Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].C[N-]C.C[N-]C.[V+4:13].[CH2:14]([Li])[CH2:15][CH2:16][CH3:17]>CCCCCC>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH2:14]([V+2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: [V+4]
Agent: C[N-]C
Solvent: CCCCCC
Product: CCCC[V+2]CCCC

Procedure:
To a dark-green solution of 0.048 g (0.21 mmol) of vanadium tetrakis(dimethylamide) in hexane was added from a syringe 0.26 ml of a 1.6 M solution of butyllithium (0.21 mmol) in hexane. Lithium dimethylamide precipitated rapidly. The total volume of liquid in the mixture was about 6 ml. After 15 minutes the mixture was filtered to give a clear green solution of dibutylvanadium bis(dimethylamide) in hexane.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:26])[O:13][C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:3]1.[H-].[Na+].Br[CH2:30][C:31]1[CH:41]=[CH:40][C:34]([CH2:35][O:36][C:37](=[O:39])[CH3:38])=[C:33]([O:42][CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:32]=1.[Cl-].[NH4+]>CN(C)C=O.O.C(OCC)(=O)C>[C:37]([O:36][CH2:35][C:34]1[CH:40]=[CH:41][C:31]([CH2:30][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:15]3[C:14](=[O:25])[O:13][C:12](=[O:26])[C:11]=3[C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:17]2)=[CH:32][C:33]=1[O:42][CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])(=[O:39])[CH3:38]
Reactant: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: CC(=O)OCc1ccc(CBr)cc1OCOCC[Si](C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(Cn2cc(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)cc1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-(1-Methyl-indol-3-yl)-4-(indol-3-yl)-furan-2,5-dione (2.21 g, 0.61 mmol) and sodium hydrid (55-60% dispersion in oil, 0.031 g, 0.76 mmol) were dissolved in dry dimethylformamide and stirred for 20 minutes at ambient temperature before adding acetic acid 4-bromomethyl-2-(2-(trimethylsilyl)ethoxymethoxy)benzyl ester (0.25 g, 0.64 mmol). The reaction was allowed to proceed for 20 hours before adding ethyl acetate (20 mL), water (5 mL) and saturated aqueous ammonium chloride (5 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (20 mL). The combined organic phases were washed with water (2×20 mL), and dried over Na2SO4. Removal of the solvent furnished crude 3-[1-(4-acetoxymethyl-3-(2-(trimethylsilyl)ethoxymethoxy)benzyl)-indol-3-yl]-4-(1-methyl-indol-3-yl)furan-2,5-dione which was dissolved in dimethylformamide (3 mL) and ammonium hydroxide (9 mL). Heating to 75° C. in a sealed tube for four hours gave, after extraction with ethyl acetate and chromatography (ethyl acetate/heptane:60/40), 98 mg of the sub-title compound as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[C:11]([N:14]3[CH2:23][CH2:22][C:17]4(OCC[O:18]4)[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[C:11]([N:14]3[CH2:15][CH2:16][C:17](=[O:18])[CH2:22][CH2:23]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2cc(N3CCC4(CC3)OCCO4)n[nH]2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCN(c2cc(-c3ccc(Cl)c(Cl)c3)[nH]n2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 8-(5-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (500 mg) in 1,4-dioxane (5 ml) is added conc. HCl (4 ml), and the mixture is stirred for 2 hours at 50° C. The solvent is removed under reduced pressure. The residue is dissolved in CH2Cl2 and washed with satd. aqueous NaHCO3 (2×), dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure to give 1-(5-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)piperidin-4-one (400 mg). m/z(+) 310/312/314 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])=[N+:2]=[N-:3].Br[C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16].O>C(O)(C)(C)C>[F:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][N:1]1[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Br)C(=O)OC
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 77.5 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(azidomethyl)-1,3-difluorobenzene in t-butanol prepared as per example 2, methyl 2-bromoacrylate (120 gms) and water (200 ml) were heated to 75-80° C. The contents was stirred at 75-80° C. for 24 hours. After the completion of reaction, the reaction mixture was cooled to room temperature. The solid obtained was filtered and then crude mass was added to cyclohexane (240 ml) and the mixture was stirred at room temperature for 2 hours. The solid was filtered and washed with cyclohexane (50 ml). The product was dried for 2 hours to give methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate. Yield: 120 gms
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.Cl[CH2:13][C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:17]([CH3:26])=[CH:16][N:15]=1.[OH-].[Na+]>C(O)C>[CH3:26][C:17]1[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:19][C:14]([CH2:13][S:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:15][CH:16]=1
Reactant: Sc1cc2ccccc2[nH]1
Reactant: Cc1cnc(CCl)cc1N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(CSc2cc3ccccc3[nH]2)cc1N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a solution of 2-mercaptoindole (1.34 g, 8.98 mmol) and 2-chloromethyl-5-methyl-4-piperidinopyridine hydrochloride (2.35 g, 9.00 mmol) in ethanol (90 ml) was added a 2N aqueous sodium hydroxide solution (9.0 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After the removal of the organic solvent by evaporation under a reduced pressure, a saturated sodium chloride solution was added to the residue and the mixture was extracted with chloroform. The chloroform layer separated was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by a silica gel column chromatography [eluent: chloroform and then chloroform-methanol (50:1)] whereby to yield the titled compound (2.51 g) as a crystalline substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:17]#[N:18])[NH:13][C:14](=[O:16])[CH3:15])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:19](=O)([O:25]C(C)(C)C)[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[BH4-].[Na+].C(OCC)(=O)C>CO.O>[C:14]([NH:13][CH:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:16])[CH3:15]
Reactant: CC(=O)NC(C#N)c1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)NC(CNC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
5.00 g of N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl](cyano)methyl]acetamide (0.018 mol), 7.86 g (0.036 mol) of diterbutyl carbonate, 4.28 g (0.018 mol) of nickel chloride (II)—hexahydrate are stirred in 25 mL of methanol at room temperature. 3.40 g (0.09 mol) of sodium borohydride are added portionwise. The reaction mixture is stirred overnight. 200 mL of ethyl acetate are added, followed by 50 mL of water. After separation, the aqueous phase id extracted twice 50 mL of ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18](=[O:24])OC(C)(C)C)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[O:15])[CH:9]=2)[CH:7]=1.Cl.CCN(CC)CC.[CH2:33]([N:35]1[C:39]2=[N:40][C:41]([CH2:64][CH3:65])=[C:42]([CH2:51][NH:52][C:53]([C:55]3[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=3)C(O)=O)=[O:54])[C:43]([NH:44][CH:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[C:38]2[CH:37]=[N:36]1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1>[CH2:33]([N:35]1[C:39]2=[N:40][C:41]([CH2:64][CH3:65])=[C:42]([CH2:51][NH:52][C:53]([C:55]3[CH:63]=[CH:62][CH:61]=[C:57]([C:18]([NH:17][CH2:16][C:4]4[CH:5]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[O:15])[CH:9]=5)[CH:7]=[C:2]([F:1])[CH:3]=4)=[O:24])[CH:56]=3)=[O:54])[C:43]([NH:44][CH:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[C:38]2[CH:37]=[N:36]1)[CH3:34]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)cc(-c2cccc(C=O)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(F)cc(-c3cccc(C=O)c3)c2)c1
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a clear solution of 1,1-dimethylethyl [(5-fluoro-3′-formyl-3-biphenylyl)methyl]carbamate (486 mg, 1.48 mmol) in DCM (2 mL) was added 4N HCl in dioxane (1 mL). Solid precipitated out from the solution after 30 min but stirring was continued at RT for another 1 h. The mixture was then concentrated under vacuum to get rid of solvent. The resulting residue was re-dissolved in DCM. Et3N (1.14 mL, 8.20 mmol) was added followed by 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (400 mg, 0.82 mmol) and HBTU (830 mg, 8.20 mmol). The mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The organic layer was then washed with water followed by a brine wash. The organic layer was concentrated under vacuum to give a crude residue. It was purified with CombiFlash chromatography, eluting with 90% ethyl acetate in hexane to obtain N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(5-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (300 mg, 55%). LC-MS m/z 664 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]#[N:17]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#CCBr
Product: N#CCN1CCN(Cc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Benzyl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=216.2: AtRet=1.50.
Reaction SMILES: C(N1C[C@H](OCC)[C@H](NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)C1)(=O)C.[CH2:31]([C:33]1[C:34]([NH:41][C@H:42]2[C@@H:46]([O:47][CH2:48][CH2:49][F:50])[CH2:45][NH:44][CH2:43]2)=[N:35][C:36]([CH2:39][CH3:40])=[CH:37][N:38]=1)[CH3:32].Cl[C:52]([O:54][CH3:55])=[O:53]>>[CH2:31]([C:33]1[C:34]([NH:41][C@H:42]2[C@@H:46]([O:47][CH2:48][CH2:49][F:50])[CH2:45][N:44]([C:52]([O:54][CH3:55])=[O:53])[CH2:43]2)=[N:35][C:36]([CH2:39][CH3:40])=[CH:37][N:38]=1)[CH3:32]
Reactant: CCc1cnc(CC)c(N[C@@H]2CNC[C@@H]2OCCF)n1
Reactant: COC(=O)Cl
Agent: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OC)C[C@@H]2OCCF)n1

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, DMSO-d6) δ) 7.61, 5.82, 4.55, 4.51, 4.39, 4.19, 3.73–3.48, 2.64–2.49, 1.20–1.14; IR (diffuse reflectance) 2967, 2934, 2873, 2450 (w), 2407 (w), 2350 (w), 2334 (w), 2226 (w), 1699 (s), 1499, 1457 (s), 1392 (s), 1158, 1142, 768, cm−1; HRMS (FAB) calcd for C16H25FN4O3+H 341.1989, found 341.1988.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Cl:7].[NH2:18][C:19]1[C:27]([Br:28])=[CH:26][C:25]([Br:29])=[CH:24][C:20]=1[C:21](O)=[O:22].BrC1C=C(C(O)=O)N(C2C(Cl)=CC=CN=2)C=1.NC1C(C)=CC(Cl)=CC=1C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]2[O:17][C:21](=[O:22])[C:20]3[CH:24]=[C:25]([Br:29])[CH:26]=[C:27]([Br:28])[C:19]=3[N:18]=2)[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Cl:7]
Reactant: O=C(O)c1cc(Br)c(Cl)n1-c1ncccc1Cl
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Agent: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: O=C(O)c1cc(Br)cn1-c1ncccc1Cl
Product: O=c1oc(-c2cc(Br)c(Cl)n2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12

Procedure:
According to the same manner as that of Reference Preparation Example 71-(5), 4-bromo-5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-3,5-dibromobenzoic acid were used in place of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid and 2-amino-5-chloro-3-methylbenzoic acid respectively to obtain 2-[4-bromo-5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80.1 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-phenoxyacetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 417 (M++1)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:15][CH:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C#N)c1ccc(Nc2nc(Cl)ncc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-2,4-dichloropyrimidine (1.37 gm, 6 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (0.96 gm, 6 mmol) and diisopropyl ethylamine (1.6 mL, 9 mmol) were combined in 30 ml acetonitrile and stirred for 16 hr at RT. LC/MS at 16 hr indicated reaction was complete. Organics were washed sequentially with 1M citric acid solution, water, then brine. Organics were dried over sodium sulfate then decanted and evaporated to yield a crude material which was carried on as-is in the next step. (1.45 gm, 69%). MS m/z 353.3 (M+H)
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)cc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(N2CCCCC2)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
Trifluoroacetic acid (5.0 mL) was added to the obtained tert-butyl 2-(2-hydroxy-4-(piperidin-1-yl)benzamido)-4-phenylbenzoate (0.084 g), followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the residue, followed by adjusting the pH to 6.5 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.063 g of 2-(2-hydroxy-4-(piperidin-1-yl)benzamido)-4-phenylbenzoic acid as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C:13]1([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:13]2([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15][CH2:14]2)[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: NC(=O)C1(N)CCC1
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ncc(NC2(C(N)=O)CCC2)nc1Cl
Yield: 15.2 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.574 mmol), 1-aminocyclobutanecarboxamide hydrochloride (108 mg, 0.717 mmol) and DIEA (0.350 mL, 2.01 mmol) in DMF (4 mL) was stirred at room temperature for 70 h. Water and EtOAc were added. Organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 1-(6-chloro-5-cyanopyrazin-2-ylamino)cyclobutanecarboxamide (22 mg).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:19]([C:21]1[C:30]([CH3:31])=[C:29]([O:32][C:33](=[O:35])[CH3:34])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:36])[CH:27]=2)[N:22]=1)=[O:20].O>CCCCCC.O1CCCC1>[OH:20][CH:19]([C:21]1[C:30]([CH3:31])=[C:29]([O:32][C:33](=[O:35])[CH3:34])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:36])[CH:27]=2)[N:22]=1)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCCCCC
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccc(F)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC/C=C/C(O)c1nc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
10.8 ml of an n-hexane solution of 10.8 mmols of diisobutylaluminium hydride was added to a solution of 1.31 g (11.9 mmols) of 1-octyne in 20 ml of n-hexane in an atmosphere of nitrogen and stirred at 50° C. for 2 hours. The reaction solution was cooled to -78° C., to which a solution of 2.22 ml (9.00 mmols) of 2-formyl-3-methyl-4-acetoxy-6-fluoroquinoline in 30 ml of tetrahydrofuran was added. The reaction temperature was raised from -78° C. to room temperature and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was added to 100 ml of water and filtered through Celite, followed by extraction with ethyl acetate, washing with water and a saturated sodium chloride aqueous solution, and drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (solvent: n-hexane ethyl acetate=8:1) to obtain 1.86 g (yield 58 %) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-4-acetoxy-6-fluoroquinoline.
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=O.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N12CCN(CC1)CC2>C(O)C>[C:12]1([CH:11]2[O:3][N:1]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C=Cc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)C1=NOC(c2ccccc2)C1
Temperature: 80 °C
Reaction time: 60 h
Yield: 24.5 %

Procedure:
A mixture of ethyl 2-nitroacetate (0.96 mL; 8.70 mmol), styrene (0.5 mL; 4.35 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.050 mg, 0.438 mmol) in ethanol (2 mL) was stirred at 80° C. for 60 hrs. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate 0.234 g (25%).
Reaction SMILES: C[NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.CCOCC>[NH:2]1[C:3]2=[C:12]3[C:7](=[CH:6][CH:5]=[CH:4]2)[CH:8]=[CH:9][CH:10]=[C:11]3[NH:13][CH2:14]1
Reactant: CNc1cccc2cccc(NC)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1cc2c3c(cccc3c1)NCN2
Yield: 170.7 %

Procedure:
The above aldehyde (1.47 g, 4 mmol) was treated with N,N'-dimethyl-1,8-diaminonaphthalene (4.2 mmol), and para-toluenesulfonic acid (5 mg) in tetrahydrofuran (15 mL) for 20 min at room temperature. The solution was diluted with ether, washed with dilute sodium carbonate, and concentrated. The residue was recrystallized from hexane-ethyl acetate to give the 2,3-dihydroperimidine 7 (1.22 g, 59%): mp 89-90° C.; NMR 7.5-6.75(m, 12H), 6.34(d, 2H), 4.24(t, 1H), 3.9(2t, 4H), 3.02(s, 6H), 1.8-1.2(m, 16H), 0.85(t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([NH:16][CH2:17]C2C=CC(OC)=CC=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.S(S([O-])=O)([O-])(=O)=[O:27].[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:17](=[O:27])[NH:16][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CNC(c2ccccc2)c2cc(Br)ccc2O)cc1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1NC(c2ccccc2)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromo-2-[(4-methoxy-benzylamino)-phenyl-methyl]-phenol (0.30 g, 0.693 mmol) is slurried in acetonitrile (3 mL). An aqueous solution of ceric ammonium nitrate (1.15 g, 2.10 mmol) is slowly added dropwise at room temperature. The reaction mixture is shaken at room temperature for 2 hours. The mixture is poured into an aqueous solution of sodium pyrosulfite and left for half an hour. The aqueous phase is exhaustively extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate. After evaporated to in vacuo the residue is triturated with acetonitrile. The insoluble product is collected by filtration and dried. This provides the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[CH:13]([Mg]Br)=[CH2:14]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[NH:10][CH:14]=[CH:13]2
Reactant: C=C[Mg]Br
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COc1ccc(Cl)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 28.7 %

Procedure:
To a solution of 4-chloro-3-nitroanisole (6.0 g, 32.0 mmol) in tetrahydrofuran (140 mL) at −40° C. was added vinylmagnesium bromide (1M in tetrahydrofuran, 112 mL, 112.0 mmol). The mixture was stirred at −40° C. for 1.5 hours and then quenched by the addition of saturated aqueous ammonium chloride solution (150 mL). The reaction mixture was allowed to warm to room temperature and then the product extracted into ethyl acetate (×2). The combined organic layers were dried over magnesium sulphate, filtered and concentrated at reduced pressure. The product was purified by silica gel chromatography eluting with 2-15% ethyl acetate in hexane to yield the title compound (D11), (1.67 g).