Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])=[C:27]([O:45][CH3:46])[CH:26]=1.Cl>O.CN(C)C=O>[CH3:46][O:45][C:27]1[CH:26]=[C:25]([CH:44]=[CH:43][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:24][N:14]1[C:15]2[CH:3]=[CH:4][CH:5]=[C:6]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])[C:7]=2[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cn2c3ccccc3c3c(OC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
302 mg of sodium hydride (60%) was added to N,N-dimethylformamide (30 mL) solution of 924 mg of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid, stirred at room temperature for 20 minutes. Thereafter, 1.31 g of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, adjusted to pH3 with 1 N hydrochloric acid, and extracted twice with ethyl acetate. The combined extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography (chloroform:methanol=50:1), and 1.88 g of the subject compound was prepared as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1.[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[N:32][C:27]2=[C:26]([C:33](Cl)=[O:34])[CH:25]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[N:11]=[CH:10][C:9]=2[NH:21][C:33]([C:26]2[CH:25]=[N:24][N:28]3[CH:29]=[CH:30][CH:31]=[N:32][C:27]=23)=[O:34])[CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(N)cnn1CCOC[Si](C)(C)C
Reactant: O=C(Cl)c1cnn2cccnc12
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1CCOC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine (580 mg, 1.72 mmol) in tetrahydrofuran (40 mL) was added of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (320 mg, 1.72 mmol) in THF (5 mL) at 0° C. After the addition, the mixture was warmed to room temperature, and then stirred overnight at this temperature. The mixture was concentrated to give 330 mg (40%) of N-(5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=483.1. 1H NMR (400 MHz, CDCl3) δ: 9.63 (s, 1H), 8.82 (m, 1H), 8.76 (s, 1H), 8.52 (m, 1H), 8.42 (s, 1H), 7.38 (dd, 1H), 7.31 (d, 1H), 7.22 (m, 1H), 7.06 (m, 2H), 5.42 (d, 2H), 3.86 (s, 3H), 3.72 (m, 2H), 0.92 (q, 2H), 0 (s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:21][CH:22]=[O:23])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1cnc2ccccc2c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-quinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH3:20][NH2:21]>C(O)C>[C:1]([NH:3][C:4]([NH:21][CH3:20])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: CN
Reactant: COc1cccnc1CSCCN=C(NC#N)SC
Solvent: CCO
Product: CNC(=NCCSCc1ncccc1OC)NC#N
Reaction time: 8 h

Procedure:
N-cyano-N'-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (1.9 g) in ethanol (10 ml) was treated with ethanolic methylamine (20 ml 33% solution) and the resultant clear solution was allowed to stand overnight. Excess of methylamine was removed by bubbling nitrogen through the solution and the crystalline precipitate was recrystallised from ethanol to yield the title product (1.2 g), m.p. 122°-123°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:31])=[N:15][C:16]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[N:17][CH:18]=1)=[O:12].CCOCC>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:31])=[N:15][C:16]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:17][CH:18]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)CCC(=O)Nc1ncc(C(=O)NCc2ccc(Cl)cc2Cl)c(O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)CCC(=O)Nc1ncc(C(=O)NCc2ccc(Cl)cc2Cl)c(O)n1
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
A solution of tert-butyl 4-({5-[(2,4-dichlorophenyl)methylcarbamoyl]-4-hydroxypyrimidin-2-yl}amino)-4-oxobutanoate (425 mg) in trifluoroacetic acid (3 mL) was left standing at room temperature for 30 minutes. Ether (60 mL) was added to the reaction solution, and the resulting suspension was filtered. The product collected by filtration was washed with ether, dried under reduced pressure, and then purified by reverse phase high performance liquid chromatography (acetonitrile/water, containing 0.1% formic acid) to obtain the title compound (144 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([OH:15])=[CH:10]2)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([Cl:24])[C:22]=1Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:22]1[C:21]([Cl:24])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[Cl:16])=[CH:10]2)=[O:4]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: COC(=O)c1cccc2cc(O)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc2cc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cnc12
Temperature: 25 °C

Procedure:
To a solution of 3-Hydroxy-8-quinolinecarboxylic acid methyl ester (313) (256 mg, 1.26 mmol) and 3,4,5-Trichloronitrobenzene (294 mg, 1.30 mmol) in Acetone (40 ml) was added K2CO3 (870 mg, 6.30 mmol). This mixture was refluxed for 3.5 hr. The reaction mixture was cooled to room temperature and insoluble materials were removed by Celite filtration. The filtrate was concentrated and the residue was purified by column chromatography. (Hexane/AcOEt=4/1, 80 g of silica gel) to afford compound 314.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: [H][H]
Reactant: C=C1CCCCCCCC(=O)CCCCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCCCCCCC(=O)CCCCCCC1
Yield: 94.1 %

Procedure:
500 mg (2 mmol) of 9-methylenecyclohexadecanone are introduced into 25 ml of ethyl acetate, and 25 mg of Pd/C are added thereto. Hydrogenation is then carried out at 40° C. and standard hydrogen pressure for 5 h. When the reaction is complete, the mixture is filtered over Celite, and the crude product is freed from solvent. Purification by flash chromatography (cyclohexane/EtOAc=25:1) gives 475 mg (94%) of a colorless oil.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH:27][NH:28][C:29](=N)[CH:30]([CH3:32])[CH3:31]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH:30]([C:29]1[N:24]=[C:23]([N:20]2[CH2:21][CH2:22][CH:17]([C:14]3[S:15][CH:16]=[C:12]([CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:26][CH:25]=4)[N:13]=3)[CH2:18][CH2:19]2)[O:27][N:28]=1)([CH3:32])[CH3:31]
Reactant: N#CN1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)n1
Reaction time: 0.25 h

Procedure:
To a solution of 4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carbonitrile (0.450, 1.22 mmol) and N-hydroxy-isobutyramidine (0.150 g, 1.47 mmol) in dry THF (10 mL) was added a 1 M solution of zinc chloride in THF (1.47 mL, 1.47 mmol) over 15 min. The suspension was left to settle for 15 minutes and the white precipitate was collected by filtration and dissolved in 4N HCl in ethanol and water (1:1). The solution was refluxed for 1 hour, cooled and the solid precipitate was filtered off. The filtrate was neutralized by the addition of excess sodium carbonate. The excess was filtered off and the filtrate was diluted with EtOAc. The solution was washed with water, separated, dried (Na2SO4), filtered and concentrated. The residual oil was chromatographed on silica gel (1:1 Hex/EtOAc) to afford the desired compound. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.62 (2H, d), 7.28 (1H, s), 7.19 (2H, d), 5.24 (2H, s), 4.26 (2H, m), 3.20 (3H, m), 2.89 (1H, m), 2.26 (2H, m), 1.92 (2H, m), 1.30 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (213.6 mg, 0.599 mmol) in tetrahydrofuran (3.0 mL) was added cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 898 μL, 0.898 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The starting material wasn't consumed completely. To the mixture was added cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 449 μL, 0.449 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (231.2 mg, 0.580 mmol, 97%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:19]([CH3:28])=[C:18]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:17]=2)[CH:8]=[C:9]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:33].[Na+]>CCO.O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:12])[C:14]([NH2:15])=[O:33])[CH:8]=[C:7]([C:16]2[N:20]([CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:19]([CH3:28])=[C:18]([S:29](=[O:31])(=[O:30])[NH2:32])[CH:17]=2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C#N)c2)n1CC1CCCCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C(N)=O)c2)n1CC1CCCCC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of compound 45 (455 mg, 1.0 mmol) and NaOH (3.2 g, 80 mmol) in EtOH (10 mL) and water (10 mL) was stirred at reflux overnight, cooled to rt, concentrated and redissolved in H2O (30 mL), acidified with 1N HCl solution to pH=6. The formed solid was collected by filtration, washed with water and dried under vacuum. The residue was purified by CC (DCM/MeOH=50/1) to give compound 47 (400 mg, 85%) of as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C(O)(=O)C>[CH3:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: CC(C)(C)CC=O
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)CCN1CCC(O)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Acetic acid (31 μL), pyrrolidin-3-ol (3.47 g, 39.8 mnol) and 3,3-dimethyl-butyraldehyde (3.99 g, 39.8 mmol) were dissolved in THF (100 mL) and stirred at room temperature for 40 min. The solution was then cooled to 0° C. on an ice bath. To the cold solution sodium triacetoxyborohydride (10.98 g, 51.8 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was basified with a 5.0 M solution of NaOH and extracted with CH2Cl2 (3×150 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to afford 1-(3,3-dimethyl-butyl)-pyrrolidin-3-ol in (6.34 g, 92.5%), which was used without purification.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:37][CH2:36]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:7])[CH:24]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCOCC1
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (80 mg) in N,N-dimethylformamide (1.0 ml) was added morpholine (0.055 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure to provide the titled compound as white powder (52.3 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:12])([CH3:11])[N:10]=2)=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[CH2:14].C1C(O)=CC=C(O)C=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:9]([CH3:11])([CH3:12])[N:10]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2=NC2(C)C)cc1
Reactant: C=Cc1ccncc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C2=NC(C)(C)C(c3ccncc3)C2)cc1

Procedure:
16 G. of 3-(p-methylphenyl)-2,2-dimethyl-2H-azirine and 26 g. of freshly distilled 4-vinylpyridine are irradiated in 2 l. of absolute benzene for 6 hours under the conditions given in Example 11 with the addition of 0.05 g. of p-hydroquinone. After evaporation of the solution under reduced pressure there remains a brown oil from which the excess 4-vinylpyridine is distilled off at 41°-42° C. and 0.01 Torr. The residue is taken up in a small amount of acetone. The crude crystallizate obtained from the acetone solution is chromatographed withe benzene/acetone (95:5) on silica gel. The combined fractions are evaporated to dryness under reduced pressure. Then, the residue is recrystallized twice with n-hexane, the solution which results is then decolorized with active carbon to yield 4-[2-(p-methylphenyl)-5,5-dimethyl-1-pyrrolin-4-yl]-pyridine with a melting point of 102° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([Cl:18])[CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccccc1C(C)(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A mixture of N-(2-tert-butylphenyl)acetamide (Reference Example 17, 5.93 g, 31.0 mmol) and sulfuryl chloride (10.5 g, 77.5 mmol) in acetic acid (190 mL) was stirred at 50° C. for 16 h. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with 10% aqueous NaHCO3, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was recrystallized from toluene/diethyl ether to give the title compound (3.73 g) as a white solid. The mother liquid was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 4:1-1:4 hexane/ethyl acetate) to provide the title compound (1.05 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](=O)[CH2:27][C:28](=O)[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:28]([CH3:29])=[CH:27][C:26]([C:22]4[O:21][CH:25]=[CH:24][CH:23]=4)=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Reactant: CC(=O)CC(=O)c1ccco1
Product: Cc1cc(-c2ccco2)nn1-c1nc(Nc2ccc(Cl)cc2)c2ncn(C)c2n1

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 1-(2-furyl)-1,3-butanedione.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:43][C:44]3[CH:54]=[C:53]([N:55]([CH3:60])[S:56]([CH3:59])(=[O:58])=[O:57])[C:52](B4OC(C)(C)C(C)(C)O4)=[CH:51][C:45]=3[C:46]=2[C:47]([NH:49][CH3:50])=[O:48])=[CH:38][CH:37]=1.[CH2:70]([O:77][C:78]1[C:79]([C:85]([O:87][CH3:88])=[O:86])=[N:80][C:81](Br)=[CH:82][CH:83]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:70]([O:77][C:78]1[C:79]([C:85]([O:87][CH3:88])=[O:86])=[N:80][C:81]([C:52]2[C:53]([N:55]([CH3:60])[S:56]([CH3:59])(=[O:58])=[O:57])=[CH:54][C:44]3[O:43][C:42]([C:39]4[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=4)=[C:46]([C:47](=[O:48])[NH:49][CH3:50])[C:45]=3[CH:51]=2)=[CH:82][CH:83]=1)[C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)OC)n3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Pd2(dba)3 (45 mg, 0.05 mmol) and X-phos (48 mg, 0.1 mmol) were added to a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (500 mg, 1 mmol), methyl 3-(benzyloxy)-6-bromopicolinate (350 mg, 1.1 mmol) and K3PO4.3H2O (798 mg, 3 mmol) in 1,4-dioxane/H2O (5 mL/0.5 mL) under N2. The mixture was stirred at 80° C. for 8 h, and after being filtered through celite, the filtrate was concentrated in vacuo, diluted with water and extracted with EtOAc. The residue was purified by column chromatography (DCM:EtOAc=40:1 to 10:1) to obtain methyl 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinate (540 mg, yield: 88%). 1H-NMR (CDCl3, 400 MHz) δ 7.88˜8.04 (m, 3H), 7.70 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.45˜7.56 (m, 3H), 7.41 (t, J=7.2 Hz, 2H), 7.32˜7.38 (m, 1H), 7.20 (t, J=8.4 Hz, 2H), 5.90 (d, J=4.0 Hz, 1H), 5.27 (s, 2H), 3.97 (s, 3H), 3.22 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 618.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([O:13][C:14]3[C:22]4[C:17](=[CH:18][C:19]([N+:23]([O-])=O)=[CH:20][CH:21]=4)[NH:16][N:15]=3)=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([O:13][C:8]3[C:7]4[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=4)[NH:10][N:9]=3)=[N:15][NH:16]2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc2c(Oc3n[nH]c4cc([N+](=O)[O-])ccc34)n[nH]c2c1
Agent: [Pd]
Product: Nc1ccc2c(Oc3n[nH]c4cc(N)ccc34)n[nH]c2c1

Procedure:
Indazolyl ethers 38 can be prepared by the procedure described in Scheme 13. 6-Nitro-1H-2-hydroindazol-3-one 37 is protected such as with Boc2O and DMAP in CH2Cl2 at a temperature of about RT, to give the protected 6-nitro-2-hydroindazol-3-one. The protected 6-nitro-2-hydroindazol-3-one is reacted with an alcohol (where Rx is an appropriate substituent selected from the possible substituents on R1) and Ph3P in a solvent, such as THF, and DEAD, at a temperature of about RT, to give the protected 6-nitro(indazol-3-yl)ether. The nitro intermediate is hydrogenated, such as with an H2 atmosphere in the presence of a catalyst, such as Pd/C, to give the protected 6-amino(indazol-3-yl)ether 38. The amine 38 is coupled with 2-chloronicotinic acid in a solvent, such as an alcohol, preferably pentanol, at a temperature above RT, preferably at a temperature above about 75° C., and more preferably at a temperature at about 130° C. to give the coupled and deprotected compound 39.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCC1(c2ccccc2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 4-(1-phenylcyclohexyl)butanoate (0.211 g, 0.77 mmol) in MeOH (5 mL) was added 1M sodium hydroxide (1.155 mL, 1.155 mmol) and the mixture was stirred at room temp for 5 hrs. Then additional 0.39 ml of 1M NaOH was added and stirring was continued for 3 hrs. To the mixture was added 2 ml of 1N HCl and extracted with EtOAc (2×). The combined extracts were washed with brine, dried over Na2SO4 and evaporated to give an oily residue, which became white solid upon storing at room temp.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12].C(CN)O>>[CH2:1]([N:9]1[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCN
Solvent: NCCO
Product: CCCCCCCCN1CC(C(=O)O)CC1=O
Yield: 125.8 %

Procedure:
129 g of octylamine, 130 g of itaconic acid and 61 g of monoethanolamine were used to obtain 303 g of N-octyl-5-oxopyrrolidine-3-carboxylic acid monoethanolammonium salt with