Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][O:17][CH3:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([NH2:38])=[CH:37][C:30]=2[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([NH:38][C:2]3[N:19]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[CH2:16][O:17][CH3:18])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:37][C:30]=2[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: COCc1ccccc1-c1cccn2nc(Cl)nc12
Product: COCc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
7-[8-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.40 g, 1.46 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.46 g, 1.75 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.5 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (d, J=6 Hz, 1H), 7.61 (d, J=6 Hz, 1H), 7.51-7.42 (m, 4H), 7.00-6.89 (m, 3H), 6.79 (s, 1H), 3.62-3.45 (m, 4H), 3.29 (s, 3H), 2.84-2.74 (m, 4H), 1.52 (s, 9H). MS=500 (MH)+.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44](O)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:44]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34][CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36]2)=[O:45])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC2C=Nc3ccccc32)NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-L-tryptophan (90 mg, 0.3 mmol). The final product was triturated with ether to yield 157 mg (81%) of the desired material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:27][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CCCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCNC1=C(C(=O)OCC)CN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 1-tert-butoxycarbonyl-3-ethoxycarbonyl-piperidin-4-one (prepared from 3-ethoxycarbonyl-piperidin-4-one and di-tert-butyl-dicarbonate in dichloromethane and triethylamine) (8.5 g) and heptylamine (3.61 g) in toluene (100 ml) was heated under reflux in a Dean and Stark apparatus for 18 hours and then evaporated to dryness to give an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[Cl:13]SCl>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([Cl:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: ClSCl
Reactant: O=C(O)CCc1cccc(F)c1
Product: O=C(Cl)CCc1cccc(F)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-fluorophenyl)propanoic acid (2.50 g, 14.9 mmol) and dichlorosulfane (10 mL) under N2 was refluxed for 3 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](N)[CH2:22][NH2:23]>C(=S)=S.O>[F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]1[NH:23][CH2:22][CH2:21][N:16]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: NCCN
Solvent: S=C=S
Solvent: O
Product: FC(F)(c1ccccc1)C(F)(F)c1ccccc1C1=NCCN1

Procedure:
2-(α,α,β,β-Tetrafluorophenethyl)benzonitrile, 2.06 g. (0.0074 mole), together with 1.2 g. (0.02 mole) of ethylenediamine and 3 drops of carbon disulfide, is heated in a sealed tube at 160°-165° C. for 18 hours. After cooling in an ice-bath, the tube is opened and the contents are poured into water. The orange gum that separates is washed with water by decantation and then dissolved in ethyl acetate. The ethyl acetate solution is extracted with 3N hydrochloric acid. The combined, ice-cold, acid extracts are rendered strongly alkaline with 40% aqueous sodium hydroxide and the oily base is extracted into ethyl acetate. The washed and dried ethyl acetate extract is concentrated under reduced pressure to a volume of about 25 ml. and 0.6 ml. of 8N ethanolic hydrogen chloride is added. Dilution with an equal volume of absolute ether precipitates the white crystalline hydrochloride salt of the product, m.p. 263°-266° C., sintering at 258° C. Recrystallization from acetone gives a purified sample, m.p. 266°-267° C.
Reaction SMILES: [C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C1(C=CC(O)=CC=1)O.C(=O)([O-])O.[Na+:32]>>[C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([O-:8])=[O:7])(=[O:3])[CH3:2].[Na+:32]
Reactant: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Product: C=C(C)C(=O)NC1=CC(C(=O)[O-])C(O)(C(C)=O)C=C1

Procedure:
2-acetyl-5-methacrylamidosalicylic acid and hydroquinone (0.5% by weight) were dissolved in an aqueous solution of excess sodium hydrogencarbonate. The solution was stirred at temperatures of 40° C. to 50° C. The solvent was removed under acidic conditions. The remaining powder was recrystallized by a mixture of water and ethanol to give sodium 2-acetyl-5-methacrylamidosalicylate.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[Br:16]Br>C(Cl)Cl>[NH2:1][C:2]1[C:13]([Br:16])=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCN(CC)Cc1cc(OC)ccc1N
Reactant: BrBr
Solvent: ClCCl
Product: CCN(CC)Cc1cc(OC)cc(Br)c1N

Procedure:
2-Amino-3-bromo-N,N-diethyl-5-methoxy-benzylamine was prepared from 2-amino-N,N-diethyl-5-methoxy-benzylamine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [Si]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)(C(C)(C)C)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:58]([O:60][C:61]1[CH:69]=[CH:68][C:64]([CH2:65][CH2:66][NH2:67])=[CH:63][C:62]=1[O:70][CH3:71])[CH3:59].F.F.F.C(N(CC)CC)C>CN(C)C(=O)C>[CH2:58]([O:60][C:61]1[CH:69]=[CH:68][C:64]([CH2:65][CH2:66][NH:67][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=3)([CH3:24])[CH3:23])[CH:15]=2)=[CH:63][C:62]=1[O:70][CH3:71])[CH3:59]
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: CCOc1ccc(CCN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOc1ccc(CCNC(=O)c2cccc(CC(C)(C)NC[C@H](O)c3ccc(O)c(CO)c3)c2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
Solutions of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methylphenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (90 mg, 0.19 mmol) in N,N-dimethylacetamide (1 mL) and 0-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) in N,N-dimethylacetamide (0.5 mL) were added to a solution of 4-ethoxy-3-methoxyphenethylamine (37 mg, 0.19 mmol) in N,N-dimethylacetamide (0.5 mL). The resulting mixture was stirred for 72 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium hydrogen carbonate solution (1 mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (700 μL), triethylamine trihydrofluoride (30 μL, 0.19 mmol) was added and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then purified directly by HPLC using a Phenomenex Luna C18 system, eluting with water/0.05% diethylamine:acetonitrile, 5:95 to 95:5, to afford the title compound in 30% yield (30.9 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[N:3]=1.[OH-].[Na+].C(=O)(O)[O-:19].[Na+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:19])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[N:3]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(-n2ccnc2)nc(Cl)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(-n2ccnc2)nc(Cl)c1C(N)=O
Temperature: 25 °C

Procedure:
A solution of 2-chloro-3-cyano-6-(imidazol-1-yl)-4-methylpyridine (2.1 g) in concentrated sulfuric acid (5 mL) was heated at 130° C. for 15 minutes. The mixture was cooled to room temperature, diluted with water (10 mL), and adjusted to pH 7 with 20% sodium hydroxide solution followed by solid sodium bicarbonate. The crystalline product was removed by filtration and dried to give 2.35 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].[Br:13][C:14]1[CH:26]=[C:25]([CH2:27][CH2:28]Br)[CH:24]=[CH:23][C:15]=1[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[Br:13][C:14]1[CH:26]=[C:25]([CH2:27][CH2:28][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)[CH:24]=[CH:23][C:15]=1[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)COc1ccc(CCBr)cc1Br
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
A suspension of (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (475 mg), ethyl 2-[2-bromo-4-(2-bromoethyl)phenoxy]acetate (520 mg) and molecular sieves 4A powder (1.42 g) in N,N-dimethylformamide (4.7 ml) was stirred for 2 days at room temperature. Purification of the reaction mixture by medium pressure liquid column chromatography on aminopropyl silica gel (eluent:dichloromethane/methanol=10/1) gave ethyl 2-[2-bromo-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate (356 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[CH2:15][OH:16])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([O:25][C@@H:26]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24]>>[CH2:23]([O:25][C@@H:26]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:16][CH2:15]/[CH:14]=[CH:13]/[C:11]2[CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]=2)=[CH:37][CH:38]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C/c1cc(-c2ccccc2)cc(-c2ccccc2)c1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(-c3ccccc3)cc(-c3ccccc3)c2)cc1)OCC
Yield: 80.1 %

Procedure:
The title compound (426 mg, 80%) was prepared from (E)-3-[1,1′;3′,1″]terphenyl-5′-yl-prop-2-en-1-ol (300 mg, 1.05 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (262 mg, 1.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH4+].[OH-:10].[OH-].[Na+]>>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:10]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: [OH-]
Agent: [NH4+]
Agent: [Na+]
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
Cell mass grown according to example A is suspended in 8 liters of a 240 g/l solution containing fumaric acid (neutralized with NH4OH NaOH in the molar ratio of 2 to 1). After 12 hours of incubation, 237 g of L-malic acid per liter of fermentation liquid is produced.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(N(CC)CC)C.[CH2:27]([O:34][C@@H:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[NH2:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[C:28]1([CH2:27][O:34][C@@H:35]2[CH2:39][CH2:38][CH2:37][C@H:36]2[NH:40][C:5]2[N:6]=[CH:1][N:2]=[C:3]3[C:4]=2[N:8]=[CH:9][N:10]3[CH:11]2[C@H:12]([OH:19])[C@H:13]([OH:18])[C@@H:14]([CH2:16][OH:17])[O:15]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: N[C@@H]1CCC[C@H]1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1OC(n2cnc3c(N[C@@H]4CCC[C@H]4OCc4ccccc4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid.
Reaction SMILES: C(N(CC)CCOC1C=CC(C([N:13]([CH2:34][CH3:35])[C:14]2[CH:19]=[C:18]([O:20]C)[CH:17]=[CH:16][C:15]=2[CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=3)[CH2:23]2)=O)=CC=1)C.[CH2:40]([N:42]([CH2:76][CH3:77])[CH2:43][CH2:44][O:45][C:46]1[CH:75]=[CH:74][C:49]([CH2:50]N(CC)C2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=[CH:48][CH:47]=1)[CH3:41]>>[CH2:76]([N:42]([CH2:40][CH3:41])[CH2:43][CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:49]([CH2:50][CH2:35][CH2:34][NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[C:27]([OH:32])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[CH:74][CH:75]=1)[CH3:77]
Reactant: CCN(CC)CCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Reactant: CCN(CC)CCOc1ccc(C(=O)N(CC)c2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Product: CCN(CC)CCOc1ccc(CCCNc2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1

Procedure:
Synthesized from 4-(2-diethylaminoethoxy)-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide according to an analogous synthetic method to Example 337, [4-(2-diethylaminoethoxy)benzyl]ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (149 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (159 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.C(O)(=O)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>CC1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:10][C:4]1[N:5]=[C:6]([CH3:9])[C:7]([NH:8][C:17](=[O:18])[CH2:16][Cl:15])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(N)nc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(N)nc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a stirred solution of 3.3 parts of 4,6-dimethyl-2,5-pyridinediamine in 30 parts of acetic acid were added 4.7 parts of 2-chloroacetyl chloride at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with methylbenzene and neutralised with sodium carbonate. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated, yielding 2.6 parts (50.7%) of N-(6-amino-2,4-dimethyl-3-pyridinyl)-2-chloroacetamide as a residue (int. 97).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH3:29])[CH:18]=2)O1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:19]1[CH:18]=[C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1-c1ccccc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2cccnc2N)ccc1-c1ccccc1

Procedure:
Pd(dppf)Cl2 (0.089 g) was added to a mixture of 4-bromo-2-methylbiphenyl (1.5 g), potassium acetate (1.787 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.312 g) in DME (25 mL) and DMSO (1.25 mL). The mixture was stirred at 80° C. under nitrogen overnight. Activated-carbon powder was added and the mixture was stirred for 5 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo to give crude 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-4-yl)-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (173 mg) was added to a suspension of 3-bromopyridin-2-amine (865 mg), the prepared 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-4-yl)-1,3,2-dioxaborolane and sodium carbonate decahydrate (2861 mg) in DME (30 mL) and water (6 mL) and the mixture was stirred at 80° C. under nitrogen for 6 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (1.25 g) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:15])[CH2:22][CH2:21]1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Reactant: NC1CC1
Product: CN(C)C1CCc2oc3ccc(C(=O)NC4CC4)cc3c2C1
Yield: 33.5 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol cyclopropylamine, 0.004 gm (32%) of the title compound were recovered.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([O:1][CH2:2][CH:3]([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(CO)COc1cccc([N+](=O)[O-])c1C#N
Product: CC(=O)OCC(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 41 %

Procedure:
Prepared as in Example 231c from 2-(3-hydroxy-2-methylpropoxy)-6-nitrobenzonitrile (Example 237d) and acetyl chloride in 41% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J=6.8 Hz, 3H), 2.00 (s, 3H), 2.28-2.33 (m, 1H), 4.05-4.08 (m, 2H), 4.18 (d, J=6.0 Hz, 2H), 7.71-7.73 (m, 1H), 7.86-7.92 (m, 2H).
Reaction SMILES: [OH-:1].[Na+:2].[F:3][C:4]([F:13])([S:9](F)(=[O:11])=[O:10])[C:5]([O:7]C)=[O:6].Cl>O>[F:3][C:4]([F:13])([S:9]([OH:1])(=[O:11])=[O:10])[C:5]([O-:7])=[O:6].[Na+:2]
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C([O-])C(F)(F)S(=O)(=O)O

Procedure:
Under cooling with an ice bath, 230 parts of a 30 mass % aqueous sodium hydroxide solution was dripped into a mixture of 100 parts of methyl difluoro(fluorosulfonyl)acetate and 150 parts of ion-exchanged water. The resultant mixture was refluxed at 100° C. for three hours, was cooled, and was neutralized with 88 parts of concentrated hydrochloric acid. The obtained solution was concentrated to obtain 164.4 parts of sodium difluorosulfoacetate (which contains an inorganic salt, and the purity is 62.7%). To a mixture of 1.9 parts of the sodium difluorosulfoacetate (the purity is 62.7%) obtained and 9.5 parts of N,N-dimethylformamide, 1.0 part of 1,1′-carbonyldiimidazole was added, and the resultant mixture was stirred for two hours. The obtained solution was added to a solution which was obtained by adding 0.2 parts of sodium hydride to a mixture of 1.1 parts of 3-hydroxy-1-adamantylmethanol and 5.5 parts of N,N-dimethylformamide, and stirring the resultant mixture for two hours. The resultant solution was stirred for 15 hours to obtain sodium salt of 3-hydroxy-1-adamantylmethyl difluorosulfoacetate, which was used as it was for the subsequent reaction.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH2:27](I)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCCCI
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Yield: 110.9 %

Procedure:
A suspension of sodium hydride (65%, 600 mg) in dimethylformamide (30 ml), a solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (5 g) in dimethylformamide (10 ml) and n-butyl iodide (5.7 g) were treated in a similar manner to that of Example 25-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]n-hexanoate (6.5 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:32])[C:15]=2[C@H:16]2[O:22][CH2:21][C@@H:20]([F:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:33].[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1B(O)O>>[NH2:24][C@H:19]1[C@H:20]([F:23])[CH2:21][O:22][C@H:16]([C:15]2[N:14]([CH3:32])[N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:33])=[C:2]([C:39]3[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=3[F:41])[N:7]=2)[CH2:17][CH2:18]1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3cc(F)ccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 103), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,5-difluorophenyl)boronic acid gave 222. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.21 (dd, J=8.6, 3.7 Hz, 1H), 8.09 (dd, J=11.0, 8.6 Hz, 1H), 7.85-7.75 (m, 3H), 7.43 (tt, J=9.2, 2.4 Hz, 1H), 4.83 (dd, J=10.3, 3.8 Hz, 1H), 4.46-4.21 (m, 1H), 4.20-3.89 (m, 2H), 3.80 (s, 3H), 3.18-3.04 (m, 1H), 2.16-2.04 (m, 1H), 1.94-1.79 (m, 1H), 1.75-1.55 (m, 4H). LCMS (ES+) m/z 464 (M+1).