Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.C(O)CCC.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]1>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:32][CH2:31][CH2:30][CH2:29][N:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: O
Product: Clc1nccc(NCCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To 2,4-dichloropyrimidine (5.0 g, 33.5 mmol), diisoproylethylamine (5.85 ml, 33.5 mmol) in 50 ml of a 1:1 mixture of n-butanol and water is added 3-morpholinopropan-1-amine (4.90 ml, 33.5 mmol). The resulting mixture was stirred for 18 hours at room temperature. The mixture is then concentrated in vacuo, diluted with 30 mL water and extracted with EtOAc (3×50 ml). Combined organic layers are washed with saturated NaHCO3 (2×20 ml) and saturated NaCl (2×20 ml), then dried over magnesium sulfate. The residue is purified over silica (25% EtOAc in Hexanes) to afford 4.5 g (51% yield) of the desired product. 1H NMR (CDCl3, 300 MHz): δ(ppm) 1.83 (q, J=2.0 Hz, 2H), 2.54 (m, 6H), 3.53 (bs, 2H), 3.79 (t, J=4.7 Hz, 4H), 6.24 (d, J=5.67 Hz, 1H), 6.92 (bs, 1H), 7.99 (bs, 1H). MS (ESI, pos. ion) m/z: 257 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:29]2([CH3:30])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:32][C:33](=[O:35])[CH3:34])[C@@H:6]1[O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].BrN1C(C)(C)C(=O)N(Br)C1=O>C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@:29]2([CH3:30])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:32][C:33](=[O:35])[CH3:34])[C@@H:6]1[O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]1OC(C)=O
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: c1ccccc1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1α,2α,3β-Triacetoxy-cholesta-5-ene (300 mg) was dissolved in a mixture of petroleum benzine (5 ml) and benzene (5 ml). To the solution was added 1,3-dibromo-5,5-dimethyl hydantoin (95 mg) and the resulting solution was heated on water bath at 70° C for 20 minutes. After cooling the solution, precipitated crystals was filtrated off and the filtrate was concentrated under reduced pressure to dryness. The resulting bromide (3 ml) as crude product was dissolved in xylene. A mixture of trimethyl phosphite (1 ml) and xylene (3 ml) was added dropwise to the solution while refluxing it mildly in an argon stream. After continuously refluxing for 2 hours, the solvent was distilled off. The resulting 1α,2α,3β-triacetoxy-cholesta-5,7-diene was dissolved in diethyl ether (10 ml) and to the solution was added slowly 4-phenyl-1,2,4-triazoline-3,5-dione. About 25 mg of triazoline was required. After continuously stirring the mixture for 1 hour, diethyl ether was distilled off and then the residue was subjected to column chromatography with the use of alumina column and a solvent (diethyl ether : hexane = 1 : 1) to obtain 1,4-addition product of 1α,2α,3β-triacetoxy-cholesta-5,7-diene as oil represented by the formula ##STR6## wherein Ac is an acetyl.
Reaction SMILES: [CH:1]([CH:4]1[CH:8]([C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6](=[O:17])[NH:5]1)([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1(C)C=CC=CC=1>[CH:1]([CH:4]1[CH:8]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:19])[NH:7][C:6](=[O:17])[NH:5]1)([CH3:3])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)C1NC(=O)NC1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)C1NC(=O)NC1C(=S)c1ccccc1

Procedure:
To a stirred mixture of 10 g of 4-isopropyl-5-benzoyl-2-imidazolidone in 100 ml toluene is added 10 g phosphorus pentasulfide. The mixture is stirred, refluxed for 24 hours and the solvent is evaporated. The residue is purified by crystallization to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:22][C@@H:21]2[CH2:23]O)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([C@H:20]2[CH2:22][C@@H:21]2[CH:23]=[CH2:25])[CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CO)c1
Reactant: O=C([O-])O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]cyclopropylmethanol (3.00 g, 8.97 mmol) in CH2Cl2 (25 mL) was treated with 3 equiv. of NaHCO3 followed by Dess-Martin periodinane (7.60 g, 18.0 mmol, 2.0 equiv.). The solution was stirred for 2 h at room temperature. Saturated aqueous Na2SO3 (5 mL) and NaHCO3 (5 mL) were then added, and the biphasic mixture was stirred for 15 min and extracted with EtOAc (2×100 mL). The organic phase was washed with brine (50 mL), dried (Na2SO4), and concentrated in vacuo. The resulting aldehyde was purified by CC and directly used in the next reaction.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:11]([CH3:28])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N:9]3[C:13]([CH3:14])=[C:12]([C:15]([N:17]4[CH2:22][CH2:21][CH:20]([N:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[CH2:19][CH2:18]4)=[O:16])[C:11]([CH3:28])=[N:10]3)[CH:4]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1nn(-c2cccc(N)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Product: Cc1nn(-c2cccc(NC(=O)c3ccc(Cl)cc3)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 62 %

Procedure:
In analogy to the procedure described in Example 38E], [1-(3-amino-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride (Example 38D]) and 4-chlorobenzoyl chloride gave the title compound in 62% yield as yellow oil. MS: 506.3 (MH+, 1 Cl).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].[C:15]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:25])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19]>>[CH3:10][O:9][Si:6]([O:11][CH3:12])([O:7][CH3:8])[CH2:5][CH2:4][C:3]([CH3:14])([CH3:13])[CH2:2][NH:1][C@H:16]([C:15]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19]
Reactant: CO[Si](CCC(C)(C)CN)(OC)OC
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Product: CCCCOC(=O)C[C@H](NCC(C)(C)CC[Si](OC)(OC)OC)C(=O)OCCCC
Yield: 93 %

Procedure:
In a manner similar to Example 2, 110.7 g (0.5 mole) of 4-amino-3,3-dimethylbutyltrimethoxysilane was allowed to react with 114.3 g (0.5 mole) of dibutyl maleate to give 209 g dibutyl N-[4-trimethoxysilyl-(2,2-dimethyl)butyl]aspartate at 97% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[N:9]/[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](=[CH:21]/[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])/[C:19]#[N:20])=[C:14]([F:27])[CH:13]=1.[OH-].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=3[F:27])([C:19]#[N:20])[CH:21]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C/N=C/c1cccc(Cl)c1
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of [1-(3-chloro-phenyl)-meth-(E)-ylidene]-methyl-amine (0.77 g, 5.00 mmol) and (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (1.72 g, 5.00 mmol) in DMSO (5 mL) was added KOH powder (0.56 g, 10.00 mmol) in one portion. The mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with EtOAc three times (3×50 mL). The combined organic layers were washed with water and brine and dried over Na2SO4, and concentrated. The residue was purified by flash column (SiO2, 1%-15% of EtOAc in hexanes) after concentration to give rac-(2S,3S,4S)-2-(3-chloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (0.73 g, 36.1%); HRMS (ES+) m/z Calcd for C22H23Cl2FN2+H [(M+H)+]: 405.1295, found: 405.1292, rac-(2S,3S,4R)-4-(4-chloro-2-fluoro-phenyl)-2-(3-chloro-phenyl)-3-(2,2-dimethyl-propyl)-pyrrolidine (0.0.42 g, 20.8%); HRMS (ES+) m/z Calcd for C22H23Cl2FN2+H [(M+H)+]: 405.1295, found: 405.1294, and (2S,3R,4R)-4-(4-chloro-2-fluoro-phenyl)-2-(3-chloro-phenyl)-3-(2,2-dimethyl-propyl)-pyrrolidine (0.42 g, 20.8%); HRMS (ES+) m/z Calcd for C22H23Cl2FN2+H [(M+H)+]: 405.1295, found: 405.1294.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[S:22][C:23]([CH:26]=O)=[CH:24][CH:25]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][NH2:32].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[S:22][C:23]([CH2:26][NH:32][CH3:31])=[CH:24][CH:25]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)s4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC)s4)cc23)CC1
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1H-indole-7-carboxamide (35 mg, 0.078 mmol) in DMSO (1.0 mL) was added acetic acid (3 drops), 2 M methylamine in THF (0.24 mL, 0.471 mmol), and reacted for 3 h. Sodium triacetoxyborohydride (100 mg, 0.471 mmol) was then added and reaction was stirred overnight. All solvent was removed in vacuo and purified by Gilson Preparatory HPLC. The impure desired fraction was concentrated under reduced pressure and loaded onto a 500 mg SCX SPE cartridge primed with 10 mL of methanol. The cartridge was then sequentially eluted with 2M NH3 in MeOH (10 mL×2). The NH3 in MeOH fractions were concentrated to give 7.3 mg of the title compound (20%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[I-:11].[Na+]>CC(=O)CC>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([I:11])=[CH:6][CH:7]=1
Reactant: N#Cc1nc(Cl)ccc1N
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: N#Cc1nc(I)ccc1N

Procedure:
A stirred suspension of 12.0 grams (0.08 mole) of 3-amino-6-chloro-2-cyanopyridine [prepared by the method of Colbry, Elslager, and Werbel; previously cited] and 26.9 grams (0.18 mole) of sodium iodide in 300 mL of n-butanone is heated at reflux for about 3 days. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is then stirred with about 50 mL of water. The resultant solid is collected by filtration and washed with water. The solid is dried, yielding 3-amino-2-cyano-6-iodopyridine.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:16](Cl)(=O)[CH3:17]>C1COCC1>[CH:10]1([C:4]2[S:3][C:2]3[N:1]=[C:16]([CH3:17])[NH:9][C:7](=[O:8])[C:6]=3[CH:5]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cc(C2CCCCC2)sc1N
Solvent: C1CCOC1
Product: Cc1nc2sc(C3CCCCC3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2-amino-5-cyclohexylthiophene-3-carboxamide (53.5 g) and THF (500 mL) were added dropwise acetyl chloride (18 mL) and TEA (36 mL) under ice-cooling, followed by stirring at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added EtOH (500 mL) and a 1 M aqueous NaOH solution (500 mL), followed by stirring at 80° C. for 24 hours. The reaction mixture was left to be cooled to room temperature, and 1 M hydrochloric acid (500 mL) was added thereto, followed by stirring. The precipitate was collected by filtration, washed with water, and dried by blowing air to obtain 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (57.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:28][N:29]=[C:30]=[O:31]>ClCCl>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([CH:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:30]([NH:29][CH3:28])=[O:31])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:17][CH2:16]1)[CH:19]=[CH:20]2
Reactant: CN=C=O
Reactant: Nc1ccc2c(c1)C(CN1CCC(n3ccc4cc(Cl)ccc43)CC1)CC2
Solvent: ClCCl
Product: CNC(=O)Nc1ccc2c(c1)C(CN1CCC(n3ccc4cc(Cl)ccc43)CC1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[1-(6-aminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole, 10h (0.9 g) in dichloromethane (10 mL) was added methylisocyanate (0.2 mL). The mixture was stirred at room temperature for 16 hours. Dichloromethane was evaporated. Upon addition of ethyl acetate the title compound 19a crystallized. The crystalline product was filtered off and dried overnight at 80° C. in vacuo. Yield 0.6 g. mp: 193-195° C. 1H NMR (DMSO-d6): δ 1.70-1.85 (m, 1 H); 1.90-2.35 (m, 7 H); 2.35-2.85 (m, 4 H); 2.65 (d, 3 H); 3.05-3.15 (m, 2 H); 3.25 (quin, 1 H); 4.35-4.45 (m, 1 H); 5.95 (dt, 1 H); 6.45 (d, 1 H); 7.00-7.20 (m, 3 H); 7.50-7.65 (m, 4 H); 8.35 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH:18]=O)[CH:14]=1)=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH2:18][N:35]3[CH2:36][CH2:37][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)[CH2:33][CH2:34]3)[CH:14]=1)=[C:5]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Reactant: c1ccc(N2CCNCC2)nc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cc(CN2CCN(c3ccccn3)CC2)no1
Yield: 32 %

Procedure:
From 5-(6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-isoxazole-3-carboxaldehyde and 1-pyridin-2-yl-piperazine according to procedure 24. Yield 32%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][C:33]=1[Cl:34])[NH:20][C:21](=[O:30])[C:22]1[C:23](=[CH:25][CH:26]=[C:27]([Cl:29])[CH:28]=1)[OH:24]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:21](=[O:30])[C:22]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=2[O:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(Cl)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)c(Cl)c3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (116 mg), 3′,4′,5-trichlorosalicylanilide (632 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (14 mg, yield 6%).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@H:15]2[O:19][C:18]([NH2:20])=[N:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:23]([O:25][C:26](=O)[C:27]#[C:28][CH2:29][O:30]C)C>C(Cl)(Cl)Cl>[CH3:23][O:25][CH2:26][C:27]1[N:17]2[CH2:16][C@@H:15]([CH2:14][O:13][C:12]3[CH:21]=[CH:22][C:9]([C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:10][CH:11]=3)[O:19][C:18]2=[N:20][C:29](=[O:30])[CH:28]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Reactant: CCOC(=O)C#CCOC
Solvent: ClC(Cl)Cl
Product: COCc1cc(=O)nc2n1C[C@@H](COc1ccc(C(C)(C)CC(C)(C)C)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-(1,1,3,3-tetramethyl-butyl) -phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 27) and 4-methoxy-but-2-ynoic acid ethyl ester (see Example 106) employing the procedure described in Example 95. [α]D25 −14.80 (c 0.5, CHCl3).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)#[N:2]
Reactant: COC(=O)c1cccc(CC#N)c1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCCCC2)c1
Yield: 66.9 %

Procedure:
Using methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol), sodium hydride (60% in oil, 1.0 g, 26 mmol), 1,5-dibromopentane (3.0 g, 13 mmol) and dimethyl sulfoxide (30 mL) as starting materials and in the same manner as in Reference Example 31, the title compound (1.4 g, 68%) was obtained as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[CH:18]([Si:20]([CH3:23])([Cl:22])[Cl:21])Cl.O=P(Cl)(Cl)Cl>[Cl-].[Al+3].[Cl-].[Cl-].CCCCCC>[CH3:18][Si:20]([Cl:22])([Cl:21])[CH:23]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[Si](Cl)(Cl)C(Cl)Cl
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: C[Si](Cl)(Cl)C1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a 100 ml, three-necked, frame dried, round bottom flask equipped with a magnetic stirrer, a reflux condenser, and a dropping funnel, aluminum chloride 1.43 g (10.7 mmol) and biphenyl 16.5 g (107 mmol) were placed under dry nitrogen atmospheric pressure. After (dichloromethyl)methyldichlorosilane 7.50 ml (53.5 mmol) was added to the solution, the reaction mixture was heated for 2.5 hrs. at 120° C. The aluminum chloride catalyst was quenched with POCl3 1.04 ml (11.2 mmol) and then stirred for another 1 hr. to complete the deactivation. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane was distilled, the reaction products were vacuum distilled at 0.2 torr to give 8.79 g of 9-(methyldichlorosilyl)fluorene (bp; 115°-120° C./0.2 torr, yield; 59%).
Reaction SMILES: ClC1C=C(CC(O)=O)C=CC=1.Cl.NCCCC(OCC)=O.CCN=C=NCCCN(C)C.Cl.C([O:36][C:37](=[O:52])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=1)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:50][C:46]1[CH:45]=[C:44]([CH2:43][C:42]([NH:41][CH2:40][CH2:39][CH2:38][C:37]([OH:52])=[O:36])=[O:51])[CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)CCCNC(=O)Cc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)CCCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCCNC(=O)Cc1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of 3-chlorophenylacetic acid (0.5 g, 2.93 mmol) and DMAP (0.36 g, 2.93 mmol) in dichloromethane (30 mL) was added ethyl 4-aminobutyrate hydrochloride (0.49 g, 2.93 mmol) at room temperature. After stirring for 10 min, EDCI (0.56 g, 2.93 mmol) was added portionwise to the mixture at room temperature. The reaction was stirred for 12 h. A 1 N aqueous HCl solution (20 mL) was poured into the reaction mixture, and 4-[2-(3-chlorophenyl)acetylamino]butyric acid ethyl ester was extracted with ether (30 mL). The ether solution was washed with water (50 mL), dried over Na2SO4, and concentrated. To the residue dissolved in ethanol (10 mL) was added 1 N aqueous NaOH solution (6 mL), and after 12 h of stirring at room temperature, the product was extracted with dichloromethane (30 mL). The organic solution was washed with water (30 mL), dried over Na2SO4, and concentrated to give 4-[2-(3-chlorophenyl)acetylamino]butyric acid (0.6 g, 80%). A mixture of this acid (0.6 g, 2.35 mmol), K2CO3 (0.49 g, 3.52 mmol), and 1-bromopentane (0.53 g, 3.52 mmol) in DMF (20 mL) was stirred overnight at room temperature. The product was extracted with ether (40 mL), and the ether solution was washed with water (50 mL), dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography (hexane:ethyl acetate=3:1) to afford 988 as an oil (0.74 g, 97%): 1H NMR (CDCl3) 0.91 (3H, t, J=6.9 Hz), 1.26-1.33 (4H, m), 1.59-1.63 (2H, m), 1.80 (2H, quint, J=6.9 Hz), 2.31 (2H, t, J=6.9 Hz), 3.27 (2H, q, J=6.9 Hz), 3.52 (2H, s), 4.04 (2H, t, J=6.9 Hz), 5.72 (1H, s), 7.13-7.17 (2H, m), 7.27-7.30 (2H, m); LC-MS (ESI) m/z calcd for C17H24ClNO3 [M+H]+ 326.14, found [M+H]+ 326.15. Anal. (C17H24ClNO3) C, H, N.
Reaction SMILES: [OH-].[Na+].CO[C:5]([C:7]1([NH:13][C:14](=[O:22])[CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].CCOCC.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(Cl)Cl>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][CH2:15][C:14]1[O:22][C:5](=[O:6])[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[N:13]=1
Reactant: COC(=O)C1(NC(=O)CCc2ccco2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1OC(CCc2ccco2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
1.7 ml of 2N aqueous NaOH solution was added to a solution of 478 mg (1.7 mmol) of 1-[[1-oxo-3-(2-furanyl)propyl]amino]cyclohexanecarboxylic acid methyl ester obtained in Reference Example 64 in 2 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 hours. Ether was added to the reaction solution to wash it. After the separated aqueous layer was neutralized by concentrated hydrochloric acid, it was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Then, 10 ml of methylene chloride and 377 mg (1.82 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the residue, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 198 mg (47%) of the title compound.