Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:34][CH2:33][CH2:32][CH:31]2[C:35]2[CH:36]=[C:37]([C:53]([OH:55])=O)[CH:38]=[C:39]3[C:44]=2[O:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][C@H:47]([CH3:51])[CH2:46]2)=[CH:41][C:40]3=[O:52])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[F:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:34][CH2:33][CH2:32][CH:31]2[C:35]2[CH:36]=[C:37]([C:53]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[O:55])[CH:38]=[C:39]3[C:44]=2[O:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][C@H:47]([CH3:51])[CH2:46]2)=[CH:41][C:40]3=[O:52])[CH:27]=[CH:28][CH:29]=1
Reactant: C1COCCN1
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N4CCOCC4)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
TBTU (138 mg, 0.43 mmol) was added to a stirred solution of 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (97 mg, 0.21 mmol), DIPEA (0.075 mL, 0.43 mmol) dissolved in DMF (1.5 mL) under nitrogen. The resulting solution was stirred at room temperature for 1.5 h. Morpholine (0.028 mL, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and evaporated to dryness to afford 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-4H-chromen-4-one (63 mg, 56%) as a yellow foam.
Reaction SMILES: [OH:1][C:2]1([C:8]2[O:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:24]I>>[CH3:24][O:1][C:2]1([C:8]2[O:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: CI
Reactant: OC1(c2ccc(Sc3ccc4ccccc4c3)o2)CCOCC1
Product: COC1(c2ccc(Sc3ccc4ccccc4c3)o2)CCOCC1
Yield: 92 %

Procedure:
Using the procedure described in Example 1, 4-hydroxy-4-[5-(naphth-2-ylthio)fur-2-yl]tetrahydropyran was reacted with methyl iodide to give 4-methoxy-4-[5-(naphth-2-ylthio)fur-2-yl]tetrahydropyran in 92% yield as an oil.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)[N:16]=[C:15]([C:26]([O:28]CC)=[O:27])[CH:14]=2)[CH:9]=[C:10]([F:12])[CH:11]=1)#[N:5].Cl>C1COCC1>[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)[N:16]=[C:15]([C:26]([OH:28])=[O:27])[CH:14]=2)[CH:9]=[C:10]([F:12])[CH:11]=1)#[N:5]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)n(-c2cccc(C#N)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
15.0 ml of water and 797 mg of lithium hydroxide (33.3 mmol) are added to 1.20 g (3.00 mmol) of the carboxylic ester of Example 134A with 90% purity in 45.0 ml of THF. The mixture is stirred at RT for 5 h and a 1N aqueous hydrogen chloride solution is subsequently added to the reaction solution. The mixture is extracted with dichloromethane and the combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 821 mg (82% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[S:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N:32]=[C:33]=[O:34]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:33]([NH:32][C:23]3[CH:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[CH:26]=[CH:27][C:22]=3[F:21])=[O:34])=[C:3]([S:19][CH3:20])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1N
Product: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 37 %

Procedure:
Using Method F2 with 4-(4-amino-3-(methylthio)phenoxy)-3-nitropyridin-2-amine (1.04 g, 3.57 mmol) and 2-fluoro-5-trifluoromethylphenyl isocyanate, the title compound (664 mg, 37%) was obtained as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].[F:28][C:29]([F:46])([F:45])[O:30][C:31]1[CH:44]=[CH:43][C:34]([O:35][C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O1CCCC1>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([NH:42][C:39]4[CH:40]=[CH:41][C:36]([O:35][C:34]5[CH:43]=[CH:44][C:31]([O:30][C:29]([F:28])([F:45])[F:46])=[CH:32][CH:33]=5)=[CH:37][CH:38]=4)[CH2:25][CH2:26]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2]
Reactant: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(Oc5ccc(OC(F)(F)F)cc5)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.2 %

Procedure:
1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (700 mg) and 4-(4-trifluoromethoxyphenoxy)phenylamine (557 mg) were suspended in 1,2-dichloroethane (20 ml) and tetrahydrofuran (20 ml). Sodium triacetoxyborohydride (558 mg) and acetic acid (0.13 ml) were added to the suspension, and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the remaining water layer was ice-cooled. A 20% sodium carbonate aqueous solution was added thereto, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (methylene chloride:methanol=100:1→methylene chloride:methanol=40:1) and recrystallized from isopropyl alcohol-isopropyl ether to afford the title compound as a yellow solid (226 mg).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1>>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13]1
Reactant: OCC1CCCNC1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(N2CCCC(CO)C2)cc1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 4-fluorobenzonitrile and 3-hydroxymethylpiperidine.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:8]=2[NH:7][CH:6]=1.[CH3:17]O>>[ClH:3].[N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:8]=2[NH:7][CH:6]=1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccc2nc[nH]c2c1
Product: Cl
Yield: 97 %

Procedure:
Under ice cooling, thionyl chloride (2.30 ml) was added dropwise to methanol (50 ml). Then, 5-benzimidazolecarboxylic acid (5.00 g) was added, followed by heating under reflux for 5 hours. The reaction mixture was distilled under reduced pressure. The residue was pulverized in diethyl ether, followed by collection through filtration, whereby colorless crystals (6.36 g, 97%) was obtained.
Reaction SMILES: CN(C)CCN.[CH:7]1([CH2:10][O:11][N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:9][CH2:8]1.C(O)(=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])=[C:30]([C:42](=O)[CH2:43][CH3:44])[CH:29]=1>CCO>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])=[C:30]([C:42](=[N:12][O:11][CH2:10][CH:7]2[CH2:9][CH2:8]2)[CH2:43][CH3:44])[CH:29]=1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1OCC1CC1
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(=NOCC1CC1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.3 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(cyclopropylmethoxy)phthalimide (326 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of a solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (316 mg, 1.0 mmol) in EtOH (2 mL), and the mixture stirred for 65 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(1-cyclopropylmethoxyiminopropyl)phenyl]trifluoromethanesulfonamide 196 (205 mg, 53%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.88, br s, 1H, 7.66, d, J=8.8 Hz, 1H, 7.49, d, J=2.4 Hz, 1H, 7.33, dd, J=2.4 and 8.8 Hz, 1H, 4.02, d, J=7.2 Hz, 1H, 2.83, q, J=7.6 Hz, 2H, 1.22, m, 4H, 0.64, m, 2H, 0.33, m, 2H. HRMS (M+) 384.0515. N-(cyclopropylmethoxy)phthalimide was prepared by the procedure described in Example 1G.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH3:11]CCCCCCCC.CNC(=NC)C1C=CC=CC=1.C(=O)(OC)OC>CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCCCCCCCC
Agent: CN=C(NC)c1ccccc1
Solvent: CO
Solvent: COC(=O)OC
Product: COc1ccccc1[N+](=O)[O-]

Procedure:
10 mol of 2-nitrophenol was charged into a stirred, heated reactor, along with 800 ml of nonane and 5% N,N'-dimethylbenzoamidine, and the mixture was heated to 150° C. Then 12 mol of dimethyl carbonate was added portionwise over 5 hr. The methanol produced by the reaction was removed by distillation over a distillation column. After completion of the reaction, the reaction mixture was refined by distillation. 2-Nitroanisole was obtained in the amount of about 9 mol, corresponding to a yield of c. 90%, based on the starting amount of 2-nitrophenol.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16]C)=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([OH:16])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ncc(C(=O)O)cc1OC1CCCC1
Reaction time: 4 h
Yield: 59.3 %

Procedure:
A solution of potassium hydroxide (168 mg) in water (1 mL) is added to a solution of methyl 5-cyclopentyloxy-6-methoxynicotinoate (250 mg) in methanol (3 mL) and the mixture stirred for 4 hours then allowed to stand at room temperature overnight. The mixture is concentrated, the residue dissolved in water and the mixture adjusted to pH 6 by the addition of concentrated hydrochloric acid. The mixture is extracted with ethyl acetate, the extracts dried (MgSO4) and concentrated to give a cream solid. The solid is dried at 100° C. to give 5-cyclopentyloxy-6-methoxynicotinic acid (140 mg), m.p. 191-2° C. [Elemental analysis: C, 60.7; H, 6.43; N, 5.78%. calculated: C, 60.75; H, 6.37; N, 5.90%.].
Reaction SMILES: C([NH:4][CH:5]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:20])[CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:3])C.[ClH:21]>>[OH2:3].[ClH:21].[NH2:4][CH:5]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:20])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O
Agent: Cl
Product: NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O
Product: O

Procedure:
To 2.7 g of 2-acetylamino-3-(2-quinolon-4-yl)propionic acid was added 30 ml of 20%-hydrochloric acid and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under a reduced pressure to dryness, the residue obtained was recrystallized from ethanol-water to obtain 1.9 g of 2-amino-3-(2-quinolon-4-yl)propionic acid hydrochloride hydrate in the form of colorless prism-like crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][S:4][N:3]=1.C1(=O)[N:11](CCCBr)[C:10](=O)[C:9]2=CC=CC=[C:8]12>>[NH2:11][CH2:10][CH2:9][CH2:8][NH:1][C:2]1[N:6]=[CH:5][S:4][N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Nc1ncsn1
Product: NCCCNc1ncsn1

Procedure:
Reaction of 3-amino-1,2,4-thiadiazole with 3-phthalimidopropyl bromide and hydrazinolysis of the product gives 3-(3-aminopropylamino)-1,2,4-thiadiazole and from this intermediate N-cyano-N'-methyl-N"-[3-(3-(1,2,4-thiadiazolyl)amino)propyl]guanidine is prepared.
Reaction SMILES: [FH:1].[FH:2].F.C(N(CC)CC)C.[C:11]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[C:11]([CH:16]1[CH2:21][CH2:20][C:19]([F:2])([F:1])[CH2:18][CH2:17]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: F
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(F)(F)CC1
Reaction time: 20 h

Procedure:
Procedure for the fluorination of carbonyls (examples 85-96): To a suspension of disubstituted aminodifluorosulfinium salt (2.0 mmol) and triethylamine trihydrofluoride (163 μL, 1.0 mmol) in dichloromethane (2.0 mL), at room temperature and under nitrogen, is added 4-carboethoxy-cyclohexanone (159 μL, 1.0 mmol). The reaction mixture was stirred 20 h, then quenched with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture was extracted using dichloromethane. The organic phases were combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents were evaporated to provide 4-carbethoxy-1,1-difluorocyclohexane admixed with 4-carboethoxy-1-fluorocyclohex-1-ene as a clear oil (refer to the following table for yields and product distribution).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl[CH2:36][C:37]1[O:38][CH:39]=[CH:40][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][C:37]2[O:38][CH:39]=[CH:40][N:41]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: ClCc1ncco1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ncco6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 2-(chloromethyl)oxazole (25.3 mg) were suspended in dimethylformamide (2.0 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. Another portion of 2-(chloromethyl)oxazole (25.3 mg) and potassium carbonate (62 mg) was added and the mixture was shaken again for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 30.9 mg; LC (method 23): tR=2.09 min; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:24].[CH3:25][NH2:26].[BH4-].[Na+].[C:29](=[O:32])([O-])[OH:30].[Na+]>O1CCCC1.CO.O>[C:3]([O:30][C:29](=[O:32])[N:26]([CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=2)(=[O:10])=[O:9])[CH:12]=1)[CH3:25])([CH3:24])([CH3:4])[CH3:2]
Reactant: Cc1cc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cnc1Cl
Reactant: O=C([O-])O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)cnc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
1-[(6-Chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (244 mg) was dissolved in absolute tetrahydrofuran (6.8 mL), a 2 mol/L solution (0.34 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to a solution of sodium borohydride (51 mg) in methanol (3 mL), and the mixture was stirred at the same temperature for 3 min. di-tert-Butyl bicarbonate (654 mg) was added, and water (5 mL) and sodium hydrogencarbonate (420 mg) were added 3 min later. The mixture was further stirred at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the title compound as an oil (yield 247 mg, 77%).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)=[O:21].C([O-])(=O)C.[NH4+]>C(OC(=O)C)(=O)C>[C:20]([OH:21])(=[O:19])[CH3:22].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[C:17]1[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2)=[O:21]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O
Product: COC(=O)c1cccc(C=c2c3ccccc3c3[nH]c(=O)c4nccn4c23)c1
Temperature: 20 °C
Yield: 55.1 %

Procedure:
0.5 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one and 1.47 g of 3-methoxycarbonyl-benzaldehyde are refluxed for 48 hours in the presence of 0.7 g of ammonium acetate in 30 ml of acetic anhydride. After cooling to a temperature in the region of 20° C., the precipitate formed is filtered off, washed with water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 50° C. 0.53 g of 10-(3-methoxycarbonyl-benzylidene)-5H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one acetate is obtained in the form of a yellow powder, the melting point of which is greater than 260° C. (Analysis, C24H19 N3O5.0.19 H2O; % calculated C: 67.13; H: 4.46; N: 9.79; O: 18.63; % found C: 66.9; H: 4.4; N: 9.9; O: 18.6).
Reaction SMILES: NC1[C:8](I)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C([N:18](CC)CC)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:5]1[C:3]([NH2:4])=[N:18][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccc(I)c1N
Reactant: CCN(CC)CC
Reactant: C#CCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Nc1ncccc1C#CCCCCl
Temperature: 50 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a stirred solution of 2-amino-3-iodoaniline (13 g) in triethylamine (260 ml) were added bis(triphenylphosphine) palladium dichloride (2 g) and copper (I) iodide (1.15 g). The mixture was cooled to 5° C. before the addition of 5-chloro-1-pentyne (6.6 ml). The mixture was heated to 50° C. and stirred 5 h. The mixture was cooled to room temperature, filtered and evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1 to 5:1 eluant) to afford 3-(5-chloropent-1-ynyl)-pyridin-2-ylamine as a red oil (10.6 g, 92%): MS (EI) 196, 194 (M),159, 157, 131, 104; 1H NMR (δ, CDCl3) 8.0 (dd, 1H, J=2,5 Hz), 7.47 (dd, 1H, J=2,7 Hz), 6.59 (dd, 1H, J=5,7 Hz), 4.94 (br s, 1H), 3.72 (t,2H, J=6 Hz), 2.68 (t,2H, J=7 Hz), 2.07 (dt,2H, J=6,7 Hz) ppm.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[N:16]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C[O:31][C:32](=[O:41])[CH:33](Br)[CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:34][CH:33]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:22])[CH:6]=[N:5]2)[C:32]([OH:31])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(c1ccccc1O)N1CCCC1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(=O)N2CCCC2)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-(pyrrolidine-1-carbonyl)-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-{6-oxo-4-[2-(pyrrolidine-1-carbonyl)-phenoxy]-6H-pyridazin-1-yl}-propionic acid as a white solid (100 mg, 32% for the final step). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91-1.18 (m, 2H), 1.31-1.86 (m, 11H), 1.86-2.05 (m, 1H), 2.06-2.21 (m, 1H), 3.10-3.48 (m, 4H), 5.26 (dd, J=10.7, 4.1 Hz, 1H), 5.77 (d, J=2.4 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.47-7.60 (m, 2H), 8.00 (d, J=2.4 Hz, 1H), 13.06 (br s, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[N:17]=[C:18]([CH3:48])[N:19]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[CH:40][CH:39]=3)[C:20](=[O:37])[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([C:16]2[N:17]=[C:18]([CH3:48])[N:19]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:46])[CH3:47])=[CH:40][CH:39]=3)[C:20](=[O:37])[C:21]=2[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:27][CH:28]=2)[CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n1-c1ccc(OC(C)C)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n1-c1ccc(OC(C)C)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.48 g), sodium hydrogen carbonate (0.69 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-cyclopropyl-1-(4-isopropoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.39 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.28 g, 64%).