Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>C(OC(O)C)C.O>[NH2:20][C:19]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: NNc1ccc(Cl)c(Cl)c1Cl
Reactant: CCOC=C(C#N)C#N
Agent: CCOC(C)O
Solvent: O
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Yield: 52.2 %

Procedure:
2,3,4-Trichlorophenylhydrazine (21.15 g) and ethoxymethylenemalononitrile (12.8 g) in ethoxyethanol (100 ml) were heated at reflux for one hour. The solution was then cooled and diluted with water. The sticky solid precipitate thus obtained was crystallized from toluene (48 ml) to give 5-amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (15 g), m.p. 154°-156° C., in the form of off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH:25]([CH3:27])[CH3:26].[NH4+].[Cl-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:25]([CH3:27])[CH3:26])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CC(C)Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)C(C)C)cc1OC
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
To a solution of 9.99 g (56.4 mmol) of (3,4-Dimethoxyphenyl)acetonitrile in 141 mL of tetrahydrofuran (THF) at −30° C., was slowly added 56.4 mL (56.4 mmol) of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF). The mixture was stirred at −30° C. for 10 minutes and 10.6 mL (113.0 mmol) of 2-bromopropane was added. The mixture was heated to reflux for 2 hours (h) then left at 22° C. for about 16 h. A saturated aqueous solution of NH4Cl was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][S:9](O)(=[O:11])=[O:10]>S1(CCCC1)(=O)=O>[S:9]([OH:11])(=[O:10])([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:8]
Reactant: Nc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O=S1(=O)CCCC1
Product: Nc1ccc(S(=O)(=O)O)cc1

Procedure:
247.7 g (2.525 mols) of aniline are reacted in 500 ml of sulpholane with 245.3 g (2.50 mols) of 100% strength H2SO4, as described in Example 1. A yield of p-sulphanilic acid of 95.9% is obtained.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2[CH:3]=[CH:2]1)C3.C[SiH:12]([Cl:14])[Cl:13].CCCCCCCCCCCCCCCC>[Pd](Cl)Cl.C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:5]1([CH2:6][SiH:12]([Cl:14])[Cl:13])[CH2:4][CH2:3][CH:2]=[CH:1]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C[SiH](Cl)Cl
Agent: Cl[Pd]Cl
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CC1C=CCC1
Reaction time: 1 h
Yield: 255.6 %

Procedure:
As described in Example 2, 2.86 g (0.0216 mol) of dicyclopentadiene, 4.97 g (0.0432 mol) of methyldichlorosilane, 0.051 g (0.000288 mol) of palladium dichloride, 86 μL (0.000267 mol) of tributylphosphine and 4 mL of toluene and 2 mL of hexadecane were placed in a reactor. The reactor was sealed and the reaction was performed at 180° C. for 1 hour. Products were subject to simple vacuum distillation, thereby providing a mixture (10.0 g) of (2-cyclopentenyl)methyldichlorosilane (0.9 g, 12%), other unreacted reactants, toluene, hexadecane, and unidentified compounds.
Reaction SMILES: C([Mg]Br)C.[CH3:5][Si:6]([CH3:12])([CH3:11])[O:7][CH2:8][C:9]#[CH:10].[N:13]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[Cl-].[NH4+]>O1CCCC1>[OH:19][C:16]1([C:10]#[C:9][CH2:8][O:7][Si:6]([CH3:12])([CH3:11])[CH3:5])[CH2:15][CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#CCO[Si](C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
Ethyl magnesium bromide in tetrahydrofuran (55 mL, 1M, 55 mmol) was slowly added to a solution of trimethyl(prop-2-yn-1-yloxy)silane in tetrahydrofuran (40 mL) maintaining a temperature of 0° C. After the complete addition the mixture was stirred at ambient temperature for 45 min before a solution of tert-butyl piperidin-4-one-1-carboxylate (10 g, 50 mmol) in tetrahydrofuran (40 mL) was slowly added at 0° C. Subsequently the reaction mixture was stirred for 18 h at ambient temperature. Then saturated ammonium chloride solution was added and the mixture was stirred vigorously until the dissolution of all solids. The phases were separated and the aqueous was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 16.42 g of desired product (96%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[N+:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
430 mL of acetic acid and 188 g of 4-nitroimidazole were charged into a 2 L-volume reactor and stirred. While stirring the mixture, 100% nitric acid(137 mL) was slowly added dropwise to the mixture at the reaction temperature of 35° C. Anhydrous acetic acid(318 mL) was added dropwise thereto at 25° C. over 1 hour. After stirring the reaction mixture at 25° C. for 2 days, the resultant was poured into 3 kg of ice cubes to obtain 1,4-dinitroimidazole as white precipitates. Then the precipitates, still cool, were immediately filtered out, washed with cold water so as to remove the residual acid, and then dried, resulting in 178.6 g(68% yield) of 1,4-dinitroimidazole in a fine white powder form. The structure of the resulted 1,4-dinitroimidazole was determined by NMR analysis, 1H-NMR and 13C-NMR. The results are shown below:
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Yield: 96.5 %

Procedure:
Dissolve dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17-one (7.0 g) in methanol (300 ml) and treat with sodium borohydride (3.0 g). After spontaneous reflux ceases, acidify the reaction mixture with 50% acetic acid (20 ml). Work up by the usual procedures to obtain dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17β-ol (6.8 g), m.p. 158°-160°; infrared absorption peaks (potassium bromide) at 3.05 μ, 6.45 μ.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=C(C4C=CC(/C=C/C(O)=O)=CC=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.C(C1C=CC(C(O)=O)=CC=1)=O>>[CH:30]1([CH2:29][N:10]2[C:11]([NH2:12])=[C:15]([NH2:14])[C:16](=[O:17])[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]2=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Agent: O=Cc1ccc(C(=O)O)cc1
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (1.00 g) and immediately condensed with 4-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367-3370) to give title compound as an off-white solid an off-white solid (720 mg, 54%), m.p. >300° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: C[Si](C)(C)[Br:3].[CH3:6][CH:7]([CH2:9][C@@H:10]1[N:19]2[C:20]([C@@:22]([NH:27][C:28]([C@@H:30]3[CH:45]=[C:44]4[C@@H:33]([CH2:34][C:35]5[C:39]6[C:40]4=[CH:41][CH:42]=[CH:43][C:38]=6[NH:37][CH:36]=5)[N:32]([CH3:46])[CH2:31]3)=[O:29])([CH:24]([CH3:26])[CH3:25])[O:23][C@@:18]2([OH:47])[C@H:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:11]1=[O:12])=[O:21])[CH3:8].N>CS(C)=O>[CH3:8][CH:7]([CH2:9][C@@H:10]1[N:19]2[C:20]([C@@:22]([NH:27][C:28]([C@@H:30]3[CH:45]=[C:44]4[C@@H:33]([CH2:34][C:35]5[C:39]6[C:38](=[CH:43][CH:42]=[CH:41][C:40]=64)[NH:37][C:36]=5[Br:3])[N:32]([CH3:46])[CH2:31]3)=[O:29])([CH:24]([CH3:25])[CH3:26])[O:23][C@@:18]2([OH:47])[C@H:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:11]1=[O:12])=[O:21])[CH3:6]
Reactant: C[Si](C)(C)Br
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Agent: N
Solvent: CS(C)=O
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]c(Br)c(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.3 ml of trimethylbromosilane (6 equivalents as calculated for α-ergocryptine to be brominated) are added to 40 ml of anhydrous dimethylsulfoxide and the solution is stirred at room temperature for 15 minutes. After adding 1 g (0.001739 mole) of α-ergocryptine, the mixture is stirred at room temperature for 10 minutes, then poured into 200 ml of ice-water and the pH value is adjusted to 8-9 by adding aqueous ammonia. The aqueous solution is extracted 3 times with 50 ml of dichloromethane each, then the combined organic phase is washed 3 times with 30 ml of 10% sodium chloride solution each. The dichloromethane solution is dried over anhydrous sodium sulfate, filtered and evaporated to 10 ml under reduced pressure. The residue is led through an aluminum oxide column moistened with 10 g of an 1:1 mixture of dichloromethane and ethyl acetate. The first fraction of 50 ml volume (containing the 2-bromo-α-ergocryptine) is evaporated to dryness, the residue is dissolved in 10 ml of dichloromethane, then 30 ml of diisopropyl ether are added to the residue and concentrated to its half volume under environmental pressure. The white crystalline precipitate is filtered off, washed and dried to give the title compound in a yield of 1.06 g (0.001617 mole, 93%), m.p.: 218° C., [α]D20 =-195° (c=1, dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:13])=[O:8]
Reactant: Nc1ccc(F)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(N)ccc1F

Procedure:
5-Amino-2-fluorobenzoic acid (100 g) was suspended in 1.3 liters of methanol, 100 g of concentrated hydrochloric acid was gradually added thereto and the mixture was heated to reflux for 24 hours. Methanol was evaporated and the residue was poured into ice water, the mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The crystals separated out therefrom were filtered to give 88 g of methyl 5-amino-2-fluorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11].O>C(O)C>[Cl:1][C:2]1[C:7]([NH:10][NH2:11])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Clc1nccnc1Cl
Solvent: CCO
Solvent: O
Product: NNc1nccnc1Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2,3-Dichloropyrazine A-1 (15 g; 100.68 mmol) and hydrazine hydrate 65% (15.509 ml; 201.37 mmol) are dissolved in 45 ml ethanol and stirred for 1 h at 80° C. While cooling down, a precipitate is formed. It is slurred up with a small amount of water and filtered off. It is washed with water and then dried to afford the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]2=[O:37])=[C:11]([OH:39])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]2=[O:37])=[C:11]([OH:39])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2ccc(OCc3ccccc3)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
A mixture of 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (10.0 g, 19.5 mmol), triethylsilane (15.6 mL, 97.5 mmol) and trifluoroacetic acid (15.0 mL, 195 mmol) was mixed and stirred for 20 min at 0° C. The mixture was concentrated under vacuum. The residue was triturated with diethyl ether to afford 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (7.40 g, 76%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.44-7.25 (m, 14H), 7.23-7.17 (m, 2H), 7.11-7.02 (m, 2H), 6.95 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 6.55-6.49 (m, 1H), 6.46 (dd, J=8.6, 2.6 Hz, 1H), 5.09 (s, 1H), 4.99 (s, 2H); MS (ES+) m/z 498.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.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.ClCCl.O.C(#N)C>[CH3:8][C:6]1[CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccccc2)ncn1
Yield: 46 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 4.90 g of 4-chloro-6-methylpyrimidine, 4.80 g of phenylboronic acid, 4.03 g of sodium carbonate, 0.16 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, in the flask were further put 2.28 g of phenylboronic acid, 2.02 g of sodium carbonate, 0.082 g of Pd(PPh3)2Cl2, 5 mL of water, and 10 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and extraction with dichloromethane was carried out. The obtained solution of the extract was washed with a saturated sodium carbonate aqueous solution, water, and then with saturated saline, and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a volume ratio of 9:1, so that a pyrimidine derivative Hmppm, which was the objective substance, was obtained (orange oily substance, yield of 46%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (b-1) of Step 1 is shown below.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (4.55 g, 29 mmol) in DMF (30 mL) was added K2CO3 (4.8 g, 34.9 mmol) followed by MeI (2.7 mL, 43.6 mmol), and the mixture was stirred at room temperature for 16 hours. Following concentration in vacuo, the residual was taken up in ethyl acetate, washed with H2O, brine, dried over Na2SO4, and concentrated. Purification by column chromatography on silica gel with ethyl acetate/hexanes 1/5 afforded 2-chloro-3-methoxybenzaldehyde 7a (4.68 g, 94%) as a colorless oil, which solidified upon standing. GCMS (EI) m/z 170, 172 (M+).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].F[C:22](F)(F)[C:23]([OH:25])=O.C(Cl)Cl>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.[Cu]I.CN(C=O)C.CCN(CC)CC.C(Cl)Cl.O>[NH2:14][C@@H:13]([C@H:23]([OH:25])[CH3:22])[C@H:17]([OH:18])[C:16]#[C:15][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1/[C:5](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:6](=[O:11])[NH:7]2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](O)[C@@H](N)[C@@H](C)O)c21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Using Method C above, 4R-(1R-Hydroxy-prop-2-ynyl)-2,2,5R-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.2 g, 0.65 mmol) (Example 105A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (30 mg) and CuI (6 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h. To above compound in CH2Cl2 (10 mL) was added a 1:1 mixture of trifLuoroacetic acid/CH2Cl2 (10 mL) and 5 drops of water at 0° C. and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with conc. NH4OH (10 mL) and diluted with EtOAc. The organic Layer was washed with brine and dried with MgSO4. The product was purified via flash column chromatography (10% MeOH in CH2Cl2). (Yield 35 mg, 35%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O>C(OCC)(=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([O:14][CH3:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:17][CH:18]=1
Reactant: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC1(c2ccc(Cl)cc2)CCNCC1
Reaction time: 6.7 h
Yield: 78.2 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(4-chlorophenyl)-4-methoxypiperidine (0.72 g) in ethyl acetate (10 ml) was added 4N HCl in ethyl acetate (5.5 ml). After stirring for 6.7 hours, the reaction mixture was poured into a mixture of ethyl acetate and water, followed by alkalification of the solution to pH 12. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 4-(4-chlorophenyl)-4-methoxypiperidine (0.39 g).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.NC1C=CC(C(F)(F)F)=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (390 mg, 2.03 mmol), 4-aminobenzotrifluoride hydrochloride (0.40 g, 2.02 mmol) and 4-aminobenzotrifluoride (1.61 g, 10.0 mmol) is stirred at 180° C. for 2 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto alumina and chromatographed over alumina (4-7% MeOH/CH2Cl2) to give 7-amino-4-(4-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (390 mg, 63%) as a cream solid. Analytically pure material was obtained by further chromatography over silica gel (5% MeOH/CH2Cl2) to give pale yellow needles. 1H NMR (DMSO) δ 10.09 (1H, brs), 9.40 (1H, s), 8.48 (1H, s), 8.13 (2H, d, J=8.2 Hz), 7.74 (2H, d, J=8.7 Hz), 6.72 (2H, brs), 6.40 (1H, s)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[C:22](#[N:25])[CH2:23][OH:24].Cl>C1(C)C=CC=CC=1>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:24][CH2:23][C:22]#[N:25])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N#CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 1,5-difluoro-2,4-dinitrobenzene (7.4 g) and triethylamine (4.4 g) in toluene (74 g) kept at room temperature, a mixture of glycolonitrile (3.1 g) and toluene (6.2 g) was dropwise added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and concentrated to give 2,4-dinitro-5-fluorophenoxyacetonitrile (8.2 g; yield, 93.8%). M.P., 112°-113° C. (recrystallized from ethyl acetate-hexane).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:21](#[N:24])[CH2:22][OH:23].O>C(#N)C>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:23][CH2:22][C:21]#[N:24])([O-:14])=[O:13]
Reactant: N#CCO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a suspension of 1,5-difluoro-2,4-dinitrobenzene (3.8 g) and anhydrous potassium carbonate (3.1 g) in acetonitrile (50 ml) kept at room temperature, a solution of glycolonitrile (1.5 g) in acetonitrile (10 ml) was dropwise added, followed by stirring at room temperature for 1 hour. The reaction mixture was heated and allowed to reflux for 30 minutes (inner temperature, 83° C.). After cooling, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and concentrated to give crystalline 2,4-dinitro-5-fluorophenoxyacetonitrile (4.0 g; yield, 89.1%).