Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(OC2C=CC(OC(C)C(O)=O)=CC=2)=CC=1.S(Cl)(Cl)=O.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C1C=CC=CC=1.O>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Agent: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Solvent: O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
34.5 g of α-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride synthesized by a conventional method (as described in, for example, Synthetic Organic Chemistry, supra) from α-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid and thionyl chloride was dissolved in 200 ml of benzene, and while maintaining the solution at 20° to 25° C., 19.5 g of aniline was added. The reaction was performed at 30° C. for 1 hour. The reaction product was poured into 300 ml of water to precipitate and washed with water, and then dried with anhydrous sodium sulfate. After drying, benzene was evaporated off, and the residue was recrystallized from a mixture of ethanol and petroleum ether (2:1 by volume) to afford 36 g of the final product having a melting point of 129° to 131° C. The yield was 90%.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)NC(=O)N[C:6]2=[O:16].N1C=CC(=O)NC1=O.C[Si](C)(C)CCO[CH2:30][Cl:31]>>[CH2:6]([O:16][CH2:30][Cl:31])[C:5]1[CH:4]=[CH:3][CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2[nH]c(=O)[nH]c(=O)c2cc1OC
Agent: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using 6,7-dimethoxyquinazoline-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 93%) as a white powder.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:18][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=1)=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC(=O)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Pyridine (14 g, 0.18 Mol) and 4-nitrophenylacetic acid (32 g, 0.18 Mol) were stirred in toluene (100 ml) whilst trimethylacetylchloride (21 g, 0.18 Mol) was added. The toluene was evaporated to yield 4-nitrophenylacetic-trimethylacetic anhydride. 3-Aminophenol (20 g, 0.18 Mol) was stirred in DMF (100 ml) and treated with the mixed anhydride and pyridine (14 g) in dimethylformamide (DMF) dropwise. The solution was diluted with water and the product isolated by filtration and dried (19 g, 39%).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.ON1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2N=N1.CN(C)[CH2:25][CH2:26][CH2:27][N:28]=C=NCC>ClCCl>[CH3:1][O:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH:28][C@H:27]([C:21]1[CH:20]=[CH:19][C:18]2[C:17](=[CH:4][CH:3]=[CH:7][CH:8]=2)[CH:22]=1)[CH2:26][CH3:25])=[O:6]
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: CO[C@H](C(=O)O)c1ccccc1
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@@H](OC)c1ccccc1)c1ccc2ccccc2c1
Yield: 94.7 %

Procedure:
A mixture of 1.3 g (7.03 mmol) of (RS)-ethyl-2-naphthalenemethylamine, 1 g (6.02 mmol) of (S)-(+)-α-methoxyphenylacetic acid, 1.1 g (8.15 mmol) of 1-hydroxybenzotriazole and 1.4 g (7.31 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was stirred in 20 ml of dichloromethane for 18 hours. The solution was extracted with 2M hydrochloric acid and saturated sodium bicarbonate solution, then dried over magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel using 25% ethyl acetate in petroleum ether and then 33% ethyl acetate in petroleum ether for the elution. After trituration with 50% diethyl ether in petroleum ether there were obtained 950 mg of 2(S)-methoxy-N[1(S)-(2-naphthyl)propyl]-2-phenylacetamide, 1H NMR (400 MHz, DMSO) δ: 0.8-0.85 (t,3H), 1.8-1.9 (m,2H), 3.3 (s,3H), 4.7 (s,1H), 4.8-4.9 (q,1H),7.25-7.5 (m,8H), 7.68 (s,1H), 7.75-7.9 (m,3H), 8.5-8.6 (d,1H), which was eluted first, and 850 mg of 2(S)methoxy-N-[1(R)-(2-naphthyl)propyl]-2-phenylacetamide, 1H NMR (400 MHz, DMSO) δ: 0.8-0.9 (t,3H), 1.75-1.9 (m,2H), 3.3 (s,3H), 4.7 (s,1H), 4.8-4.9 (q,1H), 7.25-7.5 (m,8H), 7.7 (s,1H), 7.75-7.9 (m,3H), 8.5-8.6 (d,1H), which was eluted subsequently.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[NH2:18].[C:19]([OH:27])(=[O:26])[C:20]([CH2:22][C:23](O)=[O:24])=[CH2:21]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[N:18]1[C:23](=[O:24])[CH2:22][CH:20]([C:19]([OH:27])=[O:26])[CH2:21]1
Reactant: Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2cc(F)c(OCc3cccc(F)c3)cc2F)C1
Yield: 34.5 %

Procedure:
In an analogous manner to that described in Example 1a), 2,5-difluoro-4-(3-fluoro-benzyloxy)-phenylamine was reacted with itaconic acid to yield (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (34.5% of theory) as a grey solid; MS: m/e=363 (M−H)+.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.CN(C)C=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:39][CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>O1CCCC1.CN(C)C1C=CN=CC=1>[OH:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:2]2[N:3]=[C:4]3[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]4[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=4)[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=2)[CH2:41]1
Reactant: OC1CCCNC1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(N4CCCC(O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 68.4 %

Procedure:
The 2-hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (1.00 g, 3.19 mmol) obtained in (E) was dissolved in anhydrous tetrahydrofuran (15.0 ml) and anhydrous dimethylformamide (15.0 ml), added with 4-dimethylaminopyridine (585 mg, 4.79 mmol) and p-toluenesulfonyl chloride (730 mg, 3.83 mmol), and then the mixture was stirred at room temperature for 50 minutes. Subsequently, the reaction solution was added with 3-hydroxypiperidine (646 mg, 6.38 mmol) and stirred at room temperature for 16 hours, and then added with 3-hydroxypiperidine (968 mg, 9.57 mmol) and stirred at 60° C. for 1.5 hours. After the reaction mixture was concentrated, the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2→100:5→100:10, v/v) to obtain the title compound (865 mg, 68%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[C:6]([C:14]([OH:16])=O)=[CH:5][N:4]=1.C(N(CC)C(C)C)(C)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[C:8]2[CH:9]=[C:10]([CH3:13])[N:11]([CH3:12])[C:7]=2[C:6]([C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:16])=[CH:5][N:4]=1
Reactant: C1COCCN1
Reactant: Cc1cc2c(Cl)ncc(C(=O)O)c2n1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(Cl)ncc(C(=O)N3CCOCC3)c2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-chloro-1,2-dimethyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid hydrochloride (60 mg), N,N-diisopropylethylamine (0.2 ml) and morpholine (0.04 ml) in dry dimethylformamide (2 ml) was added O-benzotriazol-1-yl-N,N,N,N′-tetramethyluronium hexafluorophosphate (131 mg). The reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed twice with saturated sodium bicarbonate and water, dried (MgSO4), filtered and evaporated to afford the title compound as a white foam 68 mg.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:5][C:6]=1[CH3:7].[Cl:14]N1C(=O)CCC1=O>C(#N)C>[Cl:14][CH2:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(N2CCOCC2)sc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1sc(N2CCOCC2)nc1CCl
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 4-(4,5-dimethyl-1,3-thiazol-2-yl)morpholine (5.0 g) in acetonitrile (100 mL) was added N-chlorosuccinimide (3.36 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine as colorless crystals (2.06 g, 35%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[Br:6][C:7]1C=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9](C(Br)Br)[CH:8]=1.Cl>C(O)(=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][C:2]=1[CH:1]=[O:4]
Reactant: Brc1ccc(-c2ccccc2)c(C(Br)Br)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cc(-c2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Bromosuccinimide (7.35 g) and benzoyl peroxide (196 mg) were added to a solution of 4-bromo-2-methylbiphenyl (5.0 g) in carbon tetrachloride (150 ml), and the mixture was stirred over night under reflux condition. After cooling to room temperature, the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated therefrom under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 4-bromo-2-(dibromomethyl)biphenyl (7.9 g). Sodium acetate (9.6 g) was added to a solution of 4-bromo-2-(dibromomethyl)biphenyl in acetic acid (240 ml) and stirred for two days under reflux condition. After cooling to room temperature, 4M hydrochloric acid (50 ml) was added to the reaction mixture, and the resulting mixture was stirred for two hours under reflux condition. After cooling to room temperature, the solvent was evaporated therefrom under reduced pressure to give the residue, ethyl acetate was added to the resulting residue, and the resultant was washed with 1M hydrochloric acid and saturated saline solution in order and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the resulting residue was dried to obtain 4-bromo biphenyl-3-carboaldehyde (5.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1.[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:44][S:41]([CH:38]4[CH2:40][CH2:39]4)(=[O:43])=[O:42])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Reactant: NS(=O)(=O)C1CC1
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 58.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.03 g, 0.06 mmol) obtained in Example 109, step 2 and cyclopropanesulfonamide (0.037 g, 0.30 mmol), the 30 title compound (0.021 g, 58%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=O.Cl.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=1[OH:29]>>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([CH2:20][NH:19][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH2:16][CH3:17])=[C:22]([OH:29])[CH:23]=1)#[N:26]
Reactant: N#Cc1ccc(CN)c(O)c1
Reactant: CCOC(C(=O)O)c1c(F)cc(OC)cc1F
Agent: Cl
Product: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1c(F)cc(OC)cc1F

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-ethoxy-acetic acid (example 101.3) was coupled with 4-aminomethyl-3-hydroxy-benzonitrile hydrochloride (example 110.2) according to general procedure B to give (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide. Colorless foam. MS 375.4 ([M−H]−)
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]([O:37][C:38](=[O:47])[N:39]([CH2:41][CH:42]([OH:46])[CH2:43][NH:44][CH3:45])[CH3:40])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:47])[N:39]([CH2:41][CH:42]([OH:46])[CH2:43][N:44]([C:20]1[S:21][C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=2[C:29]([F:30])([F:31])[F:32])[N:8]=[CH:9]3)[C:18](=[O:26])[N:19]=1)[CH3:45])[CH3:40])([CH3:36])([CH3:34])[CH3:35]
Reactant: CNCC(O)CN(C)C(=O)OC(C)(C)C
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CC(O)CN(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C(=O)OC(C)(C)C

Procedure:
[3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-2-hydroxy-propyl]-methyl-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and (2-Hydroxy-3-methylamino-propyl)-methyl-carbamic acid tert-butyl ester following General Procedure B.
Reaction SMILES: B.CSC.[C:5]([CH2:7][C@H:8]([C:10]1[N:15]=[C:14]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=1)[OH:9])#[N:6].N.CO.C(Cl)Cl>>[NH2:6][CH2:5][CH2:7][C@H:8]([C:10]1[N:15]=[C:14]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:22][CH2:23]2)[CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: N#CC[C@@H](O)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)n1
Agent: B
Agent: N
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: NCC[C@@H](O)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)n1

Procedure:
Borane-dimethylsulfide reduction of (R)-benzyl 4-(((6-(2-cyano-1-hydroxyethyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate following the method described in Example 2 gave after flash chromatography purification (30%-40% 7N NH3/MeOH—CH2Cl2 gradient) Example 36 as a colorless oil. Yield (0.27 g, 27%); 1H NMR (400 MHz, CD3OD) δ 7.63 (t, J=8.4 Hz, 1H), 7.38-7.25 (m, 5H), 7.03 (d, J=7.2 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 5.10 (s, 2H), 4.70-4.62 (m, 1H), 4.21-4.10 (m, 4H), 2.88-2.78 (m, 4H), 2.02-1.70 (m, 5H), 1.34-1.20 (m, 2H); RP-HPLC tR=9.40 min; ESI-MS m/z 400.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH:20]([CH3:22])[CH3:21])[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8]C(OC(C)(C)C)=O.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH:20]([CH3:22])[CH3:21])[NH:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:17])[CH3:18])[NH2:8]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C

Procedure:
N-tert-butoxycarbonyl L-valyl L-valine methyl ester (16.47 g, 49.85 mmol) was treated with a 50% (v/v) solution of TFA in CH2Cl2 (130 mL). The reaction mixture was stirred for 2 h at room temperature before the solvent and bulk of excess TFA were evaporated. Portions of CH2Cl2 (3×100 mL) and purified CHCl3 (6×200 mL) were added and evaporated. The residue (19.17 g) was washed with Et2O (2×80 mL) and the Et2O decanted off. An additional 80 mL Et2O was added and the suspension filtered. The collected solid was washed with Et2O (80 mL) and dried; δH (300 MHz; d6-DMSO) 8.62 (1H, d, J 7, NH), 8.17 (3H, br s, NH3+), 4.19 (1H, dd, J 7 and 6, CαH(Val2)), 3.75 (1H, br d, J 5, CαH(Val1)), 3.64 (3H, s, OCH3), 2.16-2.01 (2H, m, CH(CH3)2), 0.96-0.90 (12H, m, CH(CH3)2); δC (75 MHz; d6-DMSO) 171.4, 168.4, 158.4 (q, JCF 31), 117.1 (q, JCF 297) 57.7, 56.9, 51.7, 29.9, 29.6, 18.8, 18.1, 18.1, 17.4
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20]COC)=[CH:15][CH:14]=2)=[N:3]1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:1][C:2]1([CH3:24])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: COCOCc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Temperature: 40 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
2.62 g (8.05 mmol) of 4,4-dimethyl-2-(4'-methoxymethoxymethylbiphenyl-2-yl)oxazoline was dissolved in methanol (20 ml). 6N hydrochloric acid (10 ml) was added thereto, followed by stirring at 40° C. for 2 hours. The reaction liquid was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 2.20 g of the title compound as a crystal (yield 97%).
Reaction SMILES: Br[CH:2]([CH2:14][O:15][CH3:16])[C:3]([NH:5][C:6]([CH3:13])([CH3:12])[C:7]#[C:8][CH2:9][O:10][CH3:11])=[O:4].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([OH:24])[CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH:2]([CH2:14][O:15][CH3:16])[C:3]([NH:5][C:6]([CH3:13])([CH3:12])[C:7]#[C:8][CH2:9][O:10][CH3:11])=[O:4])[CH:21]=[N:20][CH:19]=1
Reactant: Oc1cncc(Cl)c1
Reactant: COCC#CC(C)(C)NC(=O)C(Br)COC
Product: COCC#CC(C)(C)NC(=O)C(COC)Oc1cncc(Cl)c1

Procedure:
2-Bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl)-3-methoxypropionamide was reacted with 3-chloro-5-hydroxypyridine in a similar procedure to Example 10, Stage 2 to give the required product as a pale yellow oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[NH2-:10].[Na+:11]>C(OCC)C>[CH3:1][Si:2]([CH3:9])([CH3:8])[O-:3].[Na+:11].[CH3:1][Si:2]([NH:10][Si:4]([CH3:5])([CH3:6])[CH3:7])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)[O-]

Procedure:
By product hexamethyldisiloxane in ethyl ether reacts with sodium amide to form sodium trimethylsilanolate and HMDS as follows: ##STR5##
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]3)[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:29][CH2:28][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH2:16][CH2:17]1
Reactant: NCC1CCCCC1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)ccn2)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCCCC4)n3)ccn2)CC1
Temperature: 105 °C

Procedure:
A mixture of trans-N1-(6-fluoro-2,4′-bipyridin-2′-yl)cyclohexane-1,4-diamine (15 mg, 0.052 mmol), DMSO (0.4 ml), and cyclohexylmethanamine (59.3 mg, 0.524 mmol) was heated at about 105° C. for about 24 hours, or until the product pormation was completed, as indicated by LCMS. The excess amine was removed under reduced pressure to yield a residue. The residue was mixed with 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 11.3 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 380.3 (MH+), retention time=0.61 min. 1H NMR (400 MHz, METHANOL-d4, 45° C.) δ ppm 0.97-1.11 (m, 2 H) 1.17-1.36 (m, 3 H) 1.49-1.72 (m, 6 H) 1.71-1.80 (m, 2 H) 1.84 (d, J=12.91 Hz, 2 H) 2.11-2.28 (m, 4 H) 3.13-3.25 (m, 1 H) 3.28 (d, 2 H, App.) 3.65-3.75 (m, 1 H) 6.65 (d, J=8.61 Hz, 1 H) 7.16 (d, J=7.43 Hz, 1 H) 7.43-7.48 (m, 1 H) 7.52 (t, J=7.83 Hz, 1 H) 7.64 (s, 1 H) 7.85 (d, J=7.04 Hz, 1 H)
Reaction SMILES: [Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([Cl:20])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([C:11]([F:14])([F:13])[F:12])[CH2:10][CH2:9]1)=[O:7].[C:21](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:22]>>[Cl:1][C:2]1[C:18]([N:19]=[C:21]=[S:22])=[C:17]([Cl:20])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([C:11]([F:13])([F:14])[F:12])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1c(Cl)ccc(CNC(=O)C2(C(F)(F)F)CC2)c1Cl
Product: O=C(NCc1ccc(Cl)c(N=C=S)c1Cl)C1(C(F)(F)F)CC1

Procedure:
The title compound is prepared from N-(2,4-dichloro-3-amino-benzyl)-1-trifluoromethyl-cyclopropane carboxamide (150 mg, 0.45 mmol) and 1,1′-thiocarbonyldi-2-pyridone (89 mg, 0.38 mmol) in analogy to example Af.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:20][CH3:21])=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([CH2:1][NH:25][CH3:24])[C:4]=2[O:20][CH3:21])[CH:14]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(C#N)c(Oc2cccc(C=O)c2OC)c1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(OC)ccc2C#N)c1OC
Yield: 60.5 %

Procedure:
2-(3-Formyl-2-methoxy-phenoxy)-4-methoxy-benzonitrile (0.38 g, 1.3 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (110 mg, 1.8 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 17 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was to separated and fumaric acid (0.15 g, 1.3 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-methoxy-2-(2-methoxy-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (326 mg, 58%) as an off-white solid.