Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:30]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34](=[O:48])[NH:35]3)[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH3:18])[CH:11]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:30]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34](=[O:48])[NH:35]3)[O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24])[CH3:18])[CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H](Cc1cccc(CCNC(=O)OC(C)(C)C)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Cc1cccc(CCN)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12

Procedure:
A solution of [2-(3-{(R)-2-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethylamino]propyl}phenyl)ethyl]carbamic acid tert-butyl ester (2.8 g) in 20% trifluoroacetic acid in DCM was stirred at room temperature for 3 h. Saturated aqueous sodium bicarbonate solution was added to neutralize the TFA and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were dissolved in 10 ml of dry acetonitrile, and the resulting solution was cooled with ice. To the solution was added 710 mg of 2-methylbenzoyl chloride, and the mixture was allowed to stand at room temperature for 90 minutes. The same procuedre as in Example 1 gave 260 mg (yield: 38.4%) of 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)uridine as crystals having a melting point of 108° to 109° C. This was identical with the crystals obtained in Examples 1 by the mixed examination.
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccsc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(OCc2ccsc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
To an acetic acid (4.1 mL) and dimethyl sulfoxide (70 mL) solution of 3-(4-((E)-2-nitro-vinyl)-phenoxymethyl)-thiophene (4.1 g, 15.7 mmol) described in Manufacturing Example 77-1-2 was added sodium borohydride (950 mg, 25.1 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1.5 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (1.93 g, 47%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (189 mg, 1.06 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (prepared as in Example 77, 300 mg, 0.97 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (200 mg, 2.13 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide (185 mg, 50%) as a pale orange solid: mp 144-145° C.; EI-HRMS m/e calcd for C21H26N2O3S (M+) 386.1664, found 386.1660.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](=[O:33])[CH3:32]>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:7]1[CH:6]=[N:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[C:3](=[O:15])[C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: CC(=O)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1Oc1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 17.9 %

Procedure:
A solution of 4,5-dichloro-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 20, 60.0 g, 0.24 mol) in acetone (600 mL) was treated with potassium carbonate (28.4 g, 0.21 mol), tetrabutylammonium bromide (1.2 g), potassium iodide (38.4 g, 0.23 mol) and 1-(2-hydroxy-phenyl)-ethanone (38.4 g, 0.28 mol). The resulting reaction mixture was stirred at 25° C. for 120 h. After this time, the reaction was filtered. The filtrate was concentrated in vacuo. Silica gel column chromatography (1:10 ethyl acetate/petroleum ether) afforded 5-(2-acetyl-phenoxy)-4-chloro-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (15 g, 18%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C[O-].[Na+].CO[CH:15](OC)[CH2:16][NH2:17].C(O)(=O)C.Cl>C(OCC)(=O)C.O.CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:17][CH:16]=[CH:15][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(CN)OC
Reactant: N#Cc1cccc(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Fc1cccc(-c2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
In a flask containing 3-fluorobenzonitrile (Matrix Scientific, 3.0 g, 25 mmol) was added methanol (30 mL) and sodium methoxide (Aldrich, 25% by wt. in methanol, 2.83 mL, 12.4 mmol). The reaction mixture was stirred for 1.5 hours and aminoacetaldehyde dimethyl acetal (Alfa Aesar, 2.60 g, 24.8 mmol) and acetic acid (2.83 mL, 49.5 mmol) were subsequently added and the solution was heated at reflux for one hour. After cooling to room temperature, methanol (25 mL) and 6 N HCl (8 mL) was added and the solution was heated at reflux for 16 hours. After cooling the solution to room temperature the residue was taken up in a 1:1 mixture (v/v) of water and ethyl acetate (50 mL). The aqueous layer was separated and the pH of this solution was adjusted to pH 9 with 2 N NaOH, upon which a white precipitate formed in solution. The solid was collected by filtration and dried under high vacuum to provide 2-(3-fluorophenyl)-1H-imidazole as an off-white solid (1.67 g, 41% yield, MS (ESI+) m/z 163.1 (M+1).
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[O:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:9]1[O:10][C:6]([CH3:5])=[CH:7][CH:8]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(C=O)o1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc(C)o1)CC(=O)O
Yield: 20.9 %

Procedure:
Sodium ethylate (74.2 g, 1.09 mol) was added under vigorous stirring to a solution of 5-methyl-2-furaldehyde 1 (100 g, 0.91 mol) and diethyl succinate (316 g, 1.81 mol) in ethanol (1 L). The reaction mixture was refluxed for 8 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 500 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, acidified with 10% HCl to pH 2, and subjected to extraction with 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give 45 g (0.19 mol, 21%) of the desired compound as a yellow solid.
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].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)(=[O:37])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CN1CCNCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C)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 N-methylpiperazine. MS (ES+): m/z 678.34 (100) [MH+]; HPLC: tR=0.71 min (UPLC, purity).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[O:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][CH2:11]1>CO>[CH3:1][O:2][C:3]([CH2:4][CH2:5][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:8][CH2:9][CH:10]1[O:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][CH2:11]1)=[O:6]
Reactant: C=CC(=O)OC
Reactant: NCCC1COc2ccccc2O1
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCC1COc2ccccc2O1
Reaction time: 6 h
Yield: 91.5 %

Procedure:
34.1 g (0.396 mol) of acrylic acid methyl ester are added at room temperature to a solution of 32.25 g (0.18 mol) of 2-(2-aminoethyl)-benzo-1,4-dioxan [J. Augustin et al., J. Med. Chem. 8, 446 (1965)] in 250 ml of methanol. The reaction mixture is stirred for 6 hours at 50° and, after cooling, is concentrated by evaporation in vacuo. 57.9 g (91.5%) of N,N-bis(2-methoxycarbonylethyl)-N-[2-(benzo-1,4-dioxan-2-yl)ethyl]-amine are obtained in the form of a red oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>CN(C=O)C.C1COCC1>[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: CN(C)CCO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of sodium hydride (NaH) 60% dispersion in mineral oil (4.5 g, 111 mmol, 1.1 eq.) in anhydrous DMF (200 mL) was added 2-dimethylaminoethanol (11.5 mL, 111 mmol. 1.1 eq.). The reaction mixture was heated to 50° C. for 30 min. Then, 6-chloronicotinonitrile (14.8 g, 101 mmol, 1 eq.) in THF (100 mL) was added dropwise and the mixture was stirred overnight at 50° C. The solvents were removed under reduced pressure, the resulting residue was dissolved in water and acidified with conc. HCl (hydrochloric acid) to pH 1. The solution was washed with CH2Cl2 (2×200 mL), the aqueous layer was basified with conc. NaOH (sodium hydroxide) to pH about 10 and extracted with diethyl ether. The organic phase was washed with brine, dried over Na2SO4, and filtered. Removal of the solvent in vacuo gave the title compound as an off-white solid (19.32 g, 99%) (m.p.:58° C.).
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(O)c1cccc(NS(C)(=O)=O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
650 mg (3.02 mmol) of rac-N-[3-(1-hydroxyethyl)phenyl]methanesulfonamide (Example 87A) were initially charged in 9 ml of dichloromethane. At 0° C., 1.08 g (9.07 mmol) of thionyl chloride were added dropwise, and the reaction solution was stirred at RT for 3 h. The reaction solution was evaporated.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(O)C.[CH:31]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH2:32]>>[CH:23]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([CH2:32][CH2:31][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:2]5)[CH:27]=[CH:26][C:8]=4[C:9]=3[N:10]=2)=[N:21][C:20]([CH3:22])=[N:19]1)([CH3:25])[CH3:24]
Reactant: C=CS(C)(=O)=O
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Solvent: CCO
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CCS(C)(=O)=O)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution of 8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.811 g, 0.000786 mol) in ethanol (4.0 mL, 0.068 mol) was added methyl vinyl sulfone (0.0703 mL, 0.000786 mol) via syringe. The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 491 (213.4 mg) as a colorless solid. MS(ESI+) 488.2. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2, 1H), 7.20 (dd, J=8.3, 1.7, 1H), 7.05 (d, J=1.6, 1H), 5.85-5.64 (m, 1H), 4.36 (t, J=5.0, 2H), 3.62 (m, 3H), 3.42 (t, J=5.0, 2H), 3.15 (m, 4H), 3.06 (s, 3H), 2.85 (m, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H)
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=O)C)([O-:3])=[O:2].Cl.IC>CO>[CH3:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCCC2
Agent: Cl
Solvent: CI
Solvent: CO
Product: CNc1ccc2c(c1[N+](=O)[O-])CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
A mixture of N-(1-nitro-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (800 mg, 3.88 mmol) in a 10 M solution of hydrochloric acid in MeOH were heated to reflux for 4 h. After concentration, the residue was basified with 2 N aqueous solution of NaOH to pH 9, then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (30 mL), dried, and concentrated. The residue was dissolved in DMF (20 mL), cooled to 0° C., and NaH (60% dispersion in mineral oil, 0.155 mg, 3.88 mml) was added in one portion. Iodomethane (582 mg, 3.88 mmol) was added dropwise. The resulting mixture was stirred at the same temperature for another 2 h. The reaction mixture was quenched by ice (20 g) and then extracted with EtOAc (50 mL×2). The organic layer was washed with brine (20 mL), dried, and concentrated to give a yellow solid (190 mg). ESI MS: m/z 207 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH2:11]Cl)[CH:5]=1)[CH3:2].[P:13]([O-:22])([O:19][CH2:20][CH3:21])([S:15][CH2:16][CH2:17][CH3:18])=[S:14].[K+].[I-].[Na+]>CC(C)=O>[P:13]([S:15][CH2:16][CH2:17][CH3:18])([O:19][CH2:20][CH3:21])([S:14][CH2:11][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=[C:8]([CH3:10])[N:7]=1)=[O:22]
Reactant: CCOc1cc(CCl)nc(C)n1
Reactant: CCCSP([O-])(=S)OCC
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCSP(=O)(OCC)SCc1cc(OCC)nc(C)n1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
8.0 g (0.043 mol) of 6-ethoxy-4-chloromethyl-2-methyl-pyrimidine and 10.8 g (0.045 mol) of potassium O-ethyl S-(n-propyl) dithiophosphate are suspended in 20 ml of acetone. After the addition of a small amount (spatula tip) of sodium iodide the mixture is stirred well at 45° C. for 12 hours. The mixture is then filtered through Celite, the filtrate is concentrated under reduced pressure and the thus-isolated solid is taken up in 100 ml of toluene. The toluene solution is washed once with 5% sodium carbonate solution and once with saturated sodium chloride solution and dried over anhydrous sodium sulphate, and the solvent is removed by evaporation at 60° C. under reduced pressure. In this manner there is obtained O-ethyl S-(6-ethoxy-2-methyl-4-pyrimidinylmethyl) S-(n-propyl) dithiophosphate as an almost colourless oil, nD20 1.5385.
Reaction SMILES: C(O)C.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][CH3:8].Br[C:25]1[C:30]([F:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[C:27]([F:35])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC.O.C1C=CC=CC=1>[F:31][C:30]1[CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:27]([F:35])=[CH:26][C:25]=1[C:18]1[CH:17]=[CH:16][C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(B(O)O)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3cc(F)c([N+](=O)[O-])cc3F)cc2)CC1

Procedure:
First, 50 ml of ethanol containing 7.52 g of 4-(trans-4-pentylcyclohexyl)phenylboronic acid dissolved therein, 50 ml of benzene containing 5.0 g of 4-bromo-2,5-difluoro-1-nitrobenzene dissolved therein, 21.0 ml of a sodium carbonate aqueous solution with a concentration of 2.0 mol/l, and 0.61 g of tetrakis(triphenylphosphine)palladium(0) were put in an argon-replaced 200 ml flask, and stirred under reflux for 12 hours. After the reaction, water and ether were added to the reaction solution for extraction. The resultant ether layer was washed with a saturated brine and dried with sodium :sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:toluene/hexane=1/4) and recrystallized from hexane, to obtain 6.87 g (Y: 84.4%) of 2,5-difluoro-4-nitro-4′-(trans-4-pentylcyclohexyl)biphenyl. The purity of the resultant compound was 100.0% as measured by GC. The phase transfer temperature of the compound was as follows.
Reaction SMILES: [O-]CC.[Na+].O=[C:6]1[CH:11]([C:12]([O:14]CC)=O)[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7]1.[O:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)=[CH:27][N:26]=[CH:25]1>C(O)C>[OH:14][C:12]1[C:11]2[CH2:10][CH2:9][N:8]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:7][C:6]=2[N:38]=[C:36]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([C:28]3[O:24][CH:25]=[N:26][CH:27]=3)=[CH:30][CH:31]=2)[N:37]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: N=C(N)Nc1ccc(-c2cnco2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(O)nc(Nc3ccc(-c4cnco4)cc3)nc2C1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
Sodium ethoxide (0.476 g, 7.00 mmol) was added to 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (1.899 g, 7.00 mmol, Example 1d) and 1-(4-(oxazol-5-yl)phenyl)guanidine (1.415 g, 7.00 mmol, Example 1e) in ethanol (10 mL). The reaction vial was heated a microwave reactor at 100° C. for 15 minutes. The suspension was diluted with ethanol (5 ml) and the precipitated crude product was filtered off and washed with cold ethanol to give tert-butyl 4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (1.200 g, 41.9%). No further purification. MS (ESI+)/(ESI−) m/z 410/408
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12](OC)=[O:13])[C:6]=1[N+:16]([O-])=O.[H][H]>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:16][C:12](=[O:13])[CH2:11]2
Reactant: COC(=O)Cc1cccc(CC(=O)OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1cccc2c1NC(=O)C2

Procedure:
A solution of 2-nitro-1,3-benzenediacetic acid dimethyl ester (5.98 g, 0.022 mole) in tetrahydrofuran and methanol (2:1, 100 ml) is treated with hydrogen gas in the presence of 20% Pd/C for 18 hours. The mixture is filtered and concentrated at reduced pressure to yield 2,3-dihydro-2-oxo-1H-indole-7-acetic acid methyl ester. Final purification is accomplished using flash chromatography on silica (elution with 1:19 methanol:dichloromethane) and results in pure 2,3-dihydro-2-oxo-1H-indole-7-acetic acid methyl ester, mp 156°-157° C.