Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[NH:16][C@@H:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC(OC2C=CC(NC(=S)N[C@@H](CC3C=CC=CC=3)C(NCCN3CCCC3)=O)=CC=2)=CC=1.Cl.O1CCOCC1.O(C1C=CC(N=C=O)=CC=1)C1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[CH2:28]([C@H:17]([NH:16][C:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[O:35])[CH2:18][NH:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCN1CCCC1
Agent: Cl
Agent: O=C(NCCN1CCCC1)[C@H](Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)N[C@H](CNCCN1CCCC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
(S)-2-[3-(4-Phenoxy-phenyl)-ureido]-3-phenyl-N-(2-pyrrolidin-1-yl-ethyl)-propionamide. To a solution of [(S)-2-phenyl-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (Example 9, step A) (0.1 g, 0.28 mmol) in CH2Cl2 (3 mL), a 4 M solution of HCl in dioxane (2.5 mL, 10 mmol) was added, and the mixture was stirred for 4 h at rt. The solvents were removed, and the residue was treated with CH2Cl2. The solvents were removed again under reduced pressure. The residue was dissolved in CH2Cl2 (3 mL), and TEA (0.07 g, 0.69 mmol) was added at 0° C. followed by 4-phenoxyphenylisocyanate (0.07 g, 0.33 mmol). The mixture was warmed to rt over a period of 4 h and then diluted with EtOAc (75 mL). The organic layer was washed with saturated NaHCO3 (25 mL) and brine (25 mL), and dried (Na2SO4). The solvent was removed, and the residue was purified by flash column chromatography using 0–20% MeOH (1% NH4OH)/CH2Cl2 to afford 0.03 g (25%) of the desired product. MS (electrospray): mass calculated for C28H32N4O3, 472.25; m/z found, 473.2 [M+H]+, 495.2 [M+Na]+. 1H NMR (400 MHz, DMSO-d6): 8.68 (s, 1H), 8.04 (t, J=5.5 Hz, 1H), 7.36–6.89 (m, 14H), 6.30 (d, J=8.3 Hz, 1H), 4.46 (m, 1H), 3.15 (m, 2H), 2.96 (dd, J=13.6, 5.6 Hz, 1H), 2.82 (dd, J=13.6, 7.7 Hz, 1H), 2.42–2.37 (m, 6H), 1.67–1.63 (m, 4H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:19]=[CH:18][C:17](N2C=CC=CC2=O)=[CH:16][CH:15]=1.[C:29]([O-:32])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:5]=[CH:4][C:3]([C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:27])[F:28])=[CH:19][CH:18]=3)=[CH:2][C:29]2=[O:32])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Reactant: O=c1ccccn1-c1ccc(C(F)(F)F)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 106.9 %

Procedure:
To a solution of 5-fluoro-2-nitrotoluene (0.27 g, 2.25 mmol) in DMF (4.0 mL) was added 4-(4-(trifluoromethyl)phenyl-pyridin-2(1H)-one (0.45 g, 1.87 mmol) and Cs2CO3 (0.67 g, 2.1 mmol), and the reaction was heated to 85° C. for 18 h. The reaction mixture was cooled, H2O (20 mL) was added, and the mixture was stirred for 20 min. The resulting solids were collected by filtration and washed with H2O (10 mL). Flash chromatography (silica gel, hexanes/EtOAc, 10:1 to 3:1) yielded the title compound (0.45 g, 65%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.33 (d, J=5.4 Hz, 1H), 8.12-7.89 (m, 5H), 7.65-7.60 (m, 2H), 7.33-7.22 (m, 2H), 2.55 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].[ClH:31]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CCOC(C)=O.CO.CCOC(C)=O>[ClH:31].[C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of phenyl (4-piperidinyl)methanone (18.1 g, 0.096 mol) was dissolved in toluene (200 ml) containing 1-bromo-3-phenylpropane (21.9 g, 0.11 mol, 16.7 ml), K2CO3 (30.4 g, 0.22 mol) and KI (0.2 g ) and was refluxed for 64 h. The reaction mixture was filtered and concentrated to give a light yellow oil. This material was dissolved in toluene/EtOAc (1:1) and treated with HCl 0.096 mol) dissolved in CH3OH/EtOAc (2:5, 35 ml) to give a precipitate which was filtered off and recrystallized twice from EtOH/Et2O (150 ml) to give phenyl[1-(3-phenylpropyl)-4-piperidinyl]-methanone hydrochloride, mp 199°-200° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.C(O[CH2:18][CH3:19])C.[Cl:20][Si:21]([Cl:24])(Cl)Cl>C1(C)C=CC=CC=1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([Si:21]([C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:18][CH3:19])=[CH:5][CH:4]=2)([Cl:24])[Cl:20])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCc1ccc(Br)cc1
Reactant: CCOCC
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc([Si](Cl)(Cl)c2ccc(CCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 3 L-volume four-necked flask equipped with a Dimroth condenser, a dropping funnel and a stirrer was charged with magnesium (15.7 g, 0.645 moles, in a flaky state), and the inside of the flask was purged with nitrogen. Diethyl ether (200 mL) was poured while keeping the inside of the flask at a positive pressure, and one piece of iodine was added while stirring. Furthermore, 1-bromo-4-hexylbenzene (160.9 g, 0.665 moles) and diethyl ether (500 mL) were charged into the dropping funnel while keeping the inside of the flask at a positive pressure. When the flask was heated, and refluxing started, the diethyl ether solution of 1-bromo-4-hexylbenzene was dropped from the dropping funnel under mild refluxing over about 4.5 hours, and the mixture was stirred for one hour as it was. After finishing stirring under heating, the reaction solution was cooled to room temperature and diluted with toluene. Tetrachlorosilane (44.6 g, 0.263 moles) and toluene (200 mL) were charged into the dropping funnel while keeping the inside of the flask at a positive pressure and dropped at room temperature over about 30 minutes. After completion of the dropping, stirring of the reaction solution was continued at room temperature overnight. A formed crystal of magnesium bromide was filtered, and the obtained filtrate was concentrated. The concentrated liquid was distilled in vacuo to obtain bis(4-hexylphenyl)dichlorosilane as a major distillate. This compound was confirmed to be the desired silane compound (aromatic monomer (B2) from chemical shift, branching and integration values of signals obtained by the 1HNMR measurement. In the following polymerization reaction, a purified material obtained by vacuum distillation of this major distillate just before that was provided. Also, all of the solvents to be used were dried by a molecular sieve and then used.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH:15]=[CH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH:15]=[CH2:16])=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: C=CCC(N)c1ccccc1N1CCCCC1
Product: C=CCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 47 from 1-(2-piperidino-phenyl)-3-buten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.Cl.[CH:12](OC)(OC)OC>CO>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:12])=[O:9])[N:4]=[CH:3]1
Reactant: COC(OC)OC
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1c[nH]cn1
Reaction time: 18 h

Procedure:
A solution of 4-imidazoleacetic acid hydrochloride (4.00 g, 24.6 mmol) in MeOH (100 mL) was saturated with HCl (g). Trimethyl orthoformate (10 mL, 91 mmol) was added and the mixture was stood at ambient temperature for 18 hours, then concentrated to dryness in vacuo to afford the titled ester as a white solid.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CBr)[CH:20]([C:36]1[CH:41]=[CH:40][C:39]([O:42]C)=[CH:38][CH:37]=1)[CH2:19]2>CN(C)C=O.O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:3][CH2:2][C:1]([OH:9])=[O:8])[CH:20]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[CH2:19]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C2Cc3cc(OC)ccc3C2CCCCCCCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC(c1ccc(O)cc1)C2CCCCCCCCCCCC(=O)O
Temperature: 50 °C

Procedure:
A solution of diethyl malonate (0.64 g.) in dimethylformamide (10 ml.) was added to a stirred suspension of sodium hydride (0.14 g. of a 50% suspension in mineral oil) in dimethylformamide (10 ml.) which was maintained under an atmosphere of argon, and the mixture was stirred and heated to 50° C. for 5 minutes and then cooled to laboratory temperature. 10-[(1RS, 2RS)-5-Methoxy-2-p-methoxyphenylindan-1-yl]decyl bromide (1.2 g.) was added and the mixture was stirred at laboratory temperature for 16 hours and then diluted with water and extracted with diethyl ether. The extract was dried and evaporated to dryness and a solution of the residue (1.47 g.) in ethanol (10 ml.) was added dropwise to a stirred solution of potassium hydroxide (1.4 g.) in water (10 ml.) which was heated under reflux. The mixture was stirred and heated under reflux for 10 minutes, diluted with water and extracted with diethyl ether. The aqueous solution was acidified with concentrated aqueous hydrochloric acid and extracted with diethyl ether, and the extract was dried and evaporated to dryness. There was thus obtained as residue 12-[(1RS, 2RS)-5-methoxy-2-p-hydroxyphenylindan-1-yl]dodecanoic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
To a solution of 1H-indole-3-carbaldehyde (25.0g, 172 mmol) in tetrahydrofuran (500 mL) cooled to 0° C. with an ice-bath and under an inert atmosphere was slowly added sodium hydride (4.96 g, 207 mmol), such that the temperature of the mixture remained less that 5° C. After complete addition, the mixture was allowed to stir at 0° C. for 15 minutes. To the mixture was added benzyl bromide (35.4 g, 207 mmol). The ice bath was removed and the mixture was allowed to warm to room temperature over 1.5 hours. The mixture was then partitioned between brine and ethyl acetate. The layers were separated and the aqueous layer was extracted with two additional portions of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting red solids were dissolved in methylene chloride and the solution was filtered through a plug of silica gel. The filtrate was concentrated under reduced pressure until a precipitate began to form. The product was crystallized out of the solution by the addition of an eight-fold volume of hexane. The red-tinted solid was isolated by vacuum filtration, and the process was repeated one additional time to give 1-benzyl-1H-indole-3-carbaldehyde (38.8 g, 96%) as an off-white powder. 1H NMR (400 MHz, CDCl3); δ 9.98 (s, 1H), 8.32 (m, 1H), 7.71 (s, 1H), 7.34 (m, 6H), 7.18 (m, 2H), 5.36 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:35][CH2:36][CH:37]1[CH2:39][CH2:38]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:37]1([CH2:36][N:35]([CH2:32][CH2:33][CH3:34])[C:11](=[O:12])[CH2:10][C:9]2[C:8]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=3[O:6][C:5]=2[C:3](=[O:4])[C:2]([CH3:1])([CH3:20])[CH3:21])[CH2:39][CH2:38]1
Reactant: CCCNCC1CC1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.6 μL N-propylcyclopropanemethylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 60-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.17 min. (m/Z=386.2, 302.1, 408.1).
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].CC(N(C)C)=O.[C:31](Cl)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(=O)(O)[O-].[K+]>N1C=CC=CC=1>[C:31]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[C:22]3[N:23]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[NH:8][C:9](=[O:24])[C:10]=3[N:11]=[CH:12]2)[CH2:15][C@@H:16]1[OH:17])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an oven-dried 100 mL round-bottomed flask containing a stir bar was added N2-isobutyryl-2′-deoxyguanosine (0.75 g, 1 eq.). The flask was fitted with a septum and dry dimethylacetamide (DMA, 32 mL) and dry pyridine (16 mL) were added via cannula, with swirling and stirring. The flask was purged with argon gas, the slurry was allowed to cool 10 min. in an ice bath, and palmitoyl chloride (2.5 eq.) was added dropwise over 5 min. The mixture was allowed to stir while it slowly warmed to 25° C. After 24 h, the mixture was poured into 200 mL of 0.5 M potassium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×30 mL H2O, air dried, and finally dried under high vacuum giving a white powder. This crude product was purified by flash chromatography (silica gel bed, eluted with chloroform-methanol) giving a white powder. 1H-NMR and elemental analysis data were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[OH:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[OH:36][C@H:37]1[CH2:41][CH2:40][N:39]([C:30](=[O:32])[CH:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:24][CH:25]=2)[CH3:33])[CH2:38]1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: O[C@H]1CCNC1
Product: CC(C(=O)N1CC[C@H](O)C1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and (S)-3-hydroxypyrrolidine. LCMS (M+H)+: m/z=553.3
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:12]([C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:15])[NH2:13].C(OC(OCC)OCC)C>O>[O:15]1[CH:1]=[N:13][N:12]=[C:14]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1ccc(C(=O)O)cc1
Solvent: O
Solvent: CCOC(OCC)OCC
Product: O=C(O)c1ccc(-c2nnco2)cc1
Temperature: 100 °C
Yield: 379.7 %

Procedure:
Hydrazine hydrate was added to a solution of terephthalic acid monomethyl ester (1 g, 5.5 mmol) in MeOH (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated to afford 900 mg (90.09% Yield) of 4-hydrazinocarbonyl-benzoic acid. p-Toluene sulfonic acid (48 mg, 0.277 mmol) was added to a solution of 4-hydrazinocarbonyl-benzoic acid (500 mg, 2.77 mmol) in triethylorthoformate (7.5 mL, 44.0 mmol) and stirring was continued with heating at 100° C. for 3 hrs. The reaction mixture was diluted with water, the solid was collected to afford 200 mg (37.9% Yield) of 4-[1,3,4]oxadiazol-2-yl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[N:17]=[CH:18][C:19]([C:21]4[C:22]([CH3:30])=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=4)=[N:20][C:11]2=3)[CH2:5][CH2:4]1.C(O[CH:37](OCC(C)(C)C)[N:38]([CH3:40])[CH3:39])C(C)(C)C>O1CCCC1>[CH3:37][N:38](/[CH:40]=[N:29]\[C:27](=[O:28])[C:24]1[CH:23]=[C:22]([CH3:30])[C:21]([C:19]2[CH:18]=[N:17][C:12]3[NH:13][CH2:14][C:15](=[O:16])[N:10]([CH2:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([O:2][CH3:1])[CH2:4][CH2:5]4)[C:11]=3[N:20]=2)=[CH:26][N:25]=1)[CH3:39]
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(=O)/N=C\N(C)C)cc4C)nc32)CC1
Temperature: 85 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide (0.412 g, 1.00 mmol), dimethylformamide dineopentylacetal (1.5 mL) and tetrahydrofuran (10 mL) were combined and heated at 85° C. for 3 h. Reaction was concentrated under a stream of nitrogen placed in reaction vessel. Crude product was used directly for next step (0.467 g, 1.00 mmol, 100% yield). MS (ESI) m/z 466.6 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.[CH:12]([Mg]Br)=[CH2:13].O.Cl>O1CCCC1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]([OH:10])[CH:12]=[CH2:13])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)c1c(Cl)nc(N)nc1Cl
Yield: 49 %

Procedure:
2-Amino-4,6-dichloropyrimidine-5-carbaldehyde (100 g) was suspended in tetrahydrofuran (4000 ml), and a 1 N solution of vinylmagnesium bromide in tetrahydrofuran (2200 g) was added dropwise under ice-cooling. After completion of the dropwise addition, the mixture was stirred under ice-cooling for two hours. Water (2000 ml) was added to the reaction solution, and the solution was made acidic with a 1 N hydrochloric acid solution (2500 ml), followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, followed by concentration. Methanol was added to the resulting residue, followed by stirring for one hour. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (50 g, 49%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:13][C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=[C:16]([NH2:32])[N:15]=1)(=[O:12])=[O:11].[NH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[NH2:32][C:16]1[N:15]=[C:14]([O:13][S:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])(=[O:12])=[O:11])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=1
Reactant: CCOC(=O)CN
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Product: CCOC(=O)CNCc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1

Procedure:
The sub-title compound was synthesized by the method of example 1 step (vii) from the product of example 1 step (v) (100 mg) and ethyl glycinate. The sub-title compound (23 mg) was obtained as a colourless amorphous solid; 1H NMR (300 MHz, CDCl3); 6.92 (2H, s), 6.84 (1H, s), 6.76-6.70 (2H, m), 4.68 (2H, br s), 4.18 (2H, q), 3.81 (3H, s), 3.79 (2H, s), 3.77 (2H, s), 3.39 (2H, s), 2.56 (6H, s), 2.28 (3H, s), 2.22 (3H, s), 1.26 (3H, t); LC-MS: m/z=543.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([OH:11])=O)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([Cl:15])=[O:11])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC[C@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1CCC[C@H]1C(=O)Cl
Reaction time: 0.08 h

Procedure:
To a solution of (S)-1-isopropylpyrrolidine-2-carboxylic acid (4 g, 23.4 mmol) in dry dichloromethane (40 mL) was added oxalyl chloride (4.4 mL, 46.8 mmol) drop wise under nitrogen at ice bath temperature (0-10° C.). After stirring for 5 min, a drop of dry DMF was added to the reaction mixture and was allowed to stir for 2 h at the same temperature. The volatiles were removed on a rotavapor at reduced pressure and the residue was allowed to stay at high vacuum pump for 1 h to afford (S)-1-isopropylpyrrolidine-2-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:5]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1NS(=O)(=O)c1ccc(OC)cc1
Yield: 96.2 %

Procedure:
To a solution of 0.139 g (0.412 mmol) of the product of Example 31 in 2.0 mL of DMF was added 0.70 g (1.03 mmol) of imidazole and 0.075 g (0.495 mmol) of t-butyldimethylsilyl chloride. The reaction mixture was then srtied at room temperature for 3h and then diluted with 75 mL of ether. The resulting mixture was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 0.179 g (96%) of the desired product as a white solid. Electrospray Mass Spec: 452.2 (M+H)+