Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].S(=O)(=O)(O)O.N([O-])=O.[Na+].[C-:25]#[N:26].[Na+]>O>[C:25]([C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:26]
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Reactant: [C-]#N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(C#N)c(OC)cc1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A 1.00 g portion of methyl 5-amino-2,4-dimethoxybenzoate was dissolved in 5 ml of water, 0.50 ml of concentrated sulfuric acid was added and then 356 mg of sodium nitrite dissolved in 2 ml of water was added dropwise under ice-cooling, followed by a short period of stirring. Separately, 1.00 g of cuprous cyanide was dissolved in 4 ml of water and, with ice-cooling, 2.00 g of sodium cyanide dissolved in 4 ml of water was added dropwise thereto, followed by 1 hour of stirring. This was mixed with the previously prepared solution and heated at 80° C. to effect the reaction, the resulting reaction solution was mixed with water, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and then the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1 to chloroform:methanol=50:1) to give 0.65 g of methyl 5-cyano-2,4-dimethoxybenzoate.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O.Cl>CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1S
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CSc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Thiosalicylic acid 15.419 g(0.1 M) was dissolved in 150 mL of dimethylformamide (DMF) and 41.463 g(0.3M) of K2CO3, was added to the mixture with stirring. To the above solution, 4-methoxybenzyl chloride 15.661 g(0.1M) was added and the mixture was refluxed for 10 hours. The solution then was cooled to room temperature and 150 mL of water was added and the mixture was acidified with 3M HCl. The precipitated material was collected by gravity filtration and washed with acetone to give 27.364 g(99.7%) of white powder with a melting point of 225-227° C. and the following specifications:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([NH2:26])[C:20]=2[N:19]=[CH:18]1>CC(O)=O.O>[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([N:26]3[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:10](=[O:16])[CH:11]=[C:12]3[CH3:15])[C:20]=2[N:19]=[CH:18]1
Reactant: Cc1cc(=O)c(OCc2ccccc2)co1
Reactant: Nc1cccc2[nH]cnc12
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc2[nH]cnc12
Temperature: 140 °C

Procedure:
5-(Benzyloxy)-2-methyl-4H-pyran-4-one (450 mg, 2.081 mmol) and 1H-benzimidazol-4-amine (279 mg, 2.095 mmol) were taken up in 40% HOAc/H2O (10 ml) in a microwave vial. The vial was sealed and the mixture heated to 140° C. for 30 min by microwave irradiation. The reaction was incomplete by LC/MS. The mixture was heated to 200° C. for 30 min by microwave irradiation. The reaction was incomplete by LC/MS. The mixture was heated to 170° C. for 1 h by microwave irradiation. The mixture was concentrated. The crude material was purified by preparative reversed-phase HPLC (30×150 mm Waters Sunfire (0.1% TFA), 5-35% ACN/water over 20 min at 50 mL/min, 2 injections). Fractions containing each compound were pooled separately then applied to separate Phenomenex Strata-X—C ion exchange columns (5 g). Each column was washed with H2O and MeOH (discard) then with 10% concentrated NH4OH in MeOH (collect). The collected fractions for each were concentrated separately to give the title compounds below: 1-(1H-benzimidazol-4-yl)-5-(benzyloxy)-2-methylpyridin-4(1H)-one: tan solid LC/MS rt=1.24 min, 1H NMR (500 MHz, d6-DMSO) δ 12.90 (bs, 1 H), 8.33 (s, 1 H), 7.72 (bs, 1 H), 7.49 (bs, 1 H), 7.41-7.25 (m, 7 H), 6.26 (s, 1 H), 4.94 (s, 2 H), 1.92 (s, 3 H). 1-(1H-benzimidazol-4-yl)-5-hydroxy-2-methylpyridin-4(1H)-one: tan solid, LC/MS rt=0.47 min, 1H NMR (500 MHz, d6-DMSO) δ 12.88 (bs, 1 H), 8.32 (s, 1 H), 7.70 (d, J=8.06 Hz, 1 H), 7.38-7.25 (m, 3 H), 6.25 (s, 1 H), 1.92 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:34](=[O:37])[CH2:35][CH3:36])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])[CH:17]=3)[N:12]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C@@H:11]([CH3:33])[CH2:10]2)=[CH:4][CH:3]=1.Br[C:39]1C=C2C(=CC=1)N(C(=O)C1C=CC(F)=CC=1)[C@@H](C)C[C@H]2N(C1C=CC(Cl)=CC=1)C(=O)CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC)(=O)C=C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:39][O:22][C:21](=[O:23])[CH:20]=[CH:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[C@@H:11]([CH3:33])[CH2:10][C@H:9]2[N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:34](=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(Br)cc21
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C=CC(=O)OC
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)OC)cc21
Temperature: 80 °C
Yield: 44 %

Procedure:
(±)-Cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid was made from (±)-cis-N-[6-bromo-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide. To a solution of (±)-cis-N-[6-bromo-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide (250 mg, 0.47 mmol), TEA (0.2 ml, 1.4 mmol), palladium acetate (11 mg, 0.047 mmol), 1,3-Bis(diphenylphosphino)propane (39 mg, 0.094 mmol), in 10 ml DMF was added 0.13 ml methyl acrylate (1.41 mmol). The resulting reaction mixture was heated to 80° C. overnight. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (2:3) to give (±)-cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid methyl ester (110 mg, 44%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[N+:9]([C:4]1[CH:3]=[CH:2][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:5]=1[NH2:6])([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Nc1cc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a mixture of 4-bromo-2-nitroaniline (217 mg, 1.0 mmol), phenylboronic acid (122 mg, 1.0 mmol), tetrakis-(triphenylphosphine)palladium (55 mg, 0.05 mmol) and cesium carbonate (650 mg, 2.0 mmol) was added 3 mL of ethyleneglycol dimethyl ether (DME). The reaction was heated to 80° C. and stirred under nitrogen atmosphere overnight. The mixture was filtered through a celite pad. The filtrate was concentrated and purified by biotage column chromatography to give 4-nitrobiphenyl-3-amine (207 mg)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:40](N2C=CN=C2)=[O:41])=[CH:34][C:33]=1[F:47]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])=[CH:34][C:33]=1[F:47]
Reactant: COC(=O)c1ccc(CNC(=O)n2ccnc2)cc1F
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (48.8 mg, 0.115 mmol) and 2-Fluoro-4-{[(imidazole-1-carbonyl)-amino]-methyl}-benzoic acid methyl ester (183.3 mg, 0.764 mmol) in CH2Cl2 (8 mL) was stirred rt for 16 hrs. The reaction mixture was then purified by flash column to give 4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-methyl)-2-fluoro-benzoic acid methyl ester (64.5 mg, 88%).
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[Br:6][C:7]1[C:8]([CH2:17]Br)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[O:11]>C1COCC1>[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:9]2[C:8]=1[CH2:17][N:2]([CH3:1])[C:10]2=[O:11]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CN1Cc2c(Br)cccc2C1=O
Reaction time: 2 h

Procedure:
An 8M solution of methylamine in ethanol (10 mL, 80 mmol) was added to a solution of methyl 3-Bromo-2-(bromomethyl)benzoate in THF (30 mL) and allowed to stir for 2 h. The reaction mixture was concentrated to dryness and the residue was triturated with water. The solids produced were collected by filtration and dried to afford 4-bromo-2-methyl-2,3-dihydroisoindol-1-one which used immediately in the next step. To a cold suspension of 4-bromo-2-methyl-2,3-dihydroisoindol-1-one (60 g, 265 mmol) in concentrated sulfuric acid (60 mL) was added pre-cooled mixture of conc. nitric acid (12.5 mL, 265 mmol) and conc. sulfuric acid (60 mL) over 20 min. The reaction mixture was stirred for 30 min at 0° C. and 2 h at room temperature. The reaction mixture was poured into an ice-water mixture (300 mL) and the precipitate that formed was collected by filtration and washed with water (3×100 mL). The solids were suspended in isopropanol (200 mL) and heated on a steam bath for 10 minutes. The mixture was cooled and the solid was collected by filtration and air dried to afford 53 g of the title compound (74%). 1H NMR (CDCl3, 300 MHz) δ 3.22 (s, 3H), 4.36 (s, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H).
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[S:15][C:16]([CH2:19][OH:20])=[CH:17][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][C:22]1([CH3:32])[C@@H:24]([CH:25]=[C:26]([Br:28])[Br:27])[C@H:23]1[C:29](Cl)=[O:30].Cl>C1C=CC=CC=1>[CH3:21][C:22]1([CH3:32])[C@@H:24]([CH:25]=[C:26]([Br:27])[Br:28])[C@H:23]1[C:29]([O:20][CH2:19][C:16]1[S:15][C:14]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:18][CH:17]=1)=[O:30]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C(Br)Br
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3 ml of pyridine were added dropwise at 5° C. to a solution of 2.1 gof the product of Step B in 50 ml of benzene and 3.5 g of (1R,3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylic acid chloride and the mixture was stirred at 20° C. for 8 hours and was poured into aqueous 2N hydrochloric acid. The decanted organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 95-5 benzene-ethyl acetate mixture to obtain 1.45 g of (2-phenoxy-5-thiazolyl)-methyl (1R3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]([CH3:22])[C:16]([CH3:21])([C:18]([OH:20])=O)[CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:54][O:55][C@@H:56]([C@@H:73]1[CH2:77][CH2:76][CH2:75][N:74]1[C:78](=[O:97])[CH2:79][C@@H:80]([O:95][CH3:96])[C@@H:81]([N:86]([CH3:94])[C:87](=[O:93])[C@H:88]([CH:90]([CH3:92])[CH3:91])[NH2:89])[C@@H:82]([CH3:85])[CH2:83][CH3:84])[C@@H:57]([CH3:72])[C:58]([NH:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:59]>ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]([CH3:22])[C:16]([CH3:17])([C:18]([NH:89][C@H:88]([C:87]([N:86]([C@@H:81]([C@@H:82]([CH3:85])[CH2:83][CH3:84])[C@H:80]([O:95][CH3:96])[CH2:79][C:78]([N:74]1[CH2:75][CH2:76][CH2:77][C@H:73]1[C@H:56]([O:55][CH3:54])[C@@H:57]([CH3:72])[C:58]([NH:60][C@H:61]([C:69]([OH:71])=[O:70])[CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:59])=[O:97])[CH3:94])=[O:93])[CH:90]([CH3:91])[CH3:92])=[O:20])[CH3:21])=[O:14]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN(C(=O)CCCCCN1C(=O)C=CC1=O)C(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of #249 (382 mg, 1.23 mM) in 5 mL of dichloromethane, HATU (482 mg, 1.23 mM) was added followed by triethylamine (0.52 mL, 1.23 mM). The reaction was allowed to stir for 1 hour at room temperature followed by the addition of #250 (762 mg, 1.23 mM). The reaction was allowed to stir for 3 hours. Reaction was concentrated in vacuo. Reverse phase purification (MethodL) followed by lyophilization yielded a white solid mc#120 (124 mg, 11%). HPLC (Protocol A at 45° C.;) m/z 911.5 [M+H+], retention time=9.676 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O.O>[CH3:20][O:19][C:17](=[O:18])[NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5]
Reactant: COC(=O)Cl
Reactant: Nc1ccccc1C(=O)Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1ccccc1C(=O)Nc1nnn[nH]1

Procedure:
To a solution of 5.0 g of 2-amino-N-(1H-tetrazol-5-yl)benzamide in 20 ml of dimethylformamide was added 2.3 g of methyl chloroformate. The resulting solution was warmed for 2 hours and then diluted with a small volume of water. The solid which formed on cooling was separated by filtration to give [2-((1H-tetrazol-5-yl)-aminocarbonyl)phenyl]carbamic acid methyl ester melting at about 236°-237° C. after recrystallization from ethanol.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[C:15]([CH3:17])[N:16]=[C:10]2[C:9]=1[I:18].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(Cl)Cl>[I:18][C:9]1[C:10]2[N:11]([CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: Cc1cn2ccc(N)c(I)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Nc1ccn2cc(C)nc2c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A mixture of sodium carbonate (0.57 g, 5.38 mmol) and amine 23 (1.47 g, 5.38 mmol) in 50 mL of dry CH2Cl2 was treated, under argon, over a period of 15 min with ethyl chloroformate (2.34 g, 22.6 mmol). The reaction mixture was stirred at room temperature for 24 h. Then, water (50 mL) was added and organic layer was recovered, the aqueous layer was extracted with additional CH2Cl2 (3×50 mL). The organic extracts were dried (Na2SO4), filtered and evaporated under vacuum. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford in order of elution: Compound 24 (820 mg, yield: 44%); mp 148° C.; IR (KBr) 3380, 3124, 3049, 2988, 1738, 1642, 1541; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, 3H, J=7.1 Hz), 2.31 (s, 3H), 4.13 (q, 2H, J=7.1 Hz), 6.93 (d, 1H, J=7.1 Hz), 7.78 (s, 1H), 8.35 (d, 1H, J=7.1 Hz), 8.93 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 14.5, 60.7, 81.8, 110.1, 111.5, 125.7, 137.2, 142.7, 144.5, 153.9. Anal. Calcd for C11H12IN3O2: C, 38.28; H, 3.50; N, 12.18. Found: C, 38.04; H, 3.55; N, 12.08.
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH:10]2[C:14]3=[N:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22](=[O:23])[N:13]3[CH2:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35])[CH2:25][CH3:26]>C(Cl)Cl>[O:23]=[C:22]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=[C:14]2[CH:10]([N:9]([CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[C:34]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:24][CH2:25][CH3:26])=[O:35])[CH2:11][CH2:12][N:13]12
Reactant: CCCc1ccccc1N=C=O
Reactant: CC(NC1CCn2c1nc1ccccc1c2=O)c1ccccc1
Solvent: ClCCl
Product: CCCc1ccccc1NC(=O)N(C(C)c1ccccc1)C1CCn2c1nc1ccccc1c2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To a solution of 3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one (50 mg, 0.163 mmol) in dry CH2Cl2 (1 mL), was added 2-n-propylphenyl isocyanate (26.3 mg, 0.163 mmol). The resulting reaction mixture was stirred at rt under nitrogen for 20 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by FC (AcOEt/heptane: 7/3) to give the title compound as a white foam (45%). LC-MS (MeCN/H2O: 1/1): Rt=3.00 min. m/z=467 (M+1).
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]2[O:22][CH2:23][C:24](=O)[C:16]=12>>[CH3:1][O:2][N:3]=[C:24]1[C:16]2[C:17](=[N:18][C:19]([CH3:21])=[CH:20][C:15]=2[O:14][CH3:13])[O:22][CH2:23]1
Reactant: CON=C1COc2nnccc21
Reactant: COc1cc(C)nc2c1C(=O)CO2
Product: CON=C1COc2nc(C)cc(OC)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-methoxy-6-methylfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as white solid;
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)(Cl)Cl.Cl[C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1Cl)[CH2:20]N=C([O-])C(Cl)(Cl)Cl.FC(F)(F)S(O)(=O)=O>CCCCCC>[CH2:20]([O:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:19]1[CH:28]=[CH:29][CH:30]=[CH:17][CH:18]=1
Reactant: [O-]C(=NCc1ccc(Cl)c(Cl)c1)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)[C@@H]1CCC[C@@H]1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 1.00 g of ethyl cis-2-hydroxy-1-cyclopentane carboxylate, 8.00 mL of chloroform, 16.0 mL of normal hexane, and 1.77 mL of 3,4-dichlorobenzyl-2,2,2-trichloroacetimidate was added 0.335 mL of trifluoromethane sulfonic acid at room temperature under a nitrogen atmosphere, followed by stirring for 3 hours. The insoluble materials were removed by filtration, and to the filtrate was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling to adjust the pH to about 7, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 1.27 g of ethyl cis-2-benzyloxy-1-cyclopentane carboxylate as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8](O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC(C)(C)C2O
Reactant: C1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1OC(C)(C)C2N1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (29 ml) is added to a stirred solution of the product obtained in Step 4. (25.4 g) in methylene chloride (560 ml) at RT under nitrogen. Methanesulfonyl chloride (11.1 ml) is added dropwise to the mixture which is cooled to 0° C. The mixture is stirred for 3 hours at RT, cooled to 0° C., piperidine (128 ml) added and stirring continued at RT overnight. Sat'd aq. sodium bicarbonate is added to the mixture, the phases separated and the organic phase washed with sodium bicarbonate, sat'd NaCl, dried, filtered and evaporated in vacuo. The residue is dissolved in toluene and evaporated in vacuo affording the desired product as the hydrochloride salt.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[C:16]4([CH2:21][CH2:20][N:19]([C:22]5[CH:31]=[N:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[CH2:18][CH2:17]4)[CH2:15][CH2:14][CH2:13][C:12]3=[O:32])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:35]I.O>C1COCC1>[CH3:35][N:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[C:16]4([CH2:17][CH2:18][N:19]([C:22]5[CH:31]=[N:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[CH2:20][CH2:21]4)[CH2:15][CH2:14][CH2:13][C:12]3=[O:32])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1Cc1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2c(CN3C(=O)CCCC34CCN(c3cnc5ccccc5n3)CC4)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
The title compound was synthesized from 1-((1H-indol-4-yl)methyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (prepared according to method G) via methylation as follows: NaH (7 mg, 0.18 mmol, 60% in mineral oil) was added to an ice-cold solution of 1-((1H-indol-4-yl)methyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (synthesized according to method G) (25 mg, 0.06 mmol) in THF (5 mL). The resulting mixture was stirred at rt for 10 min. The mixture was cooled to 0° C., methyl iodide (26 mg, 0.18 mmol) was added at 0° C. and stirring was continued at 0° C. for 1 h. Then the mixture was allowed to warm to rt over a period of 1 h. The mixture was poured into water and the solution was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The product was purified by preparative reversed phase HPLC (column Zorbax eclipseXDB C18 21.2×150 mm 5 ♀m, flow 20 mL/min, eluent: gradient water/acetonitrile) to yield the title compound (13 mg, 50%). [1H NMR (300 MHz, CDCl3) ♀ ppm 8.49 (s, 1H), 7.88 (d, 1H), 7.68-7.50 (m, 2H), 7.45-7.35 (m, 1H), 7.21-7.08 (m, 2H), 6.95 (d, 1H), 6.73 (d, 1H), 6.35 (d, 1H), 4.98 (s, 2H), 4.40 (d, 2H), 3.78 (s, 3H), 3.15 (t, 2H), 2.68 (t, 2H), 2.25-2.05 (m, 4H), 2.00-1.85 (m, 2H), 1.80-1.70 (m, 2H); LCMS RtF=1.50 min, [M+H]+=440.0].
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]([CH3:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])(O)=O.[Na+]>Cl>[CH3:19][O:16][C:15](=[O:17])[CH2:14][C:11]1[C:10]([CH3:18])=[N:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]=1[CH3:13]
Reactant: O=C([O-])O
Reactant: Cc1nn(Cc2ccccc2)c(C)c1CC(=O)O
Agent: Cl
Agent: [Na+]
Product: COC(=O)Cc1c(C)nn(Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid (1.00 g, 4.1 mmol) was dissolved in 3N methanolic HCl (7.5 mL) and stirred at room temperature for 18 h. The reaction mixture was neutralized with aqueous NaHCO3 solution and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated under reduced pressure.