Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[O:6])([CH3:3])[CH3:2].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([C:28]([F:31])([F:30])[F:29])[N:21]=1>ClCCCl>[CH3:27][O:26][C:24]1[N:23]=[C:22]([C:28]([F:31])([F:29])[F:30])[N:21]=[C:20]([NH:19][C:17](=[O:18])[NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])(=[O:15])=[O:14])[N:25]=1
Reactant: COc1nc(N)nc(C(F)(F)F)n1
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of 5.4 g of 2-(i-propoxycarbonyl) benzenesulfonyl isocyanate (20 mmol) in 5.4 g of 1,2-dichloroethane is added dropwise over the course of 5 min to a solution of 3.9 g of 2-amino-4-methoxy-6-trifluoromethyl-1,3, 5-triazine (20 mmol) in 150 ml of 1,2-dichloroethane at 25° C. The mixture is stirred at 25° C. for 16 h and then at 50° C. for 2 h. After removal of the volatiles under waterpump vacuum at 60° C., the residue is stirred with a mixture of ethanol and pentane, when crystallization occurs. The product is filtered off with suction and dried at 50° C. under waterpump vacuum. 6.1 g of the title compound (13 mmol; 66% of theory) are isolated with melting point 182°-185° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[OH-].[Na+].CCOCC>C(O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:7]([CH3:8])[C:6]1=[O:9])=[O:19])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccn1)C(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C1CC(c2ccccn2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A solution of the diketoester 20b (3.1 g, 11.19 mmol) in dry ethanol (35 ml) was added dropwise to a solution of sodium hydroxide (0.447 g, 11.19 mmol) in dry ethanol (15 ml) with vigorous stirring. The solution was stirred at room temperature overnight. Ether (200 ml) was added and the organic phase was washed with 2 N HCl (3×100 ml). The aqueous layer was cooled to 0° C. and made slightly basic by addition of sodium bicarbonate. The aqueous layer was then extracted with ethyl acetate (3×300 ml) and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give an oil that was purified by flash column chromatography (EtOAc/hexanes, 1:10) to give the cyclic β-ketoester 21b (2.115 g, 73%) as a yellow oil: TLC Rf=0.35 (silica gel, 33% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.62-7.60 (m, 1H), 7.54-7.52 (m, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.56 (dd, J=2.8 Hz, 7.2 Hz, 1H), 3.42-3.25 (m, 2H), 2.41 (s, 3H), 2.12 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 203.2, 169.5, 164.4, 151.4, 150.6, 136.8, 136.5, 134.2, 123.3, 61.7, 51.1, 32.5, 18.6, 14.3, 10.6; HRMS calcd for C15H17NO3+Na+ 282.1106; found 282.1109 [M+Na+].
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:19][C:4]1[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Yield: 107.2 %

Procedure:
To a cold (5° C.) vigorously stirred mixture of 121.87 g (0.936 mole) of ethyl acetoacetate, 314 ml. of benzene and 626 ml. of water was added 41.25 ml. of 33% sodium hydroxide. To the above mixture was added simultaneously, in two dropping funnels, 177.0 g (1.01 mole) of p-chlorobenzoyl chloride and 188.8 ml. of 33% sodium hydroxide in 2 hours. The reaction mixture became pasty. The reaction mixture was heated at 35° C. for 1 hour, cooled and filtered to give 170.0 g of sodium salt of ethyl 2-benzoylacetoacetate. Part (150 g) of this salt was added to a mixture of 39.0 g (0.729 mole) of ammonium chloride and 78 ml. of concentrated ammonium hydroxide in 780 ml. of water. The mixture was stirred at 40°-50° C. for 3 hours and cooled in an ice bath. The precipitate was filtered to give 115.5 g of yellow solid which was Kugelrohr distilled to give 76.0 g (38% based on ethyl acetoacetate) of crude ethyl p-chlorobenzoylacetate. A mixture of 40.0 g (0.175 mole) of crude ethyl p-chlorobenzoylacetate, 24.2 g (0.18 mole) of sulfuryl chloride and some chloroform was held at reflux for 6 hours, cooled and concentrated to give 49.0 g of crude ethyl 2-chloro-p-chlorobenzoylacetate. A mixture of 46.0 g (0.174 mole) of crude ethyl 2-chloro-p-chlorobenzoylacetate, 13.25 g (0.174 mole) of thiourea, and 174 ml. of ethanol was held at reflux for 2 hours and cooled. The precipitate was filtered and neutralized with saturated sodium bicarbonate. The insoluble material was filtered to give 37.0 g (80%) of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate, m.p. 198°-200° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=O.[CH3:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].Cl>CCCCCC.O1CCCC1>[CH3:18][O:17][C:13]1[CH:12]=[C:7]([C:8](=[O:10])[CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:6]=[C:5]([O:4][CH3:3])[C:14]=1[O:15][CH3:16]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C(=O)CC(=O)C(C)(C)C)cc(OC)c1OC
Reaction time: 5 h
Yield: 73.6 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 3.0 gm (75 mmol) of 60% sodium hydride, 10 gm (44.3 mmol) of methyl 3,4,5-trimethoxybenzoate, and 80 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and refluxed with heating while 5.3 gm (53.2 mmol) of pinacolone was added dropwise. Refluxing under heat was continued for 5 hours. After cooling the reaction mixture, 45 ml of 2N hydrochloric acid was added, the mixture was extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Hexane was added to the crude product and insoluble substances were filtered off. The filtrate was concentrated by evaporation, and recrystallization afforded 9.6 gm of the target compound as colorless needles (yield: 74%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Br:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[N:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]CC)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2>C(OCC)C.C1COCC1.CCOCC.CS(C)=O>[Br-:6].[CH2:1]([N+:12]12[CH2:13][CH2:14][C:15]([C:20]([OH:22])([C:7]3[CH:11]=[CH:10][S:9][CH:8]=3)[C:7]3[CH:11]=[CH:10][S:9][CH:8]=3)([CH2:16][CH2:17]1)[CH2:18][CH2:19]2)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: Brc1ccsc1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCCC[N+]12CCC(C(O)(c3ccsc3)c3ccsc3)(CC1)CC2
Product: [Br-]
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
A solution of n-Butyl lithium (2.5M in hexanes, 5.0 mL, 12.5 mmol) was chilled to −78° C. under Ar. 3-Bromothiophene (1.15 mL, 12.3 mmol) dissolved in ethyl ether (4.0 mL) was slowly added to the reaction mixture. The reaction was stirred for 30 min and then ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.7640 g, 4.16 mmol) in THF/Et2O (4 mL/4 mL) was added. The reaction was allowed to warm up from −78° C. to room temperature over 16 h then slowly quenched with water. The reaction was concentrated and the resulting brown solid was taken up in water and DCM. The organic phase was separated, dried over MgSO4, filtered and concentrated under vacuum to give a brown solid. The solid was dissolved in DMSO and purified by preparatory HPLC to give the title compound (0.1736 g, 9.4%). EI-MS m/z 362 (M+) Rt (1.73 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1.[F:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1.C(#N)C>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=3)=[CH:4][C:3]=2[C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1noc(=O)[nH]1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(Nc1cc(F)cc(F)c1)Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of dry toluene was 5 g of 3-(4-amino-4′-trifluoromethyl-biphenyl-3-yl)-4H-[1,2,4]oxadiazol-5-one suspended and 2.5 g of 3,5-difluorophenyl isocyanate was added, the reaction mixture was stirred at room temperature overnight, 1.3 g of 3,5-difluorophenyl isocyanate was added and stirring was continued overnight. 3,5-Difluorophenyl isocyanate (1.3 g) and 100 ml of acetonitrile was added, the reaction mixture was stirred at room temperature for 90 min. and evaporated to dryness. The residue was dissolved in 100 ml of boiling acetone, then cooled to 0° C. and filtrated. The precipitate was recrystallized from 200 ml of ethanol, after filtration while hot, the solution was added 400 ml of water. The product was isolated by filtration. Yield 4 g (54%) mp.>150° C. decomp.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16])=[O:4].[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([N:36]3[C:47]4[C:39](=[C:40]5[C:44](=[CH:45][CH:46]=4)[NH:43]C(C(O)=O)[CH2:41]5)[CH:38]=[CH:37]3)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[CH:28]1[C:29]2[CH:30]([CH2:32][O:33][C:34]([N:36]3[C:47]4[C:39](=[C:40]5[C:44](=[CH:45][CH:46]=4)[NH:43][CH:2]([C:3]([O:5][C:6]4[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=4[F:16])=[O:4])[CH2:41]5)[CH:38]=[CH:37]3)=[O:35])[C:31]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)C1Cc2c(ccc3c2ccn3C(=O)OCC2c3ccccc3-c3ccccc32)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C1Cc2c(ccc3c2ccn3C(=O)OCC2c3ccccc3-c3ccccc32)N1

Procedure:
Pentafluorophenyl trifluoroacetate (0.3 mL, 1.75 mmol) was added to a solution of acid 9 (0.3 g, 0.7 mmol) and triethylamine (0.3 mL, 2.1 mmol) in 4 mL of anhydrous DMF. After 1 h DMF was evaporated and the residue chromatographed on silica eluting with 2% acetone in methylene chloride. Concentration of the pure product fraction and drying afforded 0.29 g (70%) of PFP ester 10 as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH2:14][C:15]([OH:17])=O)=[CH:4]1)[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH2:14][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[CH:4]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1cc(CC(=O)O)c2c(O)cc(F)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1cc(CC(=O)N2CCOCC2)c2c(O)cc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of compounds 11-3 (119 mg, 0.5 mmol) in DMF (2 mL) was added morpholine (66 uL, 0.75 mmol), triethylamine (0.24 mL, 1.75 mmol) and BOP (265 mg, 0.6 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with water and extracted with EtOAc. Combined organic layers were washed with 1N HCl, water, brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, ethyl acetate:hexanes: 25:75 to 100%) gave pure 11-4 (140 mg, 91%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=O)[O:5][C:6]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:48]1([CH2:53][CH2:54][NH2:55])[CH2:52][CH2:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH:55][CH2:54][CH2:53][N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:23])[O:5][C:6]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17]
Reactant: Cc1cc(-c2cccc(C(=O)O)c2)oc1C=C1C(=O)Nc2ccccc21
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cccc(C(=O)NCCN3CCCC3)c2)oc1C=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-methyl-5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (40 mg, 0.12 mol) and HOBt (32 mg, 0.24 mol) in DMF (0.5 mL) was added EDCI (46 mg, 0.24 mmol). The reaction was stirred at rt for 10 min and then added 2-(pyrrolidin-1-yl)ethanamine (0.05 mL) followed by DIEA (0.05 mL). The reaction mixture was stirred at rt for 1 h and diluted with H2O (10 mL). The mixture was extracted with EtOAc (3×20 mL), dried over Na2SO4 and concentrated. The crude was purified by prep TLC (5%/MeOH, 1% TEA/DCM) to give 3-(4-methyl-5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide (25 mg) LCMS (ES): m/z 442 [M+1]+.
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH:10]=O.[CH3:14][O:15][C:16](=[O:28])C(NC(=O)C)P(OC)(OC)=O.N12CCCN=C1CC[CH2:32][CH2:31][CH2:30]2.[Na]>ClCCl>[CH3:32][C:31]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:30]=1)[CH:6]=[N:7][C:8]([C:16]([O:15][CH3:14])=[O:28])=[CH:9]2
Reactant: COC(OC)c1ccncc1C=O
Reactant: COC(=O)C(NC(C)=O)P(=O)(OC)OC
Reactant: C1CCC2=NCCCN2CC1
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)c1cc2cc(C)ccc2cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a cold solution of 4-Dimethoxymethyl-pyridine-3-carbaldehyde (tetrahedron letters 2004 (45), 553-556) (400 mg, 1.91 mmol) in dichloromethane (10 ml) was slowly added a solution of Acetylamino-(dimethoxy-phosphoryl)-acetic acid methyl ester (synthesis 1984, 53-60) (503 mg, 2.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 ml, 2.1 mmol). The solution was stirred at 0° C. for 1 hour then at room temperature for 18 hours. The mixture was poured onto a cold saturated solution of sodium hydrogenocarbonate, extracted with dichloromethane, dried over sodium sulfate and concentrated to dryness. The residue was dissolved in toluene (49 ml) and treated with p-toleunesulfonic acid (315 mg, 1.66 mmol). The mixture was heated at reflux temperature for 18 hours and then concentrated under vacuum. The brown residue was dissolved in ethyl acetate, washed with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated to yield methyl 6-methyl-isoquinoline-3-carboxylate (241 mg, 62%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[S:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:46][C:44]1[S:45][C:41]2[C:40]([CH:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=2[N:43]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12

Procedure:
From 2-bromo-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 450 (M{81Br}+H+, 100), 448 (M{79Br}+H+, 85).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[C:7]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:8][C:9]([CH2:24][O:25][CH2:26][CH:27]=[CH2:28])=[CH:10][C:11]=1[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[NH2:2].[CH2:34]1COCC1>[Pt]=O>[C:1]([C:4]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[C:7]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:8][C:9]([CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:10][C:11]=1[N:12]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[NH2:2]
Reactant: C=CCOCc1cc(OCC(=O)O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reactant: C1CCOC1
Agent: O=[Pt]
Product: CCCOCc1cc(OCC(=O)OC)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Platinum oxide (30 mg) was added to a stirred THF (30 mL) solution containing the compound of Example 58 (120 mg, 0.262 mmol) under a nitrogen atmosphere. The mixture was then stirred under a hydrogen atmosphere for 30 minutes. After filtration and concentration, the residue was chromatographed on silica (gradient 0-6% methanol in methylene chloride) to afford the subtitled compound (117 mg, 97%) as a white solid. IR (KBr) 3364, 3166, 1758, 1742, 1642 cm−1; 1H-NMR (CDCl3): δ 0.91 (t, J=7.4 Hz, 3H, —CH3), 1.57-1.65 (m, 2H), 3.40 (t, J=6.6 Hz, 2H, —OCH2—), 3.83 (s, 3H, —OCH3), 4.60 (s, 2H, —OCH2—), 4.91 (s, 2H, —OCH2—), 5.52 (s, 2H, —NCH2—), 5.95 (br s, 1H, —NH), 6.06 (br s, 1H, —NH), 6.58 (s, 1H), 7.04 (s, 1H), 7.07-7.10 (m, 2H), 7.20-7.41 (m, 6H); ESIMS m/e 461 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CCN(C(C)C)C(C)C.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][O:25][C:21](=[O:24])[CH:22]=[CH:23][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11]
Reactant: C=CC(=O)OC
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1C
Temperature: 110 °C
Yield: 91.1 %

Procedure:
To a solution of 2-bromo-5-nitrotoluene (3.11 g, 14.39 mmol) in propionitrile (105 mL) is added DIPEA (5.1 mL, 29.28 mmol). The mixture is degassed three times. Methyl acrylate (5.2 mL, 57.74 mmol) is added and the mixture is degassed. Tri-o-tolylphosphine (1.77 g, 5.82 mmol) and Pd(OAc)2 (0.64 g, 2.85 mmol) are added and the mixture is degassed a final two times followed by heating at 110° C. for 4 h. Upon cooling, the mixture is passed through Celite and the filtrate is concentrated. The residue is partitioned between Et2O and 1N HCl. The organics are washed with saturated NaHCO3 and brine, and dried with Na2SO4. The crude material is purified by flash chromatography to yield the title compound (2.90 g, 91%).
Reaction SMILES: [N:1]([CH:4]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:13]=[CH:12][N:11]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[N+]=[N-].CO.CCOC(C)=O>CCOC(C)=O.[Pd]>[CH2:8]([CH:5]([CH2:6][CH3:7])[CH:4]([NH2:1])[C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[N:13]=[CH:12][N:11]=1)[CH3:9]
Reactant: CCC(CC)C(N=[N+]=[N-])c1ncnn1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(CC)C(N)c1ncnn1Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a suspension of 5% Pd/C in EtOAc was added a solution of 5-(1-azido-2-ethylbutyl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole in EtOAc and the mixture was shaken on a Parr apparatus for 2 h under 3 atm of H2. The mixture was filtered through Celite, washed several times with EtOAc, concentrated in vacuo, and purified by column chromatography (SiO2, EtOAc, then, MeOH/EtOAc, 1:9, then 1:4) to yield 68% of the amine.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.C1CCN2C(=NCCC2)CC1.[B-](F)(F)(F)F.CCN([S+](F)F)CC>C(Cl)Cl>[CH3:25][C:24]1[C:23](=[O:26])[O:22][CH2:21][C:20]=1[N:4]1[CH:3]=[CH:2][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5]1=[O:19]
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC1=C(N2C=CC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (300 mg, 0.819 mmol) in DCM (8.2 mL) at 0° C. was added DBU (370 μl, 2.46 mmol), and XtalFluor-E® (562 mg, 2.46 mmol). The mixture was stirred overnight while warming up to rt, and quenched with aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LC/MS: [(M+1)]+=349
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([NH:15][CH2:16][CH2:17][NH2:18])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:13][NH:15][CH2:16][CH2:17][NH:18][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCNCCN
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNCCNc1cc([N+](=O)[O-])ccc1C#N
Reaction time: 16 h

Procedure:
A mixture of 2-fluoro-4-nitrobenzonitrile (13.2 g), N-ethylethylenediamine (16 mL) and potassium carbonate (10 g) in acetonitrile (250 mL) was vigorously stirred for 16 hours resulting in the formation of an orange solid. The mixture was diluted with water and filtered. The precipitate was washed with water and dried to provide 2-(2-methylamino-ethylamino)-4-nitro-benzonitrile (10 g): 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.55 (m, 2H), 5.8 (br, 1H), 3.4 (q, 2H), 3.1 (m, 2H), 2.8 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]([CH3:16])[CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]([CH3:16])[CH3:15])[CH3:17])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC(C)C)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C(C)C)c1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-bromo-3-(isopropylamino)-2-methylbenzoate (0.5 g, 1.75 mmol) in acetonitrile (10 mL), Cs2CO3 (1.02 g, 2.63 mmol) and methyl iodide (1.45 g, 3.5 mmol) were added to it. The resulting reaction mixture was stirred at 80° C. for 4 h. Upon completion, the solvent was removed under reduced pressure and residue dissolved in water and extracted with ethyl acetate. Crude material obtained was purified by column chromatography over silica gel affording the desired compound product without further purification (0.39 g)
Reaction SMILES: [C@H:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18](Br)[CH:19]=[CH2:20]>C(Cl)Cl>[CH2:20]([NH:10][C@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[CH:19]=[CH2:18]
Reactant: N[C@@H]1CCc2ccccc21
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN[C@@H]1CCc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1R)-indan-1-amine (1.00 g, 7.51 mmol) and triethylamine (1.52 g, 15.0 mmol) in DCM (75 mL) was added allyl bromide (1.36 g, 11.3 mmol) and the mixture was allowed to stir at ambient temperature for 3 days. An additional 1.5 equivalents of allyl bromide and 0.5 equivalents of triethylamine were then added, and the reaction mixture was stirred an additional 24 hours. LCMS analysis now indicates the reaction mixture is a 27:35:38 mixture of starting material:desired product:bis-allylation product. Use this solution as is.