Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>C(#N)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1cccc(F)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1ccc2ccc(Oc3cccc(F)c3)nc2n1
Temperature: 4 °C
Yield: 64.5 %

Procedure:
The procedure is similar to that described in Example 37, but starting with 2-amino-7-chloro-1,8-naphthyridine (18 g), 3-fluorophenol (44.8 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product produced (23.5 g; m.p. 161° C.) is dissolved in boiling acetonitrile (120 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-(3-fluorophenoxy)-1,8-naphthyridine (16.5 g) is produced, m.p. 165° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[C:18]([CH2:27][C:28]([OH:30])=[O:29])=[C:17]2[CH3:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](OC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)[CH3:33].[H-].[Na+].C(OC1C=CC(CCl)=CC=1)C1C=CC=CC=1>>[CH2:32]([O:29][C:28](=[O:30])[CH2:27][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:17]=1[CH3:31])[CH3:33]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2ccc(OCc3ccccc3)cc2)c2ccc(OC)cc12

Procedure:
1-[(4-Benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid. Using the method described in Example 6, Part A, 2.0 g (8.12 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester, 0.325 g (8.12 mmol) of 60% NaH/mineral oil, and 1.88 g (8.12 mmol) of 4-benzyloxy-1-chloromethylbenzene were reacted to give on workup 800 mg of crude 1-[(4-benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester. The crude ester in 50 mL of MeOH and 15 mL of 1N NaOH was heated at reflux temperature for 3 hours and left standing for 16 hours. After diluting with water, the mixture was made acidic with 1N HCl and extracted with EtOAc. The EtOAc solution was dried (Na2SO4) and concentrated. The residue was crystallized from MeOH to give 280 mg (32% yield) of 1-[(4-benzyloxyphenyl)-methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid, mp, 175°-179° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:23][CH:24]=1.O>CN(C)C=O>[C:25]1([C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:1][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][CH:7]4[S:11][C:10](=[O:12])[NH:9][C:8]4=[O:13])=[CH:4][CH:3]=3)[N:21]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)S1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (9.4 g) in N,N-dimethylformamide (80 ml) was added 60% sodium hydride in oil (3.4 g), and the mixture was stirred for 30 minutes. Then, a solution of 4-chloromethyl-2-phenyloxazole (9.6 g) in N,N-dimethylformamide (20 ml) was added dropwise thereto at room temperature. After being stirred at 70° C. for 1 hour, the reaction solution was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to give 5-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-2,4-thiazolidinedione (9.1 g, 47.4%). Recrystallization from ethanol yielded colorless needles. m.p. 188°-189° C. Elemental analysis for C20H16N2O4S; Calcd.: C, 63.15; H, 4.24; N, 7.36. Found: C, 63.19; H, 4.16; N, 7.23.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[S:12])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Cl[CH2:14][C:15](=O)[CH3:16].O=P(Cl)(Cl)Cl>CCO.CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:9]([C:10]=1[CH3:11])[C:15]([CH3:16])=[CH:14][S:12]2)=[O:5])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)c1[nH]c(=S)[nH]c1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)c1nc2scc(C)n2c1C

Procedure:
A mixture of 5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (5.37 mmol) and chloroacetone (6.44 mmol) in EtOH (10 mL) is heated at reflux for 150 min. The solvents are removed in vacuo and a solution of POCl3 (16.1 mmol) in MeCN (10 mL) is added. The mixture is stirred at reflux for 60 h, concentrated in vacuo and diluted with chloroform. Ice water is added and the mixture is neutralized by addition of Na2CO3. The layers are separated and the aq. layer is extracted with chloroform. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give a mixture of two regioisomers (see A.7.7) which are separated by FC (heptane to heptane/EtOAc 3/7). LC-MS: tR=0.71 min; [M+H]+=225.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][C@@H:21]2[C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)=[CH:4][C:5]([F:18])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:33]([O:26][C@@H:23]1[CH2:24][CH2:25][C@H:20]([O:19][C:3]2[CH:4]=[C:5]([F:18])[C:6]([S:8](=[O:10])(=[O:9])[NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)=[CH:7][C:2]=2[Cl:1])[C@@H:21]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[CH2:22]1)(=[O:35])[CH3:34]
Reactant: Cn1nccc1[C@H]1C[C@H](O)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC[C@H](Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2Cl)[C@@H](c2ccnn2C)C1
Yield: 91 %

Procedure:
A solution of the 5-chloro-2-fluoro-4-{[(1S,2R,4R)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (22.0 mg, 0.046 mmol) prepared in Example 165d, acetic anhydride (0.50 mL) and 4-(N,N-dimethylamino)pyridine (0.6 mg, 0.0046 mmol) in pyridine (1.0 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated, and 1 M HCl (10 mL) was then added to the residue, followed by extraction with dichloromethane (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=10:1) to yield the title compound (22.0 mg, 91%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=2[Cl:8])=[O:27])=[CH:24][CH:23]=1
Reactant: Cc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
A stirred, -60° C. solution of 3,5-dichlorotoluene (805 mg, 5.00 mmol) in tetrahydrofuran (5 mL) under nitrogen atmosphere was treated dropwise over 10 minutes with a 1.6M solution of n-butyllithium in hexane (3.3 mL, 5.25 mmol). After addition was complete residual n-butyllithium in the addition funnel was rinsed into the reaction mixture with tetrahydrofuran (1 mL). The reaction mixture was stirred 30 minutes at -55° and then a solution of p-chlorobenzoylchloride (875 mg, 5.00 mmol) in tetrahydrofuran (1.0 mL) was added dropwise over 15 minutes. The mixture was kept at -55° to -30° C. for 2 hours, stirred 2 hours at ambient temperature, and quenched by addition of saturated aqueous ammonium chloride (1.1 mL). After stirring 15 minutes, sodium sulfate (1.1 g) was added, and the mixture was stirred an additional 15 minutes. The solution was decanted, the solids were washed with diethyl ether, and the combined solution and wash were evaporated under reduced pressure. The residue was recrystallized from ethanol (15 mL) to provide 0.78 g (52%) 4-(4-chlorobenzoyl)-3,5-dichlorotoluene.
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(Cc2ccccc2)Cc2ccccc2)CC1
Yield: 22.7 %

Procedure:
4-Amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.11 g) as starting compound, benzaldehyde (0.28 g) and sodium cyanoborohydride (0.33 g) were reacted and treated in the same manner as in Example 136 to give 0.3 g of 4-amino-5-chloro-N-((1-(5-dibenzylaminopentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:15]([NH2:18])(=[S:17])[CH3:16]>C(O)C>[CH3:16][C:15]1[S:17][CH:2]=[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[N:18]=1
Reactant: O=C(CBr)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc(Cc2ccc([N+](=O)[O-])cc2)cs1
Yield: 80.9 %

Procedure:
A mixture of 1-bromo-3-(4-nitrophenyl)-2-propanone (0.80 g), thioacetamide (0.23 g) and ethanol (20 mL) was heated under reflux for 2 hrs. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-methyl-4-(4-nitrobenzyl)-1,3-thiazole as pale-yellow crystals (0.58 g, yield 79%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 118-119° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[O:7]([C:14]([NH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27]([NH:31][C:32]([C:34]3([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[CH2:36][CH2:35]3)=[O:33])=[C:26]([F:47])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:47][C:26]1[CH:25]=[C:24]([O:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:14]([N:4]3[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]3)=[O:7])[CH:22]=2)[C:29]([F:30])=[CH:28][C:27]=1[NH:31][C:32]([C:34]1([C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])[CH2:36][CH2:35]1)=[O:33]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)Oc1ccccc1
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC[C@H](O)C1
Reaction time: 2 h
Yield: 81 %

Procedure:
(S)-3-Hydroxypyrrolidine (0.0577 ml) was added to a mixture of benzyl 1-({[4-({2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (200 mg) and N-methylpyrrolidinone (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added to the mixture, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, and the solid was washed with water (20 ml, three times), and the solid was dried by hot air (80° C.) for 1 day to give the title compound (159.0 mg, 81%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:7]([OH:8])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:21][C:6]1[N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:11][C:10]=2[Cl:20])[N:4]=[C:3]([C:1]#[N:2])[C:7]=1[OH:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1O
Solvent: ClC(Cl)Cl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-hydroxypyrazole (1.0g) and N-bromosuccinimide (0.55g) in chloroform (20ml) was stirred at room temperature for 75 minutes, then washed with water (3×20 ml), filtered through phase-separation paper and evaporated. The residue was purified by dry-column chromatography (eluant ether: hexane 1:1 then 3:1) to give 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-hydroxypyrazole as a buff colored solid, m.p. 145°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20])=[O:8]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1cccc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of the 2,4,5-trichloro-phenoxy acetic acid (76.7 mg, 0.3 mmol), 3-amino benzamide (61.3 mg, 0.45 mmol), EDC (86.3 mg, 0.45 mmol) and HOBt (61.3 mg, 0.45 mmol) were dissolved in DMF (3 mL), and DIPEA (0.08 mL, 0.45 mmol) were added. The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetate and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (CH2Cl2:MeOH=6:3:1) gave 3-[2-(2,4,5-trichloro-phenoxy)acetyl-amino]-benzamide as a white solid (95.2 mg, 84.9% yield).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][CH3:36])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][CH3:36])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC[C@H](N)C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](NC1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21)C(=O)N(C)C

Procedure:
With 2.42 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 74-3 (9.03 mmol, crude form) as starting materials, respectively 1.1 μg (Isomer A, colorless powder) and 1.77 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH2:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:7][CH:8]([OH:11])[CH2:9][NH:27][CH2:26][CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: NCCOc1ccc(OCc2ccccc2)cc1
Product: CS(=O)(=O)c1ccc(OCC(O)CNCCOc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)phenol with p-benzyloxyphenoxyethylamine in accordance with the procedure of Example 15 provides 3-[4-(METHYLSULFONYL)PHENOXY]-1-[(p-BENZYLOXYPHENOXYETHYL)AMINO]-2-PROPANOL.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C@@:20]([CH3:35])([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[F:19][C@@:20]([CH3:35])([C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:32])([F:30])[F:31])=[O:25])[C:21]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: C[C@@](F)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CN1C(=O)[C@@H](NC(=O)[C@@](C)(F)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2S)-2-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white solid;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].O>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Fc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)ccc1Sc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a mixture of 3-fluorothiophenol (8.36 g, 65.2 mmol) and potassium carbonate (9.81 g, 71.0 mmol) in 115 mL of dry acetonitrile is added 2,5-difluoronitrobenzene (7.00 mL, 64.55 mmol). The mixture is allowed to stir at room temperature for 2 hours. Water and CH2Cl2 (120 mL each) are added and the layers separated. The aqueous layer is extracted with CH2Cl2 (3×50 mL). The combined organics are dried over MgSO4, filtered, and concentrated to give a bright yellow solid. The solid is triturated with hexane to give 17.1 g (99%) of the title compound as a bright yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:31])[C@@H:15]([NH2:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:31])[C@@H:15]([NH:30][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccc(O)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(O)c2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 36.2 %

Procedure:
A solution of 2-amino-5-chloro-benzoic acid (1.95 g, 11.38 mmol) in DMF (10.0 mL) was reacted with (2S)-amino-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester (3.50 g, 11.38 mmol), HBTU (3.98 g, 10.50 mmol), and DIEA (6.08 mL, 34.15 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silical gel using DCM/hexane 85:15 and increasing the gradient to DCM and finally DCM containing 0.25% methanol, to give 1.75 g of (2S)-(2-amino-5-chloro-benzoylamino)-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester as a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH3:20]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:31])=[CH:25][CH:26]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2cccs2)cc1
Yield: 68 %

Procedure:
Nitrogen was bubbled through a mixture of 2-tributylstannyl thiophene (15.68 ml, 49.4 mmol) and ethyl(4-bromophenyl)acetate (6 g, 24.7 mmol) in toluene (250 ml) before 0.5 g of tetrakis (triphenylphosphine) palladium (0) was added. The mixture was heated at reflux under nitrogen for 4 hours before it was filtered through magnesol and concentrated. The residue was purified using silica-gel column chromatography by eluting it with 20% ethyl acetate: hexane solution. Ethyl [4-(2-thienyl)phenyl]acetate was isolated as a yellow oil (4.15 g). Yield 68%; MS: 247.5 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([SH:8])[N:3]=1.IC.[C:11]([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:11])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccnc(S)n1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nccc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A mixture of compound 4-methylpyrimidine-2-thiol (500 g, 3.05 mol), iodomethane (611 g, 4.27 mol) and K2CO3 (915 g, 6.71 mol) in THF (4 L) was stirred at room temperature for 18 h. The suspension was filtered and the solid was washed with ether (500 mL×2). The filtrate was concentrated and dried in vacuum to give compound 2 (380 g, 89.2%) as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:11]([O:12][C:13](=[O:15])[CH3:14])[CH:10]([O:16][C:17](=[O:19])[CH3:18])[CH:9]([O:20][C:21](=[O:23])[CH3:22])[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=O)[O:7]1)(=[O:3])[CH3:2].[C:32](=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH:6]1[CH:11]([O:12][C:13](=[O:15])[CH3:14])[CH:10]([O:16][C:17](=[O:19])[CH3:18])[CH:9]([O:20][C:21](=[O:23])[CH3:22])[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=[CH2:32])[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1OC(Oc2ccsc2C=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1sccc1OC1OC(COC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O

Procedure:
3.30 g of 3,4,5-triacetoxy-6-(2-formyl-thiophen-3-yloxy)-tetrahydropyran-2-ylmethyl actate were dissolved in 60 ml of dioxane. 6.43 g of methyltriphenylphosphonium bromide, 5.37 g of potassium carbonate and 0.25 ml of water were added, and the solution was refluxed for 4 h. The solution was concentrated and purified by column filtration. 2.89 g of the product with the molecular weight: 456.47 (C20H24O10S), MS (ESI): 479.10 (M+Na+); 474.10 (M+NH4+) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[C:15]=[O:16])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)cc(OC)c1OC

Procedure:
600 ml of a solution of 18.3 g of 3,4,5-trimethoxyaniline in toluene was added to 140 ml of a solution of 48 ml of trichloromethyl chloroformate in toluene and the mixture was refluxed for 3 h. After cooling, the solvent was distilled off and the residue was distilled under reduced pressure (115° C./1 mmHg) to obtain 15.53 g of 3,4,5-trimethoxyphenyl isocyanate.