Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=O)=O)=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]([S:8][CH2:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: CC(C)(O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)CCSc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 42 %

Procedure:
To a solution of 2-amino-5-bromopyridine-3-sulfonyl chloride (reagent preparation 25, step 1) (0.40 g, (1.47 mmol) in a mixture of 1,4-dioxane (8.0 mL) and water (1.0 mL) was added triphenylphosphine (1.64 g, 6.25 mmol) and the reaction mixture was stirred for 50 minutes at room temperature. Potassium carbonate (0.35 g, 2.50 mmol) was introduced, followed by 4-bromo-2-methyl-2-butanol (Tetrahedron Letters 2000, 41(38), 7337-7340) (0.31 g, 1.86 mmol) and the reaction mixture was stirred at 80° C. for 16 hours. After cooling to room temperature the reaction mixture was concentrated and the residue was partitioned between brine (50 mL) and ethyl acetate (100 mL). The organic layer was separated and washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. Gradient flash chromatography (25% to 50% ethyl acetate in hexane) provided 4-[(2-amino-5-bromopyridin-3-yl)thio]-2-methylbutan-2-ol (0.18 g, 42%); MS (EI) for C10H15BrN2OS: 292 (MH+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].ClC1C=CC=C(C(OO)=[O:36])C=1.O>ClCCl>[O:36]=[S:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:1])([F:26])[F:27])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Sc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2S(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
The compound (46 mg) prepared in step (d) of Example 133 was dissolved in dichloromethane (1 ml). m-Chloroperbenzoic acid (19 mg) was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous MgSO41 and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (n-hexane:ethyl acetate=1:4) to give 4-[10-oxo-9-(2,2,2-trifluoroethylcarbamoyl)-9,10-dihydro-10λ4-thioxanthen-9-yl]butyl bromide (38 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:17])[C:5](I)=[CH:6][NH:7]2.C1(C)C=CC=CC=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:17])[C:5]([C:27]1[CH:28]=[CH:29][O:25][CH:26]=1)=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(I)c[nH]c12
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccoc3)c[nH]c12
Temperature: 110 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one (780 mg, 2.24 mmol) was suspended in a mixed solvent of toluene (10 ml) and methanol (1.6 ml), and furan-3-boronic acid (752 mg), tetrakis triphenylphosphine palladium (130 mg, 0.11 mmol), and a 2N sodium carbonate aqueous solution (2.25 ml) were added thereto in that order. The mixture was stirred under a nitrogen atmosphere at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, the residue was then purified by silica gel column chromatography (dichloromethane:methanol=60:1→50:1). The purified product was concentrated under reduced pressure and was recrystallized from ethanol to thereby obtain 180 mg of powdery pale yellow 5-fluoro-3-furan-3-yl-8-propoxy-1H-quinolin-4-one (yield: 58%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Br)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:22][C@H:23]([C:26]([OH:28])=[O:27])[CH2:24][SH:25].CCN(C(C)C)C(C)C.Cl>C(O)C.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][S:25][CH2:24][C@@H:23]([C:26]([OH:28])=[O:27])[NH2:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCCBr)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](CSCCCC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
The title compound of example 1 (3.0 g, 8.72 mmol) was added to a solution of L-cysteine (1.0 g, 8.26 mmol) and DIEA (4.4 mL, 24.7 mmol) in EtOH-H2O (1:1, 100 mL). The resulting heterogeneous mixture was stirred vigorously at room temperature (20°-22° C.) for 18 h. The mixture was rendered acidic by the addition of 1N HCl (ph=6). The solid in the reaction mixture was collected on a filter and washed with H2O and EtOH. A suspension of the solid in EtOH (70 mL) was heated with stirring then allowed to cool. The solid in the suspension was collected on a filter, washed with EtOH, Et2O and dried to give the title compound (1.2 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCl)C(=O)NCc1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52b, 3-chloro-2,2-dimethylpropionyl chloride (27.4 g) in dichloromethane (100 ml) was added to 4-chlorobenzylamine (25.0 g) and triethylamine (24.6 ml) in dichloromethane (400 ml) to give 3-chloro-N-(4-chlorobenzyl)-2,2-dimethylpropionamide, m.p. 97°-98° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].[NH2:17][OH:18]>C(O)C>[NH2:2][C:1](=[N:17][OH:18])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC(N)=NO)CC1

Procedure:
tert-Butyl 4-(cyanomethyl)piperidine-1-carboxylate (91 mmol) was dissolved in ethanol (200 mL), and an aqueous hydroxylamine solution (50%, 17 mL, 170 mmol) was added, followed by heating to reflux for 3.5 hours. The reaction solution was cooled, and subsequently concentrated under reduced pressure to afford tert-butyl 4-[2-amino-2-(hydroxyimino)ethyl]piperidine-1-carboxylate as a colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[Cl:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:4]2[C:5](=[O:14])[C:6]3[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:15])=[CH:19][CH:18]=1
Reactant: Clc1ccc(OCCCCCCBr)cc1
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCn1cnc2c1c(=O)n(CCCCCCOc1ccc(Cl)cc1)c(=O)n2C
Yield: 51 %

Procedure:
3-Methyl-7-propylxanthine and 6-(4-chlorophenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9(a) to give 1-[6-(4-chlorophenoxy)hexyl]-3-methyl-7-propylxanthine (51%).
Reaction SMILES: C(OC([N:8]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:10]=1)=O)(C)(C)C.S(=O)(=O)(O)O>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:11]1[N:10]=[C:9]([NH:8][C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[CH:19]=[CH:18][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1ccc(N(C(=O)OC(C)(C)C)c2c(F)cccc2F)nc1-c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Nc2c(F)cccc2F)nc1-c1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To Compound 8 (100 g, 0.204 mol, 1.00 eq) was added a 7M sulfuric acid solution prepared by the slow addition of concentrated sulfuric acid (285 mL, 2.85 vol, 5.24 mol) to distilled water (465 mL, 4.65 vol) while keeping the temperature below 50° C. The mixture was heated at 100±5° C. until the reaction was complete. The mixture was then cooled to 30±5° C. and additional water (750 mL, 7.5 vol) was added. Isopropyl acetate (2 L, 20 vol) was then added and the mixture was stirred for 15 minutes. Stirring was stopped and the phases were allowed to separate. The aqueous phase was separated and water (7.5 vol) was charged to the organic phase. The mixture was stirred for 15 minutes, polish filtered, then the aqueous phase was drained. The total volume of the organic layer was reduced to 4 vol by vacuum distillation at 45±5° C. The resulting slurry was cooled to −10° C. for 12 hours and filtered. The filter and cake was washed with cold isopropyl acetate (3 vol) and the solids were dried under vacuum at 50±5° C. to give the title Compound, 9, as a white solid. (1H NMR, 500 MHz; DMSO-d6) δ 12.50 (s, 1H), 9.25 (s, 1H), 8.07 (d, 1H), 7.39 (q, 1H), 7.29 (m, 1H), 7.18 (m, 3H), 7.09 (m, 1H), 6.25 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[I-].[K+].Br[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16]>C(O)(=O)C.CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>[CH3:18][O:17][C:15](=[O:16])[CH:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A mixture of 2.57 g of p-chlorophenol, 0.72 g of 60% sodium hydride-oil dispersion and 25 ml of tetrahydrofuran is stirred at room temperature for 90 minutes. To the mixture under argon is added 3.32 g of potassium iodide, 1 ml of hexamethylphosphoramide, and dropwise a solution of 7.5 g of methyl bromo{p-[3-(p-chlorphenoxy)propoxy]phenyl}acetate. The mixture is stirred at room temperature for 1 hour and refluxed for 18 hours. The mixture is poured into 500 ml of ice-water containing 1.2 ml of acetic acid. The mixture is extracted with ether and the extracts washed with saturated sodium chloride solution and dried (MgSO4). The solvent is removed under reduced pressure to give 8.0 g of product as an oil. Chilling gives crystals. Recrystallization from 90% ethanol gives white crystals, mp 80°-82° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][C:16]2[N:12]([N:13]=[N:14][CH:15]=2)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:29]([O:33][C:34]([NH:36][C@H:37]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])[CH2:38]C(O)=O)=[O:35])([CH3:32])([CH3:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)CCl>[C:29]([O:33][C:34](=[O:35])[NH:36][CH:37]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[C:46]([F:50])=[CH:45][C:44]=1[F:51])[CH2:38][C:6](=[O:7])[N:8]1[CH2:17][C:16]2[N:12]([N:13]=[N:14][CH:15]=2)[C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[CH2:9]1)([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2-n2nncc2C1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2nncc2C1)Cc1cc(F)c(F)cc1F

Procedure:
4H,6H-1,2,5,10b-Tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester was deprotected using trifluoroacetic acid and the resulting salt was coupled with (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid using HOBt, EDC and DIPEA. The desired compound was obtained as viscous oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[C:32]([CH2:33][O:34]C3CCCCO3)=[CH:31][N:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([CH3:17])=[CH:10][C:9]2[NH:18][C:19](=[O:42])[CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[C:32]([CH2:33][OH:34])=[CH:31][N:30]=[N:29]4)[CH:23]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1N(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-4-methyl-2-(3oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M77) (0.42 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (200 mg, 72%).
Reaction SMILES: [C:1]1(=[O:10])[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][NH:2]1.[Cl:11][C:12]1[N:13]=[C:14]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:15]2[S:20][C:19]([CH:21]=O)=[CH:18][C:16]=2[N:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:11][C:12]1[N:13]=[C:14]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:15]2[S:20][C:19]([CH2:21][N:7]3[CH2:8][CH2:9][C:4]4([C:1](=[O:10])[NH:2][CH2:3]4)[CH2:5][CH2:6]3)=[CH:18][C:16]=2[N:17]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C1NCC12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1NCC12CCN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of 1-oxo-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (150 mg, 0.624 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting solution stirred at RT for 1 h. The crude reaction mixture was loaded onto a Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to provide 2,7-diaza-spiro[3.5]nonan-1-one as a colourless oil. To a suspension of 2,7-diaza-spiro[3.5]nonan-1-one (0.624 mmol) in dichloroethane (13 mL) were added 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (130 mg, 0.458 mmol) and sodium triacetoxyborohydride (146 mg, 0.689 mmol) and the resulting suspension stirred at RT for 18 h. The reaction was quenched with water and loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by column chromatography to give the title compound as a white solid (93 mg, 50%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]3[CH:23]=[CH:24][N:25]=[C:19]3[CH2:18]2)[N:10]=[C:9](S(CC2C=CC=CC=2)=O)[N:8]=1.[OH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(N(CC)CC)C>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]3[CH:23]=[CH:24][N:25]=[C:19]3[CH2:18]2)[N:10]=[C:9]([N:44]2[CH2:45][CH2:46][CH:41]([OH:40])[CH2:42][CH2:43]2)[N:8]=1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(=O)Cc2ccccc2)nc1N1CCn2ccnc2C1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCC(O)CC2)nc1N1CCn2ccnc2C1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of whole amount of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-benzylsulfinylpyrimidine (prepared in the above (5)), 4-hydroxypiperidine 57 mg, triethylamine 57 mg and N,N-dimethylacetamide 3 ml is stirred at 60° C. for 1.5 hours. After cooling the reaction mixture is diluted with ice water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The residue is crystallized from a mixture of ethyl acetate and isopropyl ether to give of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-(4-hydroxypiperidin-1-yl)pyrimidine as a colorless crystalline powder 75 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3([O:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][O:14]3)[CH2:11]2)[CH2:7]1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][CH:8]2[CH:12]([CH2:11][C:10]3([O:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][O:14]3)[CH2:9]2)[CH2:13]1)[CH3:2]
Reactant: CCOC(=O)C=C1CC2CC3(CC2C1)OCC(C)(C)CO3
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CC2CC3(CC2C1)OCC(C)(C)CO3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product of Step 2 (400 mg, 1.359 mmol) and 10% Pd—C-50% wet (85 mg, 0.799 mmol) in EtOAc (8.0 mL) was stirred 16 hrs at room temperature under a hydrogen atmosphere. The catalyst was then filtered off and the volatiles were removed under reduced pressure to give ethyl[5,5-dimethylhexahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′-yl]acetate as a colorless oil. MS ESI: [M+Na]+ m/z 297.7.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br.Br[CH:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C(N(CC)CC)C>C(#N)C>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:1]=[C:2]([NH2:4])[S:3][C:7]=2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Reactant: NC(N)=S
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(N)sc2-c2cccnc2)cc1
Yield: 82 %

Procedure:
To a suspension of thiourea (516 mg) in acetonitrile (40 mL), was added 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide (2.5 g), and then triethylamine (0.95 mL) was added slowly dropwise to the mixture with stirring. After addition, the mixture was stirred at reflux for 3 h. After cooling, the crude crystalline was collected by filtration. The crystalline was washed with an aqueous saturated solution of sodium hydrogen carbonate, water, ethanol, and ethyl ether, in that order, and dried. The obtained crude crystalline was recrystallized from tetrahydrofuran to give the title compound (1.5 g, yield 90%).
Reaction SMILES: [NH2:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([P:27]([O:32]CC)([O:29]CC)=[O:28])=[CH:23][CH:22]=1)([CH2:6][CH:7]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]([OH:5])=[O:4].C[Si](I)(C)C>ClCCl>[NH2:1][C:2]([C:21]1[CH:22]=[CH:23][C:24]([P:27]([OH:29])([OH:32])=[O:28])=[CH:25][CH:26]=1)([CH2:6][CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[O:14][C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]([OH:5])=[O:4]
Reactant: CCOP(=O)(OCC)c1ccc(C(N)(CC2c3ccccc3Oc3ccccc32)C(=O)O)cc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: NC(CC1c2ccccc2Oc2ccccc21)(C(=O)O)c1ccc(P(=O)(O)O)cc1
Reaction time: 5 h

Procedure:
To a suspension of 2-amino-3-(9H-xanthen-9-yl)-2-(4-diethylphosphonophenyl)propanoic acid (114 mg, 0.25 mmol) in dry dichloromethane (10 ml) stirred under an atmosphere of nitrogen was added trimethylsilyl iodide (0.26 g, 1.29 mmol). The resulting solution was stirred at room temperature for 24 h and then further trimethylsilyl iodide (0.26 g, 1.29 ml) added. Stirring was continued for 5 h, the reaction mixture evaporated to dryness and redissolved in water. Ion exchange chromatography using the conditions described in Example 1 (vi) gave the title compound as a pale yellow powder.
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][C:8]#[CH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[Cl-].[Na+].[OH2:14]>>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:14])[C:2]=1[CH3:11])[C:8]#[CH:9]
Reactant: C#CCC1C(=O)C=CC1(C)O
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Product: C#CCC1=C(C)C(O)CC1=O

Procedure:
In an autoclave, 4-hydroxy-4-methyl-5-propargyl-2-cyclopentenone (3 g) and water (400 ml) were charged, and the resultant mixture was stirred at 150° C. for 6 hours in a nitrogen atmosphere. After cooling, sodium chloride (50 g) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified on column chromatography to give 2-propargyl-3-methyl-4-hydroxy-2-cyclopentenone (2.7 g). Yield, 90% nD21 1.5148.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1I>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[Cl:59])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Clc1ccccc1I
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: Clc1ccccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 59 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-chloro-2-iodobenzene in 59% yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>CN(C=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.8 %

Procedure:
Solid NaH (60% w/w in mineral oil, 352 mg, 4.6 mmol) was added to a stirring solution of 1-Benzyl-4-hydroxypiperidine (841 mg, 4.4 mmol) in DMF (50 mL) at 0° C. The resulting suspension was stirred for 5 min then Intermediate 19 (2.6 g, 8.8 mmol) was added. The reaction mixture was warmed to rt then heated to 70° C. over night. The resulting solution was cooled then pour into H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over Na2SO4, and concentrated to give crude either 2.96 g as yellow oil. Chromatography (1:3, hexanes/EtOAc) afforded the title compound (157 mg, 8%) as clear oil. ES/MS calcd for C24H44NO2Si+ 406.3. Found m/z=406.3 (M+H)+.