Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:23][OH:24])[CH:16]=[CH:15][CH:14]=1)([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.CC(O)C>CC(C)=O.O>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[C:21]([C:23]([OH:27])=[O:24])=[CH:20][CH:19]=[CH:18]2)([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: C=CCOP(=O)(OCC=C)OCc1cccc2cccc(CO)c12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: C=CCOP(=O)(OCC=C)OCc1cccc2cccc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of diallyl [8-(hydroxymethyl)-1-naphthyl]methyl phosphate (1.1492 g, 3.30 mmol) in acetone (20 ml) obtained from Example 25-(2) was added Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 5 ml, ca. 13.2 mmol). The reaction mixture was stirred at room temperature for 90 minutes, then cooled to 0° C., and then 2-propanol (0.5 ml) was added thereto to stop the reaction. The insoluble material was filtered off, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was dried using a vaccum pump, and then subjected to chromatography on a silica gel (30 g) column (eluent; ethyl acetate:dichloromethane=1:10˜3:10) to afford crude 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-naphthoic acid as an oil. The product was dissolved in dichloromethane (10 ml), and then oxalyl chloride (1 g, 7.88 mmol) and N,N-dimethylformamide (15 μl) were added thereto. After the mixture was stirred at room temperature for 30 minutes, crude 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-naphthoyl chloride was obtained according to a similar procedure to that described in Example 1-(12). According to a similar procedure to that described in Example 1-(12), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (542.7 mg, 1.0 mmol) described in Reference example 1, sodium hydride (55% dispersion in mineral oil; 43 mg, 1.0 mmol), and the crude 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-naphthoyl chloride obtained above were reacted in tetrahydrofuran (5 ml) and the reaction mixture was worked up to afford, after extraction, the title compound as a crude oil. The crude oil was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=1:1˜5:1) to afford the title compound (459.2 mg, 52% yield) as a pale yellow amorphous solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].C(OCC)(=O)C.Cl.[NH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[Cl:25][CH2:26][C:27](Cl)=[O:28]>O>[Cl:25][CH2:26][C:27]([NH:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: NC1CCc2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCl)NC1CCc2ccccc2C1=O
Reaction time: 1 h
Yield: 568 %

Procedure:
To a stirred solution of sodium bicarbonate (4.0 g) in water (50 ml) layered with ethyl acetate (200 ml) was added solid 2-amino-3,4-dihydronaphthalen-1(2H)-one hydrochloride (4.0 g, 2 mmol). After the solid had dissolved chloroacetylchloride (1.6 ml, 2 mmol) was added dropwise over 10 minutes. After stirring for 1 hr, the ethyl acetate layer was separated, washed with brine and dried over Na2SO4. Evaporation afforded 2.7 g (57%) of a dark solid; m.p. 118°-122° C. The product was purified by chromatography on silica using ethyl acetate: hexane (1:1 v/v) to elute, m.p. 121°-123° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].N[C:12]1[CH:16]=CS[C:13]=1[C:17](OC)=O>>[CH2:16]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:12][CH2:13][CH3:17]
Reactant: COC(=O)c1sccc1N
Reactant: COC(=O)c1ccsc1N
Product: CCCCNc1sccc1C(=O)OC
Yield: 40.7 %

Procedure:
In the same manner as in Reference Example 1-1), methyl 2-aminothiophene-3-carboxylate [Chem. Ber. 98, 3571 (1965)]was used in place of methyl 3-aminothiophene-2-carboxylate to obtain 8.69 g (40.7%) of Compound (g-1).
Reaction SMILES: Cl[Si:2]1(Cl)[CH2:5][CH2:4][CH2:3]1.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([NH:11][Si:2]1([NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:5][CH2:4][CH2:3]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cl[Si]1(Cl)CCC1
Reactant: CC(C)(C)N
Product: CC(C)(C)N[Si]1(NC(C)(C)C)CCC1
Reaction time: 72 h
Yield: 45 %

Procedure:
Bis(t-butylamino)silacyclobutane (BTBSCB) was synthesized by reacting 1,1-dichlorosilacyclobutane with an excess amount of t-butylamine (Equation 1). To do so, 19.7 ml (0.166 mol) 1,1-dichlorosilacyclobutane was added to 105 ml (0.999 mol) t-butylamine in 1 L hexanes at 0° C. After bodying for three days at the room temperature, the reaction slurry was filtered to remove t-butylamine hydrochloride salt. The filtrant was vacuum dried to give a crude liquid product which was then vacuum distilled. 16 g Product was isolated at 99.2% purity in 45% yield at 71° C. under 50 torr pressure. The structure of the product analyzed with 1H, 13C and 29Si NMR, FT-IR and GC-MS was in consistence with bis(t-butylamino)silacyclobutane.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[S:7]([O-])([OH:9])=[O:8].[Na+]>>[S:1]([S:7]([O-:9])=[O:8])([O-:4])(=[O:3])=[O:2].[Na+:5].[Na+:5]
Reactant: O=S([O-])O
Reactant: O=S([O-])[O-]
Agent: [Na+]
Product: O=S([O-])S(=O)(=O)[O-]

Procedure:
Further comparative experiments were undertaken in the same manner as above except that the 0.01 mole/liter aqueous solution of sodium sulfite was replaced with an equal volume of a 0.01 mole/liter aqueous solution of sodium hydrogensulfite or a 0.00491 mole/liter aqueous solution of sodium pyrosulfite to give the results almost identical with those shown by the curve VI in FIG. 1. The residual cyanide concentration was 24.4 ppm or 29.8 ppm after 120 minutes of the treatment with sodium hydrogensulfite or after 129 minutes of the treatment with sodium pyrosulfite, respectively.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:14])(=[O:13])[C:11]3[CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:22]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:20][CH2:19][C:16]1[CH:17]=[CH:18][C:10]2[CH:9]=[CH:8][C:7]3[CH:22]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=3[S:12](=[O:14])(=[O:13])[C:11]=2[CH:15]=1
Reactant: CSc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2(=O)=O
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: CSc1ccc2c(c1)C=Cc1ccc(CO)cc1S2(=O)=O

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-methylthiodibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Reactant: O=Cc1cccs1
Agent: [Cl-]
Product: Clc1c(NCCNCc2cccs2)ccc2ccccc12
Yield: 59 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and thiophene-2-carbaldehyde in 59% yield as a white oil.
Reaction SMILES: C(O)C.O.[OH-].[K+].[CH2:7]([O:9][CH:10]([N:12]1[C:16]2[S:17][C:18]([C:20]([O:22]CC)=[O:21])=[CH:19][C:15]=2[C:14](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13]1)[CH3:11])[CH3:8]>O1CCCC1>[CH2:7]([O:9][CH:10]([N:12]1[C:16]2[S:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:15]=2[C:14](/[CH:25]=[CH:26]/[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:13]1)[CH3:11])[CH3:8]
Reactant: CCOC(=O)c1cc2c(/C=C/c3ccccc3)nn(C(C)OCC)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(C)n1nc(/C=C/c2ccccc2)c2cc(C(=O)O)sc21
Temperature: 85 °C
Yield: 97.3 %

Procedure:
2 cm3 of ethanol, 2 cm3 of water and 0.60 g (10.8 mmol) of potassium hydroxide are successively added with stirring to a solution of 2.0 g (5.4 mmol) of ethyl 1-(1-ethoxyethyl)-3-((E)-styryl)-1H-thieno[2,3-c]pyrazole-5-carboxylate in 15 cm3 of tetrahydrofuran. The reaction medium is heated at a temperature in the region of 85° C. for 5 hours and is then cooled to a temperature in the region of 25° C. and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is dissolved in 150 cm3 of water and extracted with twice 100 cm3 of diethyl ether. The aqueous phase is acidified to a pH of about 5 by adding solid citric acid, and is then extracted with three times 100 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 1.8 g of 1-(1-ethoxyethyl)-3-((E)-styryl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid are thus obtained in the form of a pale yellow solid melting at 160° C. Mass spectrum (EI): m/z 342 [M+], 270 (base peak): [M+] —C2H5—O—CH—CH3.
Reaction SMILES: C=C.[Cl:3]Cl.[Cl:5][CH2:6][CH2:7][Cl:8]>>[Cl:3][CH:7]([Cl:8])[CH3:6].[Cl:5][CH:6]([Cl:3])[CH2:7][Cl:8]
Reactant: ClCl
Reactant: ClCCCl
Agent: C=C
Product: CC(Cl)Cl
Product: ClCC(Cl)Cl

Procedure:
The procedure was as in Example 1 but 2072 g 1,2-dichloroethane containing 1.6 g dissolved FeCl3 was introduced into the reactor. The solution contained 0.076 weight % FeCl3, determined colorimetrically. The quantities of ethylene and chlorine introduced in the presence of air underwent reaction inside the reactor to give crude dichloroethane containing 0.18 weight % 1,1,2-trichloroethane.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: OC(CCl)CCCl
Product: NC(=O)c1ccc(OCC(O)CCCl)cc1
Yield: 25 %

Procedure:
Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-hydroxybenzamide to give white title compound, m.p. 150°-153° C. in 25% yield. The recrystallizing solvent was 95% ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@H:9]([NH:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=1[O:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2)(=[O:15])=[O:14])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:40]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[CH2:8][C@H:9]([NH:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH2:40])=[CH:18][C:17]=1[O:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2)(=[O:14])=[O:15])[C:10]#[N:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](C#N)NS(=O)(=O)c1ccc(C(=O)O)cc1OCCc1cccc2ncccc12
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](C#N)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a solution of acid 4-((S)-2-tert-butoxycarbonyl-1-cyano-ethylsulfamoyl)-3-(2-quinolin-5-yl-ethoxy)-benzoic acid (0.60 g, 1.10 mmol) in THF (20 mL) was added EDCI (0.33 g, 1.70 mmol), HOBt (0.23 g, 1.70 mmol), and N-methylmorpholine (1.70 mmol, 0.20 mL). The reaction was allowed to stirred at room temperature for 1 h then followed by addition of NH4OH (10 mL). The mixture was stirred for another 12 h. To reaction was added EtOAc (100 mL) and washed with the 5% citric acid and then saturated NaHCO3. The organic phase was dried (MgSO4), and then the solvent was removed under vacuum. The resulting crude product was purified using silica gel flash chromatography (70% EtOAc in hexanes). (S)-3-[4-Carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid tert-butyl ester was obtained in 22% yield (0.130 g) as an off white foam. MS (APCI) m/z 525.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2(C(O)=O)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[S:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC[CH2:25][Cl:26].S(Cl)(Cl)=[O:28]>CN(C=O)C>[Cl:26][C:25]([C:12]1[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:28]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C2(C(=O)O)CSc3ccccc32)cc1OC
Reactant: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C(=O)Cl)sc3ccccc23)cc1OC
Reaction time: 4 h
Yield: 96 %

Procedure:
3-(3,4-Dimethoxyphenyl)benzothiophene-3-carboxylic acid (25 g; 0.08 mole) prepared according to process D, 1,2-dichloroethane (300 ml), thionyl chloride (12 ml, 0.16 mole) and DMF (1 ml) are introduced into a flask. The mixture is progressively heated to reflux temperature; the solid dissolves little by little to provide a clear yellow solution. After four hours, the solvents are evaporated to provide 2-(chlorocarbonyl)-3-(3,4-dimethoxyphenyl)benzothiophene (24.7 g; yield=96%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[N:75]1([CH:81]2[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]2)[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1>O.C1COCC1>[N:75]1([CH:81]2[CH2:86][CH2:85][N:84]([C:7](=[O:8])[CH:6]([CH2:5][C:4]3[CH:30]=[CH:31][C:32]([CH3:33])=[C:2]([CH3:1])[CH:3]=3)[CH2:10][C:11]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:28])[CH2:14][CH2:13]3)=[O:29])[CH2:83][CH2:82]2)[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.9 g (2.0 mmol) 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid, 0.71 g (2.2 mmol) TBTU, 0.28 g (2.1 mmol) HOBt, 0.39 mL (2.2 mmol) ethyldiisopropylamine, 45 mL THF and 5 mL water was stirred for 10 min at RT, combined with 0.37 g (2.1 mmol) [1,4′]bipiperidinyl and stirred for a further 4 h. The reaction mixture was evaporated down under reduced pressure, the residue was combined with saturated NaHCO3 solution and extracted three times with DCM/MeOH (95:5). The combined organic phases were dried, evaporated down under reduced pressure and purified by chromatography over silica gel. The product fractions were evaporated down under reduced pressure, the residue was triturated with diisopropylether and suction filtered.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:11]#[C:12][S:13]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=[CH:5][C:6]([O:8]CC)=[O:7].C(OCC)C.O.Cl>C1COCC1>[CH3:3][C:4]([C:11]#[C:12][S:13]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=[CH:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C=C(C)C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C)=CC(=O)O

Procedure:
Sodium hydroxide (400 mg, 10 mmol) is added to a solution of ethyl 3-methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)pent-2-en-4-ynoate (400 mg, 1.6 mmol) in 15 ml of THF. The medium is refluxed for 4 h. It is then poured into an ethyl ether/water mixture, acidified to pH 1 with concentrated hydrochloric acid solution and extracted with ethyl ether. After separation of the phases by settling, the organic phase is washed twice with water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The residue is then triturated from heptane, after which it is filtered.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[C:46]4[C:50](=[CH:51][CH:52]=3)[NH:49][CH:48]=[CH:47]4)=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[C:46]4[C:50](=[CH:51][CH:52]=3)[NH:49][CH:48]=[CH:47]4)=[CH:40][CH:39]=2)[C:35]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of triphenylphosphine (71 mg, 0.27 mmol) in methylene chloride (1.5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (48 mg, 0.27 mmol). The reaction mixture was stirred at 0° C. for 25 min and then treated with 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid (75 mg, 0.23 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (50 mg, 0.50 mmol). The resulting reaction mixture was stirred at 25° C. for 5 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 chloroform/methanol) to afford impure 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide. Repurification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded pure 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide (8 mg, 9%) as a white solid: mp 112-115° C.; EI-HRMS m/e calcd for C25H25N3OS (M+) 415.1718, found 415.1714.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[C:26]([O:29]C)(C)C>>[CH2:26]([O:29][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(C)(C)C
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Product: O=C(O)CCC(=O)OCCc1ccccc1
Temperature: 68 °C
Reaction time: 4 h

Procedure:
In a 500 mL round bottom flask, fitted with a reflux, condenser, succinic anhydride (10.03 g, 1.2 eq.) and dimethylaminopyridine (10.2 g, 1 eq.) and benzyl alcohol (9.01 g, 1 eq.) in MTBE (250 mL) were combined. The reaction mixture was placed under inert atmosphere and stirred in an oil bath at 68° C. for 4 hours. The reaction was then quenched with a solution of 10% NaHCO3 and extracted with MTBE. The organic layer was washed with NaHCO3 and brine. The organic layer was collected, dried using MgSO4, and concentrated to give a white solid. The crude product was purified using column chromatography to give 14.1 g of white crystals.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.CC(O)C.Cl[C:24]1[N:33]=[C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]3[O:42][CH2:43][O:44][C:38]=3[CH:37]=2)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:45]#[N:46])[CH:30]=2)[N:25]=1>CN(C)C=O>[CH2:10]([O:9][C:7]([CH2:6][CH2:5][CH2:4][N:3]([C:24]1[N:33]=[C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]3[O:42][CH2:43][O:44][C:38]=3[CH:37]=2)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:45]#[N:46])[CH:30]=2)[N:25]=1)[CH3:2])=[O:8])[CH3:11]
Reactant: CCOC(=O)CCCNC
Reactant: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)CCCN(C)c1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
858 mg of ethyl N-methyl-4-aminobutyrate hydrochloride, 238 mg of triethylamine, 4 ml of 2-propanol and 2 ml of N,N-dimethylformamide were added to 400 mg of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 1 hour, cooled to room temperature and filtered. The filtrate was distilled under a reduced pressure to remove the solvent and the residue was recrystallized (from ethanol/water) to give 410 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])O[C:4]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:3]1=2.[OH-].[NH4+:20]>>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[NH:20][C:4]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:3]1=2
Reactant: O=C(O)c1cc(=O)c2c(o1)-c1ccccc1SC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c2c([nH]1)-c1ccccc1SC2

Procedure:
A solution of 4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carboxylic acid (3.0 g, 11.53 mmoles, described in Example 79) in concentrated ammonium hydroxide (50 ml) is heated on a steam bath for 2.5 hr., and evaporated under reduced pressure. The residue is dissolved in water (75 ml) and added to a mixture of concentrated hyrochloric acid (5 ml) and ice. The precipitate is collected, washed with 0.07 N hydrochloric acid, acetone and ether to give the title compound as light yellow crystals, m.p. 256°-257° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[C:4]([C:15]([Cl:18])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(N([CH2:25][CH3:26])CC)C.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29]>ClCCl>[Cl:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([F:19])[C:2]([N:1]([S:30]([CH2:27][CH2:25][CH3:26])(=[O:32])=[O:31])[S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Reactant: CCN(CC)CC
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(Cl)c(C(=O)OCc2ccccc2)c1F)S(=O)(=O)CCC
Temperature: 0 °C
Yield: 72 %

Procedure:
Benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 15.37 mmol) was dissolved in dry dichloromethane (270 mL). Triethylamine (5.36 mL, 2.5 eq.) was added, and the mixture was chilled to 0° C. Propane-1-sulfonyl chloride (3.63 mL, 32.3 mmol, 2.1 eq.) was then added via syringe, and a precipitate resulted. Once the addition was complete, the mixture was allowed to warm to room temperature, and the starting material was consumed as determined by TLC (3:1 hexane:ethyl acetate). The mixture was then diluted with dichloromethane (200 mL), washed with 2M aqueous HCl (2×100 mL), saturated Na2HCO3 solution, dried over sodium sulfate and concentrated. The resulting residue was purified on a 65 Biotage chromatography system (40% ethyl acetate/hexane) to produce benzyl 6-chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (5.5 g, 72%) as an oil that slowly solidified upon standing. NMR (CDCl3, 400 MHz) δ 7.28-7.45 (m, 7H), 5.42 (s, 2H), 3.58-3.66 (m, 2H), 3.43-3.52 (m, 2H), 1.08 (t, 6H, J=8).