=1.5, 4.5 Hz, 2H), 7.98 (s, 1H), 7.60 (s, 2H), 7.29 (s, 1H), 4.71 (s, 3H), 4.63 (s, 3H), 3.00 (s, 3
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C@H:10]([CH2:25][CH2:26][CH3:27])[C@H:11]([CH3:24])[C:12](N1C2C=CC=CC=2OC1=O)=[O:13]>O1CCCC1>[CH2:1]([NH:8][C:12](=[O:13])[C@@H:11]([CH3:24])[C@H:10]([OH:9])[CH2:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC[C@@H](O)[C@H](C)C(=O)n1c(=O)oc2ccccc21
Solvent: C1CCOC1
Product: CCC[C@@H](O)[C@H](C)C(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
Benzylamine (0.6 mL, 5.5 mmol) is added dropwise to a solution of N-[(2S*,3R*)-3-hydroxy-2-methylhexanoyl]-2-benzoxazolinone (1.31 g, 5.0 mmol) in 10 mL of tetrahydrofuran. A mildly exothermic reaction ensues. After 15 min, the solvent is evaporated. The residue is redissolved in 50 mL of CH2Cl2 and washed successively with equal volumes of 1 N HCl, 1 N NaOH, water, and brine. After drying over MgSO4, the solution is evaporated to yield 1.12 g (95% yield) of the product as a white solid which was recrystallized from ethyl acetate/hexanes as white needles, mp 114-115° C. 1H-NMR (d6-DMSO, 400 MHz) δ 8.27 (t, J=6, 1H), 7.30 (m, 2H), 7.22 (m, 3H), 4.49 (d, J=6, 1H), 4.27 (dd, J=6, 15, 1H), 4.20 (dd, J=6,15, 1H), 3.44 (m, 1H), 2.20 (q, J=7, 1H), 1.43 (m, 1H), 1.22 (m, 3H), 1.04 (d, J=7, 3H), 0.79 (t, J=7, 3H). 13C-NMR (d6-DMSO, 100 MHz): 175.2, 140.2, 128.6, 127.6, 127.1, 71.8, 46.9, 42.2, 37.6, 19.0, 14.7, 14.5.