Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](Cl)=[O:14])[N:12]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([N:25]([O:26][CH3:27])[CH3:24])=[O:14])[N:12]=1
Reactant: CNOC
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride (4.71 g, 13.4 mmol, prepared by the method described in Example 13, step 1) in 10 mL dichloromethane was added to a solution of N,O-dimethylhydroxyamine hydrochloride (1.44 g, 14.7 mmol) and triethylamine (5.6 mL, 40.2 mmol) in 60 mL dichloromethane in an ice water bath under argon with stirring. The bath was removed upon completion of addition. Stirring was continued for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated down under reduced pressure. The crude product was purified on silica gel, eluting with ethyl acetate to yield 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N-methyl-1H-imidazole-4-carboxamide as an off-white solid (4.20 g, 83%): Rf=0.22 (ethyl acetate).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15]Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[C:17]([NH:25][CH:26]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:27][P:28]([CH2:31][C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])=[O:33])([OH:30])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C>[C:17]([NH:25][CH:26]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:27][P:28]([CH2:31][C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:33])([O:30][CH2:15][O:14][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:29])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC(Cc1ccccc1)CP(=O)(O)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)CC(Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
An equimolar mixture of triethylamine and chloromethyl pivalate are added to a solution of (S)-1-[[[2-(benzoylamino)-3-phenylpropyl]hydroxyphosphinyl]acetyl]-L-proline, phenylmethyl ester, prepared, for example, as set forth in Example 1(g), in dimethylformamide under argon. The mixture is stirred for several hours at room temperature, diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. Thecrude product is chromatographed to give (S)-1-[[[2-(benzoylamino)-3-phenylpropyl][(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]acetyl]-L-proline, phenylmethyl ester.
Reaction SMILES: ClC1C=C2NC(=O)C3(C(CC(C)(C)C)[CH2:14][C:13](=[O:21])[NH:12][CH:11]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)C2=CC=1.C(OC([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([Cl:44])[CH:42]=2)/[C:37](=[CH:45]/[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)/[C:36]1=[O:52])=O)C.CO.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:44][C:41]1[CH:42]=[C:43]2[NH:35][C:36](=[O:52])[C:37]3([CH:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:14][C:13](=[O:21])[NH:12][CH:11]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:38]2=[CH:39][CH:40]=1
Reactant: CC(C)(C)CC1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCOC(=O)N1C(=O)/C(=C\c2ccccc2)c2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1CC(c2ccccc2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1c in toluene (30 mL) was added E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in Example 12b (0.4 g, 1.22 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 1 h. After the solution was cooled to room temperature, methanol (40 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in methanol (30 mL) and 1N of NaOH solution (5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h, then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:4) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow oil (Yield 0.5 g, 100%).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@@H:18]([CH3:42])[C:19](=[O:41])[NH:20][C@@H:21]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[C:22](=[O:32])[NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][C@@H:18]([CH3:42])[C:19]([NH:20][C@@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:22]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:32])=[O:41]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of material from Example 99 (577 mg, 0.579 mmol) in anhydrous DMF (4 mL) is added piperidine (1 mL, 10.1 mmol). The resulting solution is stirred at room temp for 20 min, then the solvent is removed in vacuo. The resulting solid is evaporated sequentially from ethyl acetate, 1,2-dichloroethane and dichloromethane and dried under high vacuum for several hours to give the title compound as a white solid in quantitative yield that contains 1 equivalent of 1-((9H-fluoren-9-yl)methyl)piperidine as a side product. LC/MS (Condition A): ret. T=4.05 min, (M+H)+ 366.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33]>[Cl-].[Na+].O.CN(C=O)C>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:36][CH2:35]1)[CH3:33]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CCN1CCNCC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To a DMF solution (10 ml) of 3-nitro-benzoic acid (334 mg) and N-ethyldiisopropylamine (1 ml), HOBt (270 mg) and WSCI (575 mg) were added, followed by stirring at room temperature for 10 minutes. To this, 1-ethyl-piperazine (305 μl) was added, followed by stirring at room temperature for 22 hours. Brine (30 ml) was added, followed by extraction with ethyl acetate (30 ml×2), and the organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 20/1), to obtain the desired compound (365.3 mg, 69%).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#N)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:33].[Na+].[OH2:35]>>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([OH:35])=[O:33])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [Na+]
Product: O=C(O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carbonitrile (176 g, 0.415 moles) (Preparation 13) in industrial methylated spirits (770 ml) was added a solution of sodium hydroxide (33.3 g, 0.83 moles) in deionised water (110 ml). The resultant slurry was heated under reflux for 2.5 hours during which time a clear solution formed. The mixture was allowed to cool to ambient temperature over 16 hours which resulted in the formation of a precipitate. Water (200 ml) was then added, and the mixture was distilled at atmospheric pressure. Over the course of the distillation, water (500 ml) was added periodically to the mixture, and a total of 720 ml of distillate was collected. The resultant mixture was allowed to cool slowly to ambient temperature with stirring and a thick precipitate formed. The slurry was cooled in an ice-bath, and the solid was collected by filtration. The filter cake was washed with a solution of deionised water (225 ml) and industrial methylated spirits (25 ml). The damp filter cake was suspended in a mixture of deionised water (965 ml) and dichloromethane (965 ml) and the pH of the mixture was adjusted to pH 1.2 by the addition of concentrated hydrochloric acid. The phases were separated and the aqueous layer was extracted with dichloromethane (300 ml). The organic phases were combined and the solvent was distilled at atmospheric pressure until 750 ml of distillate had collected. Ethyl acetate (1100 ml) was added and distillation was continued until a further 750 ml of distillate had collected and an off-white precipitate had formed. The resulting slurry was allowed to cool to ambient temperature and was further cooled in an ice-bath. The solid was collected by filtration and the filter cake was washed with chilled ethyl acetate (2×350 ml). The resultant solid was dried in an oven at 70° C. under reduced pressure to give the title compound as an off-white solid (163 g), m.p. 155° C. (with decomposition).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13]1>N1C=CC=CC=1.ClCCl.CCOCC>[CH:12]1([CH2:15][CH2:16][O:17][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14][CH2:13]1
Reactant: OCCC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
p-Toluenesulfonyl chloride (7.20 g, 37.8 mmol) was added to a cooled (0° C.) solution of 2-cyclopropylethanol (4.00 g, 46.4 mmol) in pyridine (10 mL) and dichloromethane (60 mL). The reaction mixture was stirred at room temperature overnight, then diluted with ether (200 mL) and washed sequentially with water, 10% HCl, water and brine and then dried over anhydrous Na2SO4. Toluene-4-sulfonic acid 2-cyclopropylethyl ester (8.1 g, 89%) was obtained after removal of solvent and used for next step reaction without further purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1)=[O:10])#[CH:2].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:15]1[CH:14]=[CH:13][C:12]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:11]([C:9]([N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[C:1]#[C:2][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])[CH:16]=1
Reactant: Brc1ccccc1
Reactant: C#CC1CCCCN1C(=O)c1cc(C)ccc1-n1nccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCCCC2C#Cc2ccccc2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of (2-ethynylpiperidin-1-yl)[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (25 mg, 0.085 mmol), bromobenzene (25 mg, 0.15 mmol), CuI (4.9 mg, 0.025 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF (0.5 mL) was purged subsurface with nitrogen. Palladium tetrakis (9.8 mg, 0.0085 mmol) was added and the reaction was heated at 90° C. overnight. The reaction was stirred over excess Quadrapure TU overnight, then filtered and dried. The residue was subjected to purification via reverse phase HPLC to provide the title compound which gave a high resolution mass spectrum (ES+) m/z of 371.1872, calculated for M+H+ [C23H22N4O: 371.1866].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=1[CH3:24].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:21]3[N:20]=[N:19][C:18]([Cl:17])=[C:23]([CH3:24])[C:22]=3[CH3:25])[CH2:15][CH2:16]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNCC2)cn1
Reactant: Cc1c(Cl)nnc(Cl)c1C
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)cn1
Temperature: 190 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To the solution of 3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (250 mg, 1.07 mmol) in NMP (5 mL) is added 3,6-dichloro-4,5-dimethyl-pyridazine (237 mg, 1.33 mmol) and TEA (446 μl, 3.21 mmol), the reaction mixture is stirred at 190° C. for 60 min. Water is added to the mixture and extracted with EtOAc. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by HPLC, (acetonitrile/water: 10%˜95% with 3% 1-propanol) to give white powder (165 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:36][CH2:37][C:38]1[N:42]([C:43]2[S:44][C:45]([CH2:57][CH3:58])=[CH:46][C:47]=2[C:48](=[O:56])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])[C:41]([CH3:59])=[N:40][N:39]=1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:48]([C:47]1[CH:46]=[C:45]([CH2:57][CH3:58])[S:44][C:43]=1[N:42]1[C:41]([CH3:59])=[N:40][N:39]=[C:38]1[CH2:37][NH:36][C:11]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:13])=[O:56]
Reactant: Cc1c(C(=O)O)[nH]c2ccccc12
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2[nH]c3ccccc3c2C)s1
Reaction time: 6 h
Yield: 14.9 %

Procedure:
3-Methylindole-2-carboxylic acid (0.5 g) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (2.1 g) was dissolved in DMF (42 ml). Triethylamine (1.6 ml) and Bop reagent (1.32 g) were added under ice-cooling, and the mixture was stirred for 6 hours. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous citric acid solution, saturated brine, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as an eluent and recrystallized from a mixed solvent of ethyl acetate and hexane to give 0.22 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-yl-methyl)-3-methyl-1H-indole-2-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:12]([NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)Nc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 6-aminoisoquinoline in DMF is added DMAP and benzyl isocyanate and the solution was stirred at room temperature for 4 hours. The mixture was poured into NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, 5% MeOH/CH2Cl2) provided 1-benzyl-3-(isoquinolin-6-yl)urea (E88).
Reaction SMILES: C([O:3][C:4](=[CH:8][C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:11][CH2:10]1)[C:5]([OH:7])=[O:6])C.C(O)(=O)C.O>S(=O)(=O)(O)O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1([CH2:8][C:4](=[O:3])[C:5]([OH:7])=[O:6])[CH2:11][CH2:10]1
Reactant: CCOC(=CC1(c2ccccc2Cl)CC1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C(=O)CC1(c2ccccc2Cl)CC1
Yield: 106.8 %

Procedure:
11.2 g of 2-ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acid is stirred in 230 ml of 1 M sulfuric acid and 42 ml of concentrated acetic acid for 24 hours at 110° C. Water is added, it is extracted with ethyl acetate, and ethyl acetate solution is washed with water. After drying (Na2SO4) and concentration by evaporation, 10.7 g of the product is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:18][N:19]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:7]=[C:6]([CH2:8][N:9]3[C:13]([CH3:14])=[N:12][C:11]([C:15]4[O:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=5)=[CH:18][N:19]=4)=[N:10]3)[CH:5]=[CH:4][N:3]=2)[CH2:34][CH2:33]1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1ccnc(Cl)c1
Solvent: CS(C)=O
Product: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)oxazole (60 mg, 0.14 mmol) and 1-methyl-piperazine (1 mL) in DMSO (2 mL) was stirred at 140° C. for 16 h under Ar atmosphere. The mixture was then cooled to RT, and purified by prep-HPLC (Mobile phase: A=0.1% TFA/H2O, B=MeCN; Gradient: B=5%-95% in 8 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to afford the title compound a solid. MS (ES+) C24H24F3N7O2 requires: 499. found: 500 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J=5.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 2H), 7.51 (s, 1H), 7.29 (d, J=9.0 Hz, 2H), 6.48 (d, J=5.0 Hz, 1H), 6.38 (s, 1H), 5.32 (s, 2H), 3.62 (m, 4H), 2.67 (m, 4H), 2.50 (s, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[CH2:20][O:19]2)=[C:13]([Cl:26])[CH:12]=1.O>C(O)C>[Cl:26][C:13]1[CH2:12][C:11](=[N:10][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH:16]=[CH:15][C:14]=1[CH2:17][N:18]1[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[CH2:20][O:19]1
Reactant: O=Cc1ccccc1O
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: O
Solvent: CCO
Product: CC1(C)CON(CC2=C(Cl)CC(=NCc3ccccc3O)C=C2)C1=O

Procedure:
A warmed solution of 0.48 gram (0.004 mole) of salicylaldehyde in 35 mL of ethanol was stirred, and 1.0 gram (0.004 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone was added in one portion. The reaction mixture was heated an additional 30 minutes and then 15 mL of water was added. The mixture was filtered, and the filtrate was cooled. The resultant oily suspension solidified when abraded. The solid was collected by filtration to yield, when dried, 0.87 gram of 2-[[2-chloro-4-[(2-hydroxyphenyl)methylimino]phenyl]-methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 105°-107° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[O:11][C:6]2=[CH:5][CH:4]=1.CCN(CC)CC.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC#N>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][C:3]2[N:8]=[C:7]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=4)[O:11][C:6]3=[CH:5][CH:4]=2)[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(-c2nc3nc(CBr)ccc3o2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3oc(-c4cccc([N+](=O)[O-])c4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Bromomethyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine (250 mg, 0.75 mmol) was dissolved in 5 mL of CH3CN along with Et3N (0.200 mL, 1.5 mmol) and 140 mg of Boc-piperazine. The reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and the resulting residue was mixed with 25 mL of CH2Cl2 and washed with brine. The organic layer was dried (Na2SO4) and concentrated to afford essentially quantitative yield of 4-[2-(3-nitro-phenyl)-oxazolo [4,5-b]pyridin-5-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[CH3:26]I.O>C1COCC1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CI
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Yield: 101 %

Procedure:
23.3 mL of lithium bis(trimethylsilyl)amide (1.0 M, 23 mmols) was added dropwise to 4.75 g (23 mmol) of methyl 4-tert-butylphenylacetate in 100 mL of dry THF at −78° C. while stirring under nitrogen. The mixture was stirred at this temperature for 45 minutes, then 1.5 mL (24 mmol) methyl iodide was added dropwise and the solution was stirred for an additional 1 hour at −78° C. The mixture was poured into 200 mL of H2O and the desired product was extracted with 500 mL diethyl ether. The organic layer was backwashed once with 500 mL H2O, dried over K2CO3, and concentrated under reduced pressure to yield 5.12 g of a dark oil. The oil was purified via silica gel chromatography eluting with a solvent gradient of hexanes to hexanes/ethyl acetate 19:1. The fractions containing the desired product were combined and concentrated under reduced pressure to yield the title compound 2.65 g (53%).
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:6]2[C:5]1=[O:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:20]
Reactant: CC(C)(O)CN1CC2CN(C(=O)OC(C)(C)C)CCN2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)CN1CC2CNCCN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2-hydroxy-2-methyl-propyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (compound 106-C-1) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. After the reaction mixture was stirred at rt for 1 hour, the solvent was removed in vacuum to give the crude product 106-C, which was used directly in the next step.