Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)Cl)=[CH:4][N:3]=1.C(=O)([O-])[OH:12].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:12])=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: Clc1ccc(C(Cl)Cl)cn1
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(Cl)nc1
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of 7.0 g (0.0356 mol) of 2-chloro-5-dichloromethyl-pyridine and 100 ml of water is heated to reflux. The pH is kept between 4 and 7 by adding a saturated sodium hydrogencarbonate solution dropwise. After 2 hours, the mixture is cooled, extracted using ethyl acetate and the solvent is carefully removed from the organic phase by distillation in a water jet vacuum. 4.6 g (95% of theory) of 6-chloro-nicotinaldehyde of melting point 70° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=O.C>C(O)C>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[N:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:16]=[CH:17][C:18]=1[OH:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5.30 g (40 mmol) of (t-butoxycarbonyl)hydrazine in 40 ml of 80% aqueous ethanol was added a solution of 5.52 g of 3,4-dihydroxybenzaldehyde in 40 ml of the same solvent. After stirring for three hours at room temperature, the mixture was clarified with charcoal, filtered and the filtrate evaporated in vacuo. The residue was triturated with petroleum ether, filtered off by suction and dried in vacuo; yield: 8.5 g.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:6]=1[C:7]([CH:9]1[CH2:11][CH:10]1[C:12]#[N:13])=[O:8]>C(OCC)C>[F:4][C:5]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:6]=1[C:7]([CH:9]1[CH2:11][CH:10]1[C:12]#[N:13])([OH:8])[CH3:1]
Reactant: N#CC1CC1C(=O)c1ccc(F)cc1F
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)(c1ccc(F)cc1F)C1CC1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.2 ml (15.6 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 2.15 g (10.4 mmol) of the compound from Example 123A in 50 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.16 g (93% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33].CCN(CC)CC>ClCCl>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.5 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), 1-propanesulfonyl chloride (11 μL, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) were dissolved in dichloromethane (1.0 mL) and allowed to stir at 25° C. for 16 hours. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propylsulfonamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide (5.3 mg, 10%). ESI-MS m/z calc. 506.6, found 507.3 (M+1)+; retention time 3.48 minutes.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:20]#[C:21][Si](C)(C)C)[C:16]=3[CH:26]=1)=[O:11])[CH2:2]2.C([O-])(O)=O.[Na+]>CO>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:20]#[CH:21])[C:16]=3[CH:26]=1)=[O:11])[CH2:2]2
Reactant: C[Si](C)(C)C#Cc1coc2ccc(C(=O)N[C@H]3CN4CCC3CC4)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C#Cc1coc2ccc(C(=O)N[C@H]3CN4CCC3CC4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-[(trimethylsilyl)ethynyl]-1-benzofuran-5-carboxamide (255 mg, 0.70 mmol) is dissolved in MeOH (6 ml). The solution is treated with saturated NaHCO3 (2 ml) and the reaction is stirred overnight at RT. The volatiles are removed in vacuo and the residue is chromatographed over 30 g silica gel (230-400 mesh) eluting with 8% MeOH/CHCl3+1% conc. NH4OH. The appropriate fractions are combined and concentrated to give 190 mg of a yellow foam. The foam is crystallized from Et2O to provide 138 mg (67%) of Example 22 as a pale yellow solid. HRMS (ESI) calcd for C18H18N2O2+H: 295.1446, found 295.1458 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(-c2cccs2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccs2)cc1
Yield: 35.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-yl)benzamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424 mmol), 4-(thiophen-2-yl)benzoyl chloride (0.102 g; 0.445 mmol), and triethylamine (0.149 mL; 1.06 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.058 g (36%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-2-yl)benzamide as a white solid.
Reaction SMILES: C([O:8][C:9]([CH:11]([CH2:25][CH2:26][C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:12][P:13]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:15])[OH:14])=[O:10])C1C=CC=CC=1>O.[Pd]>[C:19]1([CH2:18][CH2:17][CH2:16][P:13]([CH2:12][CH:11]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:9]([OH:10])=[O:8])([OH:15])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=C(O)CCC(CP(=O)(O)CCCc1ccccc1)C(=O)O
Yield: 87 %

Procedure:
2,4-Di(benzyloxycarbonyl)butyl(3-phenylpropyl)phosphinic acid (15) (1.4 g, 2.8 mmol) in 20 mL of water containing 150 mg of 10% Pd/C was hydrogenated at 40 psi overnight. Filtration through a Celite pad followed by evaporation on high vacuum gave 0.8 g (89%) of 2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=CH2CH2CH2Ph) as a light yellow viscous oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=2)[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([CH3:37])[C:34]([NH2:36])=[O:35])#[CH:26].F[B-](F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:36][C:34](=[O:35])[CH:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]#[C:26][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=2)[N:3]=1)[CH3:37]
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: CC(C)(C)OC(=O)n1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C(=O)OC(C)(C)C)c2)ncc1C(F)(F)F

Procedure:
A degassed mixture of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylate A61 (0.373 g, 1.03 mmol), 2-(2-ethynylphenyl)propanamide K7 (0.452 g, 2.40 mmol), PdCl2(PPh3)2 (0.015 g, 0.02 mmol), t-Bu3PH.BF4 (0.011 g, 0.038 mmol) and CuI (0.007 g, 0.04 mmol) in 1,4-dioxane (6.0 mL) and DIPEA (0.90 mL, 5.2 mmol) was heated in the microwave at 100° C. for 30 minutes. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A62 (0.309 g, 58%). LCMS-D: rt 3.533 min; m/z 502.2 499.2 [M−H]−.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>C(OCC)C>[CH3:29][O:28][C:24]1[CH:23]=[C:19]([C:20]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:21])[CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: CCOCC
Product: COc1cc(C(=O)Nc2ccccc2Nc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as 3,4,5-trimethoxybenzoyl chloride (2.31 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. The reaction mixture was then stirred overnight at room temperature. The solvents were then removed in vacuo leaving N-[(3,4,5-trimethoxyphenyl)carbonyl)-N'-phenyl-phenylenediamine.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:19])[CH3:18].[H][H]>C(OCC)(=O)C>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1cc(OC)c(C(C)=O)c(O)c1CC=C(C)C
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C(C)=O)c(O)c1CCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
An ethyl acetate solution of 22.2 g of 2'-hydroxy4',6'-dimethoxy-3'-(3-methyl-2-butenyl)acetophenone was added into a sufficiently hydrogen gas-absorbed suspension of 1.5 g of 5% palladium-carbon in 20 ml of ethyl acetate, and the mixture was stirred at room temperature for 2 hours in a hydrogen gas atmosphere. After the reaction, the reaction mixture was filtered and the solvent was removed by distillation. The residue was recrystallized from n-hexane to obtain 20.4 g (yield=91.2%) of 2'-hydroxy-3'-isopentyl-4',6'-dimethoxyacetophenone in the form of a colorless needle.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[C:42]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:44])[CH3:43]>>[C:42]([N:45]1[CH2:50][CH2:49][N:48]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=4[O:40][CH3:41])[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH2:47][CH2:46]1)(=[O:44])[CH3:43]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C(C)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 1-acetylpiperazine. MS (ES+): m/z 706.38 (100) [MH+]; HPLC: tR=0.99 min (UPLC, purity).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([CH3:10])[CH3:9])[N:5]=[C:4]([NH:12][CH:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:28][N:29]([CH:31]=[N:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([CH3:9])[CH3:10])[N:5]=[C:4]([NH:12][CH:13]([CH:23]2[CH2:24][CH2:25]2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1)[CH3:30]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(F)c1nc(N)nc(NC(CCCc2ccccc2)C2CC2)n1
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1nc(NC(CCCc2ccccc2)C2CC2)nc(C(C)(C)F)n1

Procedure:
A solution of 1.71 g (5 mmol) of 2-amino-4-(1-fluoro-1-methylethyl)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazine and 2 ml of N,N-dimethylformamide dimethyl acetal in 30 ml of toluene is refluxed for 2 hours. All volatile constituents are subsequently carefully distilled off. This gives 1.94 g (97.5% of theory) of 2-dimethylaminomethyleneamino-4-(1-fluoro-1-methylethyl)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazine as colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:12]=3[CH2:14][O:15]C(=O)C)[C:7](=[O:26])[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[C:12]=3[CH2:14][OH:15])[C:7](=[O:26])[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(COC(C)=O)c(N3CCOCC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(CO)c(N3CCOCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (550 mg) in ethanol (10 ml) is added 2N aqueous potassium carbonate (1 ml), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with water and extracted with dichloromethane. The extract is dried and concentrated. The residue is crystallized by adding thereto diethyl ether to give ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (353 mg), as pale yellow powder, m.p. 212°-216° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:33])[CH3:16])[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)Cc3ccccc3-4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 9H-fluorene-2-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][C:14]1([CH3:22])[O:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][O:15]1>C(Cl)Cl>[CH3:13][C:14]1([CH3:22])[O:19][CH2:18][CH:17]([CH2:20][O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16][O:15]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC(COS(C)(=O)=O)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (4.4 mL, 56 mmol) was added slowly to a solution of Et3N (9.8 mL, 71 mmol) and (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (6.87 g, 47.0 mmol) in CH2Cl2 (100 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The mixture was extracted with CH2Cl2 and the organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a colorless liquid: yield 10.02 g (95%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3](=O)/[CH:4]=[C:5](\O)/[C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:9][CH:10]=1.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[NH:34][NH2:35].C(O)(=O)C>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[N:34]1[C:5]([C:6]2[S:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)=[CH:9][CH:10]=2)=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[N:35]1
Reactant: NNc1cc(Cl)ccc1Cl
Reactant: CS(=O)(=O)c1cccc(-c2ccc(/C(O)=C/C(=O)C(F)(F)F)s2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cc(Cl)ccc3Cl)s2)c1
Temperature: 102.5 °C
Reaction time: 3 h

Procedure:
Into an 8 mL vial was weighed 202.7 mg (539 μmol) of (Z)-1,1,1-trifluoro-4-hydroxy-4-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)but-3-en-2-one, 117.4 mg (550 μmol) of 2,5-dichlorophenylhydrazine hydrochloride, 3 mL of acetic acid, and 1 mL of DMF. The resulting reaction was stirred at 100-105° C. for 3 h then was concentrated to dryness in vacuo. The residue was purified by silica gel flash chromatography (3×23 cm, 1:1 ethyl acetate-hexanes) and was dried affording the product as a faintly yellow solid, yield: 89 mg (55%). 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.87 (d, J=9 Hz, 1H), 7.75 (d, J=9 Hz, 1H), 7.6 (m, 2H), 7.5 (m, 2H), 7.27 (d, J=4 Hz, 1H), 6.90 (s, 1H), 6.87 (d, J=4 Hz, 1H), 3.09 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])(O)=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[CH2:4][C:3]1[N:19]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:18][C:2]=1[CH3:10]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)CC(=O)C(C)Br
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 95 °C
Yield: 34.9 %

Procedure:
To a solution of 140 g (0.67 mol) of methyl 4-bromo-3-oxo-pentanoate in 300 mL of anhydrous toluene was added 210 g (1.73 mol) of benzamide, 132 g (0.93 mol) of sodium hydrogen phosphate, and ˜20 mL of EtOH. The suspension was stirred with heating to 95° C. for 24 h, then cooled to 0° C., filtered, and the solids washed with cyclohexane (2×100 mL) followed by 20% EtOAc in hexanes (200 mL). The combined filtrates were washed with 2×100 mL 10% KOH solution and brine (100 mL). The organics were dried (MgSO4), concentrated to a thin oil, and purified by chromatography on 1 kg of silica gel (230-400 mesh). Gradient elution of the column with 10% to 50% EtOAc in Hexanes gave 54 grams (35% yield) of the title compound as a pale yellow oil; 1H NMR (CDCl3, 400 MHz) δ8.0-7.98 (m, 2H), 7.43-7.40 (m, 3H), 3.73 (s, 3H), 3.59 (s, 2H), 2.37 (s, 3H); low resolution MS (ES+)m/e 232.4 (MH+); TLC Rf=0.64 (4/1 hexanes/EtOAc).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-[(N-Boc)amino]-4-thiazolecarboxylate (1 mmole) in CH2Cl2 (10 mL) was cooled to −78° C., and treated with DIBAL-H (1M, 5 mL). The reaction was stirred at −60° C. for 3 h, and quenched with a suspension of NaF/H2O (1 g/1 mL). The resulting mixture was filtered and the filtrate was concentrated to give 2-[(N-Boc)amino]-4-hydroxymethylthiazole as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>C(O)C>[N+:8]([C:7]1[C:2]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCc1ccccn1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCc1ccccn1
Yield: 95.1 %

Procedure:
To a stirred solution of 2-chloro-3-nitropyridine (26.56 g, 0.168 mol) in absolute ethanol (250 mL) was added 2-(aminomethyl)pyridine (20.0 g, 0.185 mol) and triethylamine (16.99 g, 0.168 mol). The solution was heated at reflux for 2 hr and evaporated under reduced pressure. The residue was triturated in ethyl acetate several times and filtered. The filtrate was washed 3 times with a saturated sodium chloride solution, dried (sodium sulfate), filtered and evaporated under reduced pressure to give 36.8 g of N-(3-nitro-2-pyridinyl)-2-pyridinemethanamine (95% yield). A 1.0 g portion of the solid was recrystallized from isopropyl ether and dried under high vacuum to give 0.57 g of N-(3-nitro-2-pyridinyl)-2-pyridinemethanamine, mp 112°-115° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][CH2:43][CH:39]3[CH2:40][CH2:41][CH2:42][O:38]3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: OCC1CCCO1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2CCCO2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (150 mg, 0.59 mmol), triphenylphosphine (150 mg, 0.59 mmol), tetrahydro-2-furanmethanol (60 mg, 0.59 mmol) in CH2Cl2 (8 mL) at rt was slowly added a solution of diisopropyl azodicarboxylate (200 mg, 1.0 mmol) in CH2Cl2 (3 mL). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]3[O:10][C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C.S(=O)(=O)(O)O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]3[O:10][CH:9]2[OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC2CCCCC2C1c1cccc(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: OC1OC2CCCCC2C1c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 3-(3-chlorophenyl)hexahydro-1-benzofuran-2(3H)-one (540 mg, 2.19 mmol) in dry tetrahydrofuran (7 mL) was cooled to −78° C. under nitrogen and was treated dropwise with a solution of DiBAL (1.0 M in toluene, 3.07 mL, 3.07 mmol). The resulting solution was stirred at −78° C. for 2 h, after which time the reaction was treated a 1 M aqueous solution of sulfuric acid to dissolve precipitated salts. The reaction mixture was allowed to warm to room temperature and was partitioned between diethyl ether and water. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water, and brine and was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% EtOAc/hexane to 35% EtOAc/hexane) to yield 0.38 g (69%) the lactol, 3-(3-chlorophenyl)octahydro-1-benzofuran-2-ol as a white foam. HRMS: calcd for C14H17ClO2−H, 251.0817; found (ESI, [M−H]−), 251.0835.