Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 100 %

Procedure:
26 ml (262 mmol) of an aqueous solution of sodium hydroxide having a concentration of 10N are added to a solution of 13.4 g (65.7 mmol) of methyl 4-but-2-ynyloxybenzoate diluted in 200 ml of tetrahydrofuran and 25 ml of water. The reaction medium is stirred at reflux for 5 h then at 45° C. for 18 h. The reaction medium is hydrolysed, diluted with ethyl acetate then brought to pH=6 using an aqueous solution of hydrochloric acid having a concentration of 1N. The product is extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. 12.5 g (100%) of 4-but-2-ynyloxybenzoic acid are obtained in the form of a white solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.CO[C:12]1[CH2:17][N:16]([CH3:18])[CH2:15][C:14](=[O:19])[CH:13]=1.CO.Cl>CCOCC.C1COCC1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:12]2[CH2:17][N:16]([CH3:18])[CH2:15][C:14](=[O:19])[CH:13]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: COC1=CC(=O)CN(C)C1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C2=CC(=O)CN(C)C2)cc1

Procedure:
A solution of p-tolyl magnesium bromide (0.23 M) in ether (150 ml) was treated with a solution of 5-methoxy-1-methyl-1,6-dihydro-3[2H]pyridone (28.2 g, 0.2 M) in THF (200 ml) at such a rate as to maintain a gentle reflux. After 1 hour the reaction mixture was poured on to methanol (500 ml) and treated with 12 N hydrochloric acid (50 ml). Removal of the resulting crystals by filtration followed by air-drying gave the title compound (21 g) as the hydrochloride five quarters hydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH2:21][N:22]3[CH2:26][CH2:25][CH:24]([NH:27]C(OC(C)(C)C)=O)[C:23]3=[O:35])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CCN(CC)CC.[Cl:50][C:51]1[CH:52]=[CH:53][C:54]2[CH:58]=[C:57]([S:59](Cl)(=[O:61])=[O:60])[S:56][C:55]=2[CH:63]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH2:21][N:22]3[CH2:26][CH2:25][CH:24]([NH:27][S:59]([C:57]4[S:56][C:55]5[CH:63]=[C:51]([Cl:50])[CH:52]=[CH:53][C:54]=5[CH:58]=4)(=[O:61])=[O:60])[C:23]3=[O:35])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCc2ccc(CN3CCC(NS(=O)(=O)c4cc5ccc(Cl)cc5s4)C3=O)cc2C1
Reaction time: 4 h
Yield: 70.8 %

Procedure:
To a solution of 7-(3-tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (0.347 g, 0.72 mmol) in 8 mL of CH2Cl2 is added 2 mL of TFA. After 4 hours, the solution is concentrated. The residue is dissolve in CH2Cl2 and Et3N (0.30 mL, 2.17 mmol) and 6-chloro benzo[b]thiophene sulfonyl chloride (0.23 g, 0.87 mmol) are added. After 16 hours, the solution is concentrated. The residue is purified by column chromatography eluting with 10% EtOAc/CH2Cl2. The product (0.25 g, 0.51 mmol) was obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5][O:4]1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>ClCCl>[CH3:24][C:23]1[CH:25]=[CH:26][C:20]([S:17]([O:1][CH2:2][CH:3]2[O:4][CH2:5][C:6](=[O:9])[NH:7][CH2:8]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: O=C1COC(CO)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CNC(=O)CO2)cc1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a stirred solution of 6-(hydroxymethyl)morpholin-3-one (Step-2 of Intermediate-9) (4.1 g, 31.29 mmole) in dichloromethane (25 mL), triethylamine (8.31 mL, 62.59 mmole) and TsCl (tosyl chloride) (6.56 g, 34.42 mmole) were added at 0° C. The reaction mixture was allowed to RT and further stirred overnight. Reaction mixture was diluted with dichloromethane (30 mL), and washed with brine solution (2×30 mL) and DM water, separated the organic layer, dried over Na2SO4, concentrated and further purified by flash chromatography (n-hexane:ethyl acetate, 1:4) to get the title compound as a white solid (3.8 gm). m/z 286.1
Reaction SMILES: [S:1]([NH2:5])(N)(=[O:3])=[O:2].[CH3:6]N.[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH2:15][CH2:16][C:17]1[C:18]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=3)C(=O)[O:24][N:23]=2)=[N:19][O:20][N:21]=1.[OH-].[Na+]>N1C=CC=CC=1.O>[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:34][C:29]1[CH:28]=[C:27]([NH:26][C:22]([C:18]2[C:17]([CH2:16][NH:15][S:1]([NH:5][CH3:6])(=[O:3])=[O:2])=[N:21][O:20][N:19]=2)=[N:23][OH:24])[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CN
Reactant: NS(N)(=O)=O
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
Sulfamide (32 mg, 0.33 mmol) and methylamine (15 μL, 0.33 mmol) were dissolved in pyridine (1.0 mL). The solution was heated to 120° C. for 5 minutes in a microwave. 3-[4-(aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (32 mg, 0.075 mmol) was than added and the solution was heated to 120° C. for 3 minutes. A solution of sodium hydroxide in water (1 mL, 1 N) was added and the solution stirred at room temperature for 30 minutes. Acidification with acetic acid and purification by preparative LCMS gave the desired product (2.3 mg, 7%). MF=C11H12ClFN6O4S; LCMS calculated for C11H13ClFN6O4S (M+H)+: m/z=378.9.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[N:32]=1>CN(C)C=O>[CH3:38][O:37][C:33]1[N:32]=[C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cccc(CCl)n1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-6-methoxypyridine (20.0 mg, 0.13 mmol) described in Manufacturing Example 99-1-2, which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature, and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (26.1 mg, 61%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]([CH3:15])([CH3:14])[C:12]#[CH:13]>C(OCC#C)C#C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:9][C:11]([CH3:15])([CH3:14])[CH:12]=[CH:13][C:7]=2[CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)Cl
Agent: C#CCOCC#C
Product: CC1(C)C=Cc2cc(C#N)ccc2O1

Procedure:
According to EPO 0 076 075 describing the possibilities for preparing Kromakalim 4-cyano-phenol of the formula (I) ##STR4## is reacted with 3-chloro-3-methyl-butyne resulting in propargyl-ether of the formula (IX) ##STR5## which is then subjected to ring closure to produce 6-cyano-2,2-dimethyl-2H-1-benzopyran of the formula (III) ##STR6## The compound of the formula (III) is then converted through 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol to 6-cyano-3,4-dihydro-3,4-epoxy-2,2-dimethyl-2H-1-benzopyran of the formula (V). ##STR7## From the compound of the formula (V) the end-product of the formula (VI) can be obtained by three independent routes.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2cccnc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2cccnc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyridin-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 403.35 g/mol.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>CCCCCC>[CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+:10]
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li+]
Product: c1ccc2[cH-]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
Indene (10.0 g, 0.0861 moles) was stirred in hexane (150 mL) as n-BuLi (0.8783 moles, 54.8 mL of 1.6 M solution in hexane) was added drop wise. The mixture was allowed to stir overnight at room temperature during which time a solid precipitated. After the reaction period the solid was collected via suction filtration, washed with hexane, dried under vacuum, and was used without further purification or analysis (9.35 g, 89.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=2)[CH2:9]/[C:10](=[N:32]\[OH:33])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CC(=O)Nc1cccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1cccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 151, step 3, N-(3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)phenyl)acetamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=442.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[CH3:11][C:4]1[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)[CH:3]=1
Reactant: Cc1cc(Cl)nn2cnnc12
Reactant: C1=CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N2CC=CCC2)nn2cnnc12
Temperature: 25 °C

Procedure:
A solution of 84.3 g of 6-chloro-8-methyl-1,2,4-triazolo [4,3-b]pyridazine, 62.4 g of 1,2,5,6-tetrahydropyridine and 101 g of triethylamine in one liter of ethanol was refluxed under nitrogen for 21 hours. The bulk of the solvent was removed at the rotary evaporator. The residual semi-solid was dissolved in 1000 ml of dichloromethane and washed with 500 ml of saturated sodium bicarbonate solution. The aqueous layer was back washed with fresh dichloromethane (2×200 ml) and the combined organic layers were dried over anhydrous sodium sulfate. Evaporation of the solvent gave a light-brown oil which slowly solidified. This was taken up in 230 ml of hot ethyl acetate and cooled. After cooling the mixture slowly to room temperature and then to 5° C., the cream colored needles which formed were collected, washed with ethyl ether/ethyl acetate (2/1) then with ethyl ether and dried to give 8-methyl-6-(1,2,5,6-tetrahydropyridin-1-yl)-1,2,4-triazolo-[4,3-b]pyridazine melting at about 103°-106° C.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Li]C(C)(C)C.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:25][C:11]1[C:12]2[NH:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1cccc2c1Nc1ccccc1S2
Temperature: 25 °C

Procedure:
This compound was prepared according to a procedure by A. R. Katritzky et al., Synthesis, 1988, 215-217. To a solution of phenothiazine (10.0 g, 50.18 mmol) in anhydrous THF (200 mL) and cooled to −78° C. was added a solution of n-BuLi (24.1 mL, 60.2 mmol, 2.5 M in hexanes) dropwise. The mixture was stirred until a yellow precipitate formed, and then allowed to warm to room temperature, until a clear yellow solution resulted. The solution was again cooled to −78° C. and CO2 gas was bubbled through the mixture for 5 min. The resulting solution was allowed to warm to RT and the solvent was evaporated to give a residue. The residue was again dissolved in anhydrous THF (200 mL) and cooled to −78° C., before t-BuLi (50 mL, 85 mmol, 1.7 M in pentane) was added dropwise. The resulting mixture was allowed to warm to −20° C. and was stirred at this temperature for 2 h. The reaction mixture was again cooled to −78° C. and a solution of hexachloroethane (100 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at this temperature for 1 hour then allowed to warm to −20° C. and stirred for 2 h. The reaction mixture was quenched with ice cold 1 N HCL and extracted with EtOAC. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give a residue. The residue was purified by flash silica gel chromatography to give of an beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][CH:14]=[CH2:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:25][CH:24]=[CH2:23])=[C:8]([CH2:13][CH:14]=[CH2:15])[CH:7]=1
Reactant: C=CCc1cc(CCC(=O)OC)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(CCC(=O)OC)cc1CC=C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl-3(3-allyl-4-hydroxyphenyl)propionate (12.3 g), anhydrous potassium carbonate (13.8 g), and allylbromide (8.64 mls) in acetone (300 ml) was stirred at ambient temperature for two days. The reaction mixture was filtered and the residue washed with acetone. The filtrate and washings were combined and evaporated to give methyl-3-(3-allyl-4-allyloxyphenyl)proprionate as a pale yellow oil (14.0 g); NMR: 2.58(2H,t), 2.75(2H,t), 3.31(2H,d), 3.55(3H,s), 4.52(2H,d), 4.95-5.45(4H,m), 5.85-6.11(2H,m), 6.85(1H,d) and 7.0(2H,m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)C(C)C)(C)C.[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([Cl:27])=[CH:22][N:21]=1>C(O)(C)C>[Cl:19][C:20]1[N:25]=[C:24]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[C:23]([Cl:27])=[CH:22][N:21]=1
Reactant: COc1ncccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ncccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a suspension of 2-methoxy-pyridin-3-ylamine (1.00 g, 0.00806 mol) and N,N-diisopropylethylamine (2.1 mL, 0.012 mol) in isopropyl alcohol (20 mL) was added 2,4,5-trichloropyrimidine (1.0 mL, 0.0089 mol). The mixture was stirred at room temperature overnight. The suspension was filtered, the solid was washed with isopropanol (10 mL) then hexane (20 mL). The solids were dried under vacuum to provide (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-pyridin-3-yl)-amine (1.23 g, 56%) as a white solid. LC/MS (ESI+): 271.40 (M+H).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:22])[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[C:25]([O:24][CH2:23][CH:12]1[NH:11][C:15](=[O:16])[C:14]([CH3:21])([CH3:20])[C:13]1=[O:22])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)(C)C(=O)C(COC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OCC1NC(=O)C(C)(C)C1=O
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-5-tert-butoxy-2,2-dimethyl-3-oxopentanoate (8.7 g) in methanol (100 mL) was added 10% palladium carbon (containing 50% water, 4.0 g), and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound as colorless to crystals (yield: 3.81 g, 81%).
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=O.Cl.[NH:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]1=[NH:23].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:14][C:9]1[CH:8]=[C:7]([C:5]2[N:23]=[C:18]3[NH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:3](=[O:15])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: COC(=O)CC(=O)c1ccc(C)c(C)c1
Reactant: N=C1NCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2cc(=O)n3c(n2)NCCC3)cc1C

Procedure:
A suspension of 3-(3,4-dimethyl-phenyl)-3-oxo-propionic acid methyl ester (1.2 g, 5.8 mmol), tetrahydro-pyrimidin-2-ylideneamine hydrochloride (0.78 g, 5.8 mmol), and potassium carbonate (0.80 g, 5.8 mmol) in ethanol (20 mL) was heated to reflux for 4 h. Water (5 mL) was added to the reaction at room temperature and tan solid was collected by filtration. M+1=256.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][C:47]([NH2:49])=[O:48])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][C:47]([NH2:49])=[O:48])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound. HR-MS (ES, m/z) calculated for C36H44N5O3Cl2 [(M+H)+] 664.2816, observed 664.2810.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([OH:25])[CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:28][C:29](OC(C)=O)=[O:30]>N1C=CC=CC=1>[C:29]([O:25][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:26][CH3:27])[N:15]=[C:14]([C:4]1[CH:5]=[CH:6][C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:2]([F:1])[CH:3]=1)[NH:23][C:22]2=[O:24])(=[O:30])[CH3:28]
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)[nH]c(=O)c2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)[nH]c(=O)c2cc1OC(C)=O
Temperature: 105 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4(3H)-one (3.2 g, 8.83 mmol), Ac2O (40 mL) and pyridine (5 mL) was heated at 105° C. for 4 h. The mixture was poured onto ice-water (300 mL). The mixture was stirred for 1 h, upon which the solid which had formed was collected via filtration. The solid was washed with water and EtOH and dried under vacuum to give the desired product 2-(3-fluoro-4-(phenyl)phenyl)-7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate. MS 405.2 (M+1) HPLC retention time 8.23 mins.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17]>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[S:21][C:20]=1[C:19]([O:18][CH2:16][CH3:17])=[O:22]
Reactant: CCOC(=O)CS
Reactant: N#Cc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2nccnc2c1N
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A mixture of 3-chloropyrazine-2-carbonitrile (17.9 g, 128 mmol), sodium carbonate (17.7 g, 167 mmol) and ethyl-2-mercaptoacetate (18.4 mL, 167 mmol) in ethanol (120 mL) was heated to reflux for 4.5 h. Quenched with water (1.5 L) and stirred for 30 min. The resulting precipitate was collected and washed with water. The residue was dissolved in diethyl ether and a black precipitate was filtrated off. Ether was evaporated to give pure compound ethyl 7-aminothieno[2,3-b]pyrazine-6-carboxylate 7 (19.6 g, 68.5%). 1H-NMR (400 MHz, CDCl3) 1.42 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.2 Hz, 2H), 6.19 (br s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: Cl[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)Cl.[OH:22][CH2:23][CH2:24][CH2:25]/[C:26](=[CH:36]\[S:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)/[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].N1C=CN=C1>O>[Si:2]([O:22][CH2:23][CH2:24][CH2:25]/[C:26](=[CH:36]\[S:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)/[C:27]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:28])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccccc1)/C(=C/Sc1ccccc1)CCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
1.87 g of chloro t-butyl diphenylsilane was dropped into 10 ml of methylene chloride solution including 1.64 g of (E)-5-hydroxy-N-phenyl-2-(phenylthiomethylene)pentanamide and 0.82 g of imidazole at room temperature. After stirring at room temperature for 2 hours, the resulting solution was added with water and extracted with ethyl acetate. The organic layer was washed 3 times, then washed with brine, and dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.81 g the title compound.