Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:46]([C:43]3[CH:44]=[CH:45][C:40]([CH3:39])=[CH:41][CH:42]=3)(=[O:48])=[O:47])[N:17]=[C:16]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
According to the procedure described in Example 4a) 129 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 104 mg 5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=5.04 min, [M+1]+=692.65, [M−1]−=690.76.
Reaction SMILES: [F:1][C:2]1([F:20])[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:27]([CH2:29][C:30]#[N:31])=[O:28])N=C(C)C=1.C(N(CC)C(C)C)(C)C.O1CCOCC1>O>[F:20][C:2]1([F:1])[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[N:4]([C:27](=[O:28])[CH2:29][C:30]#[N:31])[CH2:3]1
Reactant: FC1(F)CNC12CCCN(c1ncnc3[nH]ccc13)C2
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
An optically-active compound of 4-(3,3-difluoro-1,6-diaza-spiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (6.6 g) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (7.7 g), N,N-diisopropylethylamine (4.3 ml) and 1,4-dioxane (132 ml), and the mixture was stirred at 100° C. for 2 hours. The mixture was cooled to room temperature. Then, thereto was added water, and the mixture was extracted with ethyl acetate. The separated aqueous layer was further extracted with ethyl acetate 5 times. The combined organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=3/2 to 2/3). To the resulting residue was added n-heptane, and the mixture was concentrated under reduced pressure. To the resulting residue was added diethylether, and the mixture was slurry-washed and filtered to give a solid (7.5 g). The filtrate was concentrated under reduced pressure. To the resulting residue was added diethylether, and the mixture was slurry-washed to give a solid (0.2 g). The combined solid was purified by silica gel column chromatography (eluent: chloroform/methanol=97/3 to 9/1). To the resulting solid was added ethanol, and the mixture was concentrated under reduced pressure to give the titled compound (7.1 g).
Reaction SMILES: COC[C@@H]1[C@H](C=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1.CC12C(C)(C)[C:28]([C:34]([O:36][CH2:37][C@H:38]3[C@@H:40]([CH2:41][O:42]CC)[C@@:39]3([CH3:59])[C:45]3[CH:54]=[CH:53][C:52]4[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=4[CH:46]=3)=O)(CC1)OC2=O>>[CH2:34]([O:36][CH2:37][C@@H:38]1[C@H:40]([CH:41]=[O:42])[C@:39]1([CH3:59])[C:45]1[CH:54]=[CH:53][C:52]2[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=2[CH:46]=1)[CH3:28]
Reactant: CCOC[C@@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 97 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 12a but using Intermediate 8b as the starting material afforded the title compound (36 mg, 97% yield) as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([NH2:19])=[NH:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[C:24]([O-:27])([O-])=[O:25].[Cs+].[Cs+].[OH:30]/[CH:31]=[C:32](/[CH2:37][C:38]1[CH:39]=[N:40][N:41]([CH3:43])[CH:42]=1)\[C:33](OC)=O>CN1C(=O)CCC1>[F:21][C:20]([F:23])([F:22])[C:24]([OH:27])=[O:25].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]3[NH:19][CH:33]=[C:32]([CH2:37][C:38]4[CH:39]=[N:40][N:41]([CH3:43])[CH:42]=4)[C:31](=[O:30])[N:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: COC(=O)/C(=C\O)Cc1cnn(C)c1
Reactant: N=C(N)NCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cn1cc(Cc2c[nH]c(NCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Product: O=C(O)C(F)(F)F
Temperature: 130 °C
Yield: 54.5 %

Procedure:
To the mixture of N-[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl) methyl]guanidine (150 mg, 0.328 mmol) and Cs2CO3 (428 mg, 1.314 mmol) in NMP (1.5 mL) was added methyl (2Z)-3-hydroxy-2-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-propenoate (77 mg, 0.394 mmol). It was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound as a white solid (54 mg, 27.3% yield). LCMS: rt=2.88 min, [M+H+]=490
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH3:10])[CH2:7][CH2:8][CH3:9])=[O:5].[CH3:15][NH:16][CH2:17][CH2:18]C.C12C(=CC=CC=1)[NH:25][C:24](=O)OC2=O>>[NH:16]1[CH2:15][CH2:24][N:25]=[C:17]1[CH2:18][NH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH3:10])[CH2:7][CH2:8][CH3:9])=[O:5]
Reactant: CCCNC
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCN(C)C(=O)c1ccccc1N
Product: CCCN(C)C(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-methyl-N-propylbenzamide (prepared from N-methylpropylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-methyl-N-propylbenzamide.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:17])=[C:6]([CH:13]=[CH:14][C:15]=1[F:16])[O:7][CH2:8][C:9]([O:11]C)=[O:10])=[O:3].[OH-].[Na+]>O.C(O)(C)C>[NH2:1][C:2]([C:4]1[C:5]([F:17])=[C:6]([CH:13]=[CH:14][C:15]=1[F:16])[O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:3]
Reactant: COC(=O)COc1ccc(F)c(C(N)=O)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1c(F)ccc(OCC(=O)O)c1F
Yield: 8 %

Procedure:
Methyl 2-[3-(aminocarbonyl)-2,4-difluorophenoxy]acetate (7 mmol, 1 equiv.) was added to a solution of NaOH (1 g, 25 mmol, 3.6 equiv.) in water (20 ml) and isopropyl alcohol (5 ml). The mixture was stirred under reflux for 1.5 h, diluted with water (40 ml) and extracted with CH2Cl2 (40 ml). The aqueous phase was acidified to pH 1 with conc. HCl solution. The precipitant solid was filtered and dried in vacuo to give the desired compound (130 mg, 8%), mp 152-153° C. HPLC-MS (method 1): m/z 312 [M−H+2CH3CN]−, Rt=0.91 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=C[N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=N[NH:38]C(=O)C=1)C1C=CC=CC=1.BrCC(C1C=CC(CO)=CC=1)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[N:38][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Agent: O=C(CBr)c1ccc(CO)cc1
Solvent: CS(C)=O
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1

Procedure:
5-Benzyloxy-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 15b from 5.20 g (25.7 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 7.70 g (28.6 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a) using DMSO as solvent.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].N1CC[CH2:24][CH2:23]1>CN(C=O)C>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH:1]=[CH:19][N:17]3[CH2:16][CH2:24][CH2:23][CH2:18]3)[O:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2o1
Reactant: COC(OC)N(C)C
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2nc(C=CN3CCCC3)oc2c1

Procedure:
A solution of 2-methyl-6-nitro-benzoxazole (30 mmol), dimethyl formamide dimethyl acetal (60 mmol) and pyrrolidine (60 mmol) in DMF (45 mL) is stirred at 100° C. for 16 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (Na2SO4) and filtered. The filtrate is concentrated. The residue is washed with cooled EtOAc to afford 6-nitro-2-(2-pyrrolidin-1-yl-vinyl)-benzooxazole as a solid. 1H NMR (300 MHz, CDCl3): δ 1.80-2.25 (broad, 4H), 3.10-3.80 (broad, 4H), 5.06 (d, H), 7.44 (d, H), 7.96 (d, H), 8.21 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I.O>CN(C=O)C.C(OCC)(=O)C>[Cl:14][CH2:15][CH2:16][CH2:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccccc1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(CCCCl)c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of methyl phenylacetate (2.0 g) in DMF (5 mL) was added to a solution of sodium hydride (containing mineral oil at 40%, 590 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (2.99 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product of methyl 5-chloro-2-phenylpentanoate. Hydrazine monohydrate (8 mL) was added to a solution of the resulting crude methyl 5-chloro-2-phenylpentanoate (3.279 g) in ethanol (20 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 730 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[NH:9][C:10]=1[CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:5])C.C[O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=1>>[C:13]12([CH2:12][CH2:11][C:10]3[NH:9][C:8]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[N:7][C:6]=3[C:4]([NH:40][C:36]3[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=3)[C:33]([OH:41])=[O:32])=[O:5])[CH2:22][CH:17]3[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]3)[CH2:20]1)[CH2:14]2
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cccc(N)c1
Product: O=C(O)c1cccc(NC(=O)c2nc(-c3ccc(Cl)c(Cl)c3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-Adamantan-1-yl-2,3-dioxo-pentanoic acid ethyl ester monohydrate (Example 44) was reacted with 3,4-dichlorobenzaldehyde according to the procedure of Example 20, step b to produce 5-(2-adamantan-1-yl-ethyl)-2-(3,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester. The ester was hydrolyzed according to the procedure of Example 20, step c and the resulting 5-(2-adamantan-1-yl-ethyl)-2-(3,4-dichloro-phenyl)-1-H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid methyl ester using essentially the same procedure as in Example 52, step a. Deprotection was carried out following essentially the procedure of Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.89 (2H, br s), 9.90 (1H, s), 8.50 (1H, s), 8.32 (1H, s), 8.03 (2H, m), 7.76 (1H, d), 7.63 (1H, d), 7.43 (1H, t), 2.98 (2H, m), 1.97 (3H, s), 1.70-1.39 (14H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 56.90; H, 6.44; N, 7.08%; C36H46Cl2N4O8.1.6 H2O requires: C, 56.72; H, 6.50; N, 7.35%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[F:49][C:50]1[CH:76]=[C:75]([F:77])[CH:74]=[CH:73][C:51]=1[O:52][CH:53]1[CH2:58][CH2:57][N:56]([C:59]2[N:60]=[C:61]3[CH2:72][CH2:71][NH:70][CH2:69][C:62]3=[N:63][C:64]=2[NH:65][CH:66]([CH3:68])[CH3:67])[CH2:55][CH2:54]1>CC(N(C)C)=O>[F:49][C:50]1[CH:76]=[C:75]([F:77])[CH:74]=[CH:73][C:51]=1[O:52][CH:53]1[CH2:54][CH2:55][N:56]([C:59]2[N:60]=[C:61]3[CH2:72][CH2:71][N:70]([C:6]([CH:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[O:8])[CH2:69][C:62]3=[N:63][C:64]=2[NH:65][CH:66]([CH3:68])[CH3:67])[CH2:57][CH2:58]1
Reactant: O=C(O)C1CCCO1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)C1CCCO1)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of tetrahydrofuran-2-carboxylic acid (10.9 μL, 0.113 mmol) in DMA (0.35 mL) at room temperature was added DIPEA (39.5 μL, 0.226 mmol), followed by HATU (43.0 mg, 0.113 mmol). After stirring for 5 min, the reaction mixture was treated with a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (39.0 mg, 0.075 mmol) in DMA (0.4 mL). The reaction mixture was stirred at 60° C. for 30 min. The reaction mixture was allowed to cool to room temperature and was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (16.0 mg, 34.5%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (m, 6H), 1.97 (m, 4H), 2.16 (m, 4H) 2.82 (m, 2H), 3.10 (m, 2H), 3.45 (m, 2H), 3.89 (m, 4H), 4.14 (m, 1H), 4.44-4.87 (m, 4H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 502.6.
Reaction SMILES: I[CH:2]1[C:7](=[O:8])[N:6]([CH3:9])[C@H:5]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C@@H:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3]1.[F:26][C:27]([F:38])([F:37])[C:28]([NH:30][C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1)=O.C([N:42](CC)C(C)C)(C)C>CN(C=O)C>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C@@H:5]1[C@@H:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3][C@@H:2]([N:35]2[CH2:34][CH2:33][N:32]3[N:42]=[C:28]([C:27]([F:38])([F:37])[F:26])[N:30]=[C:31]3[CH2:36]2)[C:7](=[O:8])[N:6]1[CH3:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1cnccn1)C(F)(F)F
Reactant: CN1C(=O)C(I)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: CN(C)C=O
Product: CN1C(=O)[C@H](N2CCn3nc(C(F)(F)F)nc3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Temperature: 47 °C

Procedure:
tert-Butyl [(2R,3S)-5-iodo-2-(2,5-difluorophenyl)-1-methyl-6-oxopiperidin-3-yl]carbamate (560 mg, 1.201 mmol) was dissolved in DMF (5 mL) at room temperature. 2,2,2-Trifluoro-N-pyrazin-2-ylacetamide (300 mg, 1.561 mmol) was added, followed by N,N-diisopropylethylamine (0.420 mL, 2.402 mmol). The reaction was heated at 47° C. for 4.5 h. The DMF was removed by evaporation under reduced pressure, the residue was purified by column chromatography on silica gel Biotage 25M™, eluting with CH2Cl2/MeOH/aqueous NH3 (gradient from 4% to 8%) to give the title compound. LC-MS: 474.83 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH2:20][S:21]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=[O:23])=[O:22])[C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12](O)=[O:13])=[O:9])=[O:4].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(P(=O)(OCC)OCC)#N.Cl>CN(C)C=O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[S:21]([CH2:20][CH:7]([C:8](=[O:9])[N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:13])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])(=[O:22])=[O:23]
Reactant: CCCCCN(CC(=O)O)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Reactant: C1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCN(CC(=O)N1CCCCC1)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C

Procedure:
To a solution of N-[2-(2-methoxycarbonylethyl)-3-(2-naphthylsulfonyl)propionyl]-N-pentylglycine (0.30 g), piperidine (0.12 ml) in N,N-dimethylformamide (5 ml) was added diethyl cyanophosphonate (0.1 ml) with stirring at 0° C. After stirring at room temperature for 16 hours, a dilute hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and evaporated at reduced pressure. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (20:1) to give 0.18 g of methyl 5-(2-naphthylsulfonyl)-4-(N-pentyl-N-piperidinocarbonylmethylcarbamoyl)pentanoate as oil. ##STR26##
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.C(C(NC(=O)[C@H](N1C=CC(C2C=CC([C:96]3[CH:101]=[CH:100][C:99]([C:102](=[O:104])[NH2:103])=[CH:98][CH:97]=3)=CC=2)=C1)CC(O)=O)CO)C1C=CC=CC=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:96]3[CH:101]=[CH:100][C:99]([C:102](=[O:104])[NH2:103])=[CH:98][CH:97]=3)=[CH:33][CH:34]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(C)(C)C
Yield: 55 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinarnic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl ester was deprotected. The crude amine salt and crude 3-(4′-carboxamidobiphenyl-4-yl)-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 4(b)) were condensed in wet 1,2-dichloroethane at 90-100° C. to yield 180 mg (55%) of 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester. 1H NMR: δ 7.90 (d, 2H, J=8.4Hz), 7.70 (d, 2H, J=8.7 Hz), 7.60 (dd, 3H, J=8.7, 11.5 Hz), 7.38-7.22 (m, 8H), 7.10 (t, 1H, J=2.2 Hz), 6.82 (t, 1H, J=2.5 Hz), 6.62 (t, 1H, J=3.0 Hz), 6.32 (d, 1H, J=9.0Hz), 5.63 (d, 1H, J=4.70 Hz), 5.14 (d, 3H, J=3.7 Hz), 4.00 (d, 1H, J=8.7 Hz), 3.48 (dd, 1H, J=7.2, 13.1 Hz), 3.39 (d, 1H, J=5.9 Hz), 3.14 (dd, 1H, J=8.7, 16.8 Hz), 2.78 (d, 3H, J=4.7 Hz), 0.92 (s, 9H). IR (KBr): 3356, 2929, 1735, 1657, 1402 cm−1. Anal. Calculated for C35H39N4O5•0.5 H2O: C, 69.63; H, 6.51; N, 9.28. Found: C, 69.85, H, 6.46; N, 9.14.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)(=O)C>[O:26]=[C:24]([NH:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1)[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Temperature: 23 °C

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (50 mg, 0.164 mmol) and acetic anhydride (0.5 mL) were warmed to 60° C. for 1 h. After cooling to 23° C., the reaction was diluted with ethyl acetate (50 mL), washed with NaOH (1N, 50 mL), and dried (Na2SO4). Concentration in vacuc afforded 6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (57): Mass Spectrum (CI) 347 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([F:16])[CH:8]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:12])=[C:9]([F:16])[CH:8]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
A solution of 4-(4-chloro-3-(trifluoromethyl)phenoxy)-2-fluorobenzoic acid (Preparation 44, 400 mg, 1.19 mmol), DMAP (365 mg, 2.97 mmol, 2.5 eq), diisopropylethylamine (0.7 mL, 2.97 mmol) and EDCl (700 mg, 2.97 mmol) in dichloromethane (10 mL) was allowed to stir for 10 minutes at room temperature under nitrogen. Methane sulphonamide (400 mg, 3.57 mmol) was added in one portion and the reaction mixture left to stir for 16 hours. The reaction was quenched with 6N HCl (20 mL) and the organic layer removed. The DCM layer was extracted into 1N NaOH (30 mL) and the organic layer discarded. The aqueous phase was adjusted to pH 5 using acetic acid and extracted into ethyl acetate (2×30 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the title compound as a white solid (168 mg, 34%).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]([F:9])[CH:8]=1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][NH2:28])[CH:22]=1.ClC1C=C(N2C(C3C=C(OC(F)(F)F)C=C(F)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[N:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[N:28]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(Cl)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1

Procedure:
807 mg (2.90 mmol) of the compound from example 7A is reacted with 464 mg (3.19 mmol) 3-pyridylhydrazine hydrochloride in a manner analogous to the synthesis of the compound from example 8A. Following hydrolysis, 353 mg (38% of theoretical yield) of the title compound is produced.