Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[OH:13][C:14]1[CH:19]=[C:18]([CH3:20])[O:17][C:16](=O)[CH:15]=1>>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[N:1]1[C:18]([CH3:20])=[CH:19][C:14]([OH:13])=[CH:15][C:16]1=[O:17]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Product: COC(=O)c1ccc(Cl)c(-n2c(C)cc(O)cc2=O)c1

Procedure:
A condensation reaction with methyl 3-amino-4-chlorobenzoate (14.5 g, 78.2 mmol) and 4-hydroxy-6-methyl pyranone under reaction condition similar to the one described in Example 465-step 3 gave 12.32 (53.8%) of desired product.
Reaction SMILES: [C:1]1([C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]([OH:15])=O)=O)[S:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>C(O)C>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13](=[O:15])[NH:18][N:17]=1
Reactant: NN
Reactant: O=C(O)c1ccsc1C(=O)c1cccs1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2cccs2)c2sccc12
Yield: 88.6 %

Procedure:
0.70 g of 2-(2-thenoyl)-3-thiophene carboxylic acid and 0.22 g of hydrazine hydrate were dissolved in 20 ml of ethanol, and the solution was refluxed for 5 hours. After cooling the solution, it was crystallized by adding ether, thereby obtaining 0.61 g of 7-(2-thienyl)thieno[2,3-d]-pyridazine-4(5H)-one.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[OH:19])([CH3:4])[CH3:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:7][C:6]=1[OH:19])([CH3:4])[CH3:3]
Reactant: COc1cc(C(C)(C)O)c(O)cc1N1CCNCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)C)c(O)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a stirred suspension of 2-(1-Hydroxy-1-methyl-ethyl)4-methoxy-5-piperazin-1-yl-phenol (0.5 g, 1.9 mmol) in dichloromethane under nitrogen at room temperature was aded trifluoroacetic acid (7.2 mL, 93.86 mmol) followed by triethyl silane (3.0 mL, 18.8 mmol). The reaction mixture was stirred for 18 hours at room temperature, and then was evaporated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The organic layer was separated, washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure to afford 0.47 g (99% ) of 2-Isopropyl-4-methoxy-5-piperazin-1-yl-phenol as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>O1CCCC1>[O:1]=[C:2]1[CH2:6][S:5][CH2:4][N:3]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: O=C1CSCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CSCC1=O

Procedure:
A solution of 4-oxothiazolidine (50 g) in tetrahydrofuran (900 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (22.6 g) in tetrahydrofuran (850 ml) at room temperature and the mixture was allowed to warm up to reflux temperature. After the mixture was refluxed for an additional 30 minutes, ethyl bromoacetate (60 ml) was added dropwise under that condition. The mixture was refluxed further 1 hour and then cooled. Insoluble materials were removed by filtration. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography by eluting with chloroform to give ethyl 4-oxo-3-thiazolidinylacetate (78.5 g) as light brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[Cl-].[Li+].N12CN=CC1CCCC2.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)([CH:36]=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)([CH:36]=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:32][CH2:31]1)=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(C2CCCCC2)CC1
Agent: C1=NCN2CCCCC12
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)C=CC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of trimethyl phosphonoacetate (1.41 ml, 8.72 mmole), lithium chloride (477 mg, 11.3 mmole), and 1,8-diazabicyclo[4.3.0]non-7-ene (DBU) (1.55 ml, 11.3 mmole) in anhydrous acetonitrile (25 ml) is added 4-cyclohexyl-4-formyl-piperidine-1-carboxylic acid tert-butyl ester, 7, (2.58 mg, 8.72 mmole) under argon at room temperature. The mixture is stirred for one hour and the solvent then removed under reduced pressure. The crude product is purified over silica (methylene chloride:methanol=15:1, Rf=0.78) to afford 2.64 g (86% yield) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4](=[CH2:10])[CH:5]([OH:9])[CH2:6][CH2:7][CH3:8].[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4](=[CH2:10])[CH:5]([O:9][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C(=O)OC)C(O)CCC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC)C(CCC)OC(C)=O
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A mixture of 3-hydroxy-2-methylenehexanoic acid methyl ester (55.37 g, 350 mmol) and DMAP (4.28 g, 35 mmol) in toluene (400 mL) is cooled to 0-5° C. and to it is added acetic anhydride (42.88 g, 420 mmol) dropwise in ˜30 minutes while maintaining the temperature at 0-5° C. The resulting solution is allowed to warm to room temperature in 1 hour. After stirring for 3 hours at RT, the reaction mixture is cooled to 0-5° C. and to it is added 1 N HCl acid (80 mL), in 20 minutes. The organic layer is separated and washed sequentially with water (80 ml), saturated aqueous sodium bicarbonate solution (2×80 mL) and water (80 mL). The organic layer is concentrated on Rotavap under reduced pressure (20 mbar) until no further solvent distills to afford 3-acetoxy-2-methylenehexanoic acid methyl ester (68.39 g, yield: 97.5%) as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C.[Cu]I.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>[C:19]1([C:25]#[C:26][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C#Cc1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of methyl 2-bromobenzoate 34 (166 μL, 1.163 mmol) in acetonitrile (2906 μL) was added triethylamine (972 μL, 6.98 mmol) and phenylacetylene 35 (140 μl, 1.279 mmol). Then copper (I) iodide (11.07 mg, 0.058 mmol), and bis(triphenylphosphine)-palladium(II) chloride (20.40 mg, 0.029 mmol), were successively added, degassing between and after each addition of catalysts. The mixture was stirred at 75° C. overnight. The reaction mixture was partitioned between EtOAc and 1M HCl. The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with water, brine, dried over MgSO4. The residue was purified via Biotage using EtOAc/Hex ((0:100 to 10:90); 25+S column), to afford compound 36 (157 mg, 57%). LRMS (ESI): (calc.) 236.08 (found) 237.2 (MH)+
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:16]=1[C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:16]=1[C:25](=[CH2:1])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(=O)c1c(OCOC)cccc1OCOC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)c1c(OCOC)cccc1OCOC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (3.13 g, 8.75 mmol) in dry tetrahydrofuran (30 ml) at 0° C. KHMDS (1.745 g, 8.75 mmol) was slowly added and the reaction mixture was stirred for 15 minutes at 0° C. and for 45 minutes at room temperature. The reaction mixture was cooled to 0° C. and a solution of ethyl (2,6-bis{[(methyloxy)methyl]oxy}phenyl)(oxo)acetate (Intermediate 80, 1.74 g) in dry tetrahydrofuran (10 mL) was slowly added and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound as a colourless oil (1.37 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:12][C:5]1[CH:4]=[C:3]([F:13])[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)c(F)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)c(F)cc1Cl
Reaction time: 72 h
Yield: 45.4 %

Procedure:
To a solution of methyl 5-amino-2-chloro-4-fluorobenzoate (152 mg, 0.75 mmol) and pyridine (0.07 mL, 0.82 mmol) in 3 mL CH2Cl2 was added methanesulfonyl chloride (0.06 mL, 0.82 mmol). After 3 days at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and filtered through a silica plug to provide methyl 2-chloro-4-fluoro-5-[(methylsulfonyl)amino]benzoate (96 mg, 44%) as a solid (ESI-MS 280 (M−H)), which was hydrolyzed using aqueous NaOH to provide 2-chloro-4-fluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 266 (M−H)), which was used without further purification.
Reaction SMILES: C([NH:4][C@H:5]([PH:19]([OH:21])=[O:20])[C:6]([CH2:15][CH:16]([CH3:18])[CH3:17])(C(O)=O)[C:7]([O:9]CC)=[O:8])(=O)C.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:4][C@H:5]([PH:19]([OH:21])=[O:20])[CH:6]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)O)[C@H](NC(C)=O)[PH](=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CC(C(=O)O)[C@H](N)[PH](=O)O

Procedure:
A mixture of 13.47 g of ethyl hydrogen 2-[(R)-(acetamido)(hydroxyphosphinyl)methyl]-2(RS)-isobutylmalonate and 8.42 g of triethylamine in 420 ml of dry toluene was heated under reflux for 2 hours. After cooling, the solvent was removed by evaporation and the residue was dissolved in a mixture of 96 ml of water and 144 ml of concentrated hydrochloric acid and the solution was heated under reflux for 4 hours under a nitrogen atmosphere. The solution was evaporated to dryness and the 2-[(R)-(amino)(hydroxyphosphinyl)methyl]-4-methylvaleric acid obtained was dissolved in 225 ml of aqueous saturated sodium hydrogen carbonate solution and 45 ml of tetrahydrofuran. 30 g of solid sodium hydrogen carbonate and 45 ml of benzyl chloroformate were added and the mixture was stirred at room temperature for 48 hours in a nitrogen atmosphere. The solution was extracted twice with diethyl ether and the aqueous solution was acidified by the careful addition of hydrochloric acid and then extracted five times with dichloromethane containing 10% methanol. The extracts were dried over magnesium sulfate and evaporated to give a colorless gum which was crystallized from ethyl acetate. There were obtained 7.0 g of 2(R or S)-[(R)-benzyl-oxyformamido)(hydroxyphosphinyl)methyl]-4-methylvaleric acid as a single diasteroisomer in the form of a white solid; MS: 344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](Cl)[CH3:9].[C:24]([O-:27])(=[O:26])[CH3:25].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:24]([O:27][CH:8]([C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)[CH3:13])[C:2]=1[Cl:1])[CH3:9])(=[O:26])[CH3:25]
Reactant: CC(Cl)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC(C)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl

Procedure:
In 50 ml of acetic acid was dissolved 3.1 g of 5-chloro-6-(1-chloroethyl)-4-[1-(4-difluoromethoxyphenyl)ethylamino]-pyrimidine, and to the mixture were added 3.0 g of potassium acetate and 3.0 g of potassium carbonate. The mixture was refluxed under heating for 30 hours.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)=[O:9])=[C:6]([O:30]C)[CH:5]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)=[O:9])=[C:6]([OH:30])[CH:5]=1
Reactant: COc1cc(Cl)ccc1C(=O)NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A solution of the product of step (b) (3 g) in dichloromethane (50 ml) was cooled to −78° C. and a 1.0M solution of boron tribromide in dichloromethane (8.5 ml) added. After 1 hour the solution was allowed to warm to room temperature. After 3 hours, methanol (6 ml) was added and the solution concentrated. This process was repeated, the residue dissolved in methanol, treated with concentrated hydrochloric acid and stirred at room temperature for 3 hours. The solution was concentrated, sodium bicarbonate solution and ethyl acetate were added, the organic phase separated, dried and concentrated to a gum which was purified by chromatography (dichloromethane:methanol, 97:3) to give the product as a solid (2.0 g), m.p. 238-240° C.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][CH:9](OC)OC)=[CH:4][C:3]=2[O:2]1.[CH:18](=O)[C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1.[ClH:30]>>[ClH:30].[CH3:23][O:22][C:21]1[C:24]([O:25][CH3:26])=[CH:27][C:28]2[CH2:19][C:18]3[C:14]4[C:5](=[CH:4][C:3]5[O:2][CH2:1][O:17][C:16]=5[CH:15]=4)[CH:6]=[N:7][C:8]=3[C:9]=2[CH:20]=1
Reactant: COC(CNCc1ccc2c(c1)OCO2)OC
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Product: COc1cc2c(cc1OC)-c1ncc3cc4c(cc3c1C2)OCO4
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Concentrated HCl (20 mL) was added to a mixture of (3,4-methylenedioxybenzyl)-(2,2-dimethoxyethyl)amine (12b, 1.79 g, 7.49 mmol) and veratraldehyde (10a, 3.04 g, 0.018 mol). The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was then cooled and washed with ether (50 mL×3). Then it was brought to a basic pH with NH4OH. The mixture was extracted with chloroform (50 mL×4), washed with water (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in an organic solvent (200 mL chloroform). The mixture was filtered and HCl (2 M in ether, 40 mL) was added to the filtrate. The yellow precipitate that formed (0.7649 g, 29%) was collected by filtration. An analytical sample was prepared by recrystallizing 0.3655 g from methanol (50 mL), mp 257-259° C. 1H NMR (300 MHz, TFA) δ 8.88 (s, 1H), 7.69 (s, 1H), 7.39 (s, 1H), 7.33 (s, 2H), 6.21 (s, 2H), 4.18 (s, 2H), 4.02 (s, 3H), 4.01 (s, 3H); low resolution ESIMS m/z (rel intensity) 322 (100, MH+); high resolution ESIMS m/z (rel intensity) 322.1084 (100, MH+) (calculated mass 322.1079); IR (KBr) 3435, 3043, 2966, 2841, 2648, 2027, 1623, 1589, 1494, 1470, 1458, 1419, 1379, 1323, 1291, 1275, 1256, 1220, 1198, 1147, 1122, 1092, 1035, 969, 935, 902, 872, 835, 818, 785, 762, 743, 572 cm−1. Anal. Calcd for C19H16NO4Cl(H2O)0.7: C, 61.61; H, 4.74; N, 3.78. Found: C, 61.40; H, 4.98; N, 3.75.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6](I)=[CH:7][C:8]([F:11])=[N:9][CH:10]=1)=[N+:2]=[N-:3].[F:13][C:14]1[C:15]([C:29]2[S:33][C:32]3[C:34](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:36]=[CH:37][C:31]=3[CH:30]=2)=[N:16][C:17]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])=[N:18][CH:19]=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.Cl[Pd]Cl>[N:1]([CH2:4][C:5]1[C:6]([C:34]2[C:32]3[S:33][C:29]([C:15]4[C:14]([F:13])=[CH:19][N:18]=[C:17]([NH:20][CH2:21][CH2:22][N:23]5[CH2:27][CH2:26][NH:25][C:24]5=[O:28])[N:16]=4)=[CH:30][C:31]=3[CH:37]=[CH:36][CH:35]=2)=[CH:7][C:8]([F:11])=[N:9][CH:10]=1)=[N+:2]=[N-:3]
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCN5CCNC5=O)ncc4F)sc23)OC1(C)C
Reactant: [N-]=[N+]=NCc1cnc(F)cc1I
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 85 °C
Yield: 98.5 %

Procedure:
Combine 5-azidomethyl-2-fluoro-4-iodo-pyridine (70 mg, 0.25 mmol) and 1-(2-{5-fluoro-4-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (100 mg, 0.21 mmol) bis(diphenylphosphino)ferrocene)dichloro palladium (8.5 mg, 0.01 mmol) and NaHCO3 (35 mg, 0.41 mmol) in DMSO (87 mL) and water (3 mL). Purge the mixture through nitrogen for 5 min twice. Heat the mixture at 85° C. for 1 hour in an oil bath. Cool to room temperature. Dilute the reaction mixture with chloroform/isopropyl alcohol 93/1), and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over sodium sulfate. After filtration, remove the organic solvent to give a crude mixture. Purify the crude by column chromatography (10% methanol in dichloromethane) to afford the title compound (105 mg, 100%). MS (ES) m/z 508 [M+1]+.
Reaction SMILES: C([C:6]([CH:20](OCC)OCC)([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:29][C:30]([NH2:32])=[NH:31]>C(O)C>[NH2:32][C:30]1[N:31]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:20][N:29]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C#N)(Cc1ccc(OC)c(OC)c1)C(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OC
Yield: 52.4 %

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(3,4-dimethoxyphenyl)propionitrile (3.75 g) and an equivalent amount of potassium hydroxide in ethanol (70 ml) was heated at reflux for one hour. A solution of guanidine (0.035 mol) in ethanol (50 ml) was added and reflux was resumed. Ethanol was boiled off until the reaction temperature reached 85° C. After 17 hours at reflux the mixture was allowed to cool and the product was filtered and washed with ethanol giving a white solid which was purified as described in Example 5 to yield 1.4 g (54%) of the title compound, m.p. 231°-233° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]1=[O:10].[CH3:12][Li]>CCOCC>[CH3:12][C:3]1([OH:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CCC(C)(C)C(=O)C1
Reactant: [Li]C
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C(C)(O)C1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 26.4 g of 2,2,5,5-tetramethylcyclohexanone in 250 ml of ether is added dropwise at -20° C. to 102.8 ml of methyl lithium (2 molar in ether). After stirring at 0° C. for 2.5 hours, the mixture is poured into ice/1N hydrochloric acid and extracted with ether. The organic phase is washed with water, dried and evaporated. The residue is distilled in a water-jet vacuum. There are obtained 22.6 g of 1,2,2,5,5-pentamethylcyclohexanol as a colorless liquid, b.p. 81°-87° C./17 mm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH:15][CH2:16][CH:17]1[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH2:18]1.[ClH:27]>>[ClH:1].[ClH:27].[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2]([O:15][CH2:16][CH:17]3[O:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][CH2:18]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2nccnc2Cl)CC1
Reactant: OCC1COc2ccccc2O1
Agent: Cl
Product: CN1CCN(c2nccnc2OCC2COc3ccccc3O2)CC1
Yield: 87 %

Procedure:
The title compound was prepared according to the procedure described in Example 90, Step 2, starting from 1-(3-chloro-2-pyrazinyl)-4-methylpiperazine (described in Example 169, Step I) and 2-hydroxymethyl-2,3-dihydro-1,4-benzodioxine. Yield 87%; mp 160-167° C. Anal. (C18H22N4O3.2 HCl) H, N; C: calcd, 52.06; found, 52.6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18]3(OCC[O:27]3)[CH:17]=[CH:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C=CC2=O
Yield: 51776.1 %

Procedure:
A solution of 1.04 g (2.57 mmol) of 43, 117 mg (0.617 mmol) of pTsOH in acetone (70.3 mL) and H2O (11.4 mL) was stirred at rt for 1.5 h. The reaction mixture was adjusted to pH 7 with 5% NaHCO3 and concentrated by rotovap to about 30 mL without heating. The solution was poured into H2O (50 mL) and extracted with EtOAc (3×, 70 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving a white solid. Crystallization of the residue from CH2Cl2/hexanes gave 477 g (52%) of 44 as fine white needles. Data for 44: TLC, T-1, Rf 0.5; 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 3H, H-18), 5.05 (s, 2H, benzylic-H), 6.10 (dd, 1H, J=5.9, 3.2 Hz, H-15), 6.76 (d, 1H, J=2.7 Hz, H-4), 6.81 (dd, 1H, J=8.6, 2.7 Hz, H-2), 7.22 (d, 1H, J=8.6 Hz, H-1), 7.31–7.45 (m, 5H, Ar—H), 7.64 (dd, 1H, J=5.9, 1.1 Hz, H-16).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[CH:21][N:22]([CH3:24])C)#N>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:11]3[C:12](=[CH:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=3)[N:20]=[CH:21][N:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 148 °C

Procedure:
A solution of 23.74 ml of 3-bromo aniline and 40.5 g N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine in 100 ml of glacial acetic acid was stirred and heated in an oil bath at 148° C. for 1.5 hours. On cooling, filtration of the resulting solid gives a quantitative yield of N-(3-bromophenyl)-6-nitro4-quinazolinamine: mp=267-270° C.; mass spectrum (m/e): 345.