Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([CH:10]=[CH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:21][CH3:22])[NH:14][CH:13]=1)([O-])=O>C1COCC1>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[C:12]([CH2:11][CH2:10][NH2:7])=[CH:13][NH:14]2
Reactant: COc1cccc2[nH]cc(C=C[N+](=O)[O-])c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2[nH]cc(CCN)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Combine LiAlH4 (6.78 g; 178.74 mmol; 6 eq) and anhydrous THF. Dissolve 3-(2-nitrovinyl)-4-methoxy-1H-indole (6.5 g; 29.79 mmol) in anhydrous THF and add dropwise to the LiAlH4 solution with vigorous stirring. After the addition is complete, heat to reflux. After 1 hour cool to ambient temperature and stir. After 16 hours, quench the excess LiAlH4 as described in J. Med. Chem. 1995, 38, 2050. Filter the gray suspension through celite and rinse the celite with ethyl acetate. Evaporate the filtrate in vacuo to residue. Chromatograph the residue on silica gel eluting with 1 L of CHCl3MeOH/NH4OH (95:10:1) and then 1 L of CHCl3/MeOH/NH4OH (90:10:1) as the mobile phase. Pool fractions containing the product and evaporate to give the title compound as a tan solid: 1H NMR (300 MHz, d6-DMSO): 2.96 (t, 2H); 3.42 (t, 2H); 3.83 (s, 3H); 6.42 (dd, 1H); 6.93 (m, 3H); 10.7 (s, 1H); MS (ES+): m/z 191 (M+H)+; 174 (M−NH2)+; 159 (M−OCH3)+; (ES−): m/z 189 (M−H)−.
Reaction SMILES: C(OC([NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([CH3:22])=[C:20]3[C:15]([C:16](=[O:31])[C:17]([C:26]([O:28]CC)=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[C:14]([CH3:32])[C:13]=2[F:33])[CH2:8]1)=O)C.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([CH3:22])=[C:20]3[C:15]([C:16](=[O:31])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[C:14]([CH3:32])[C:13]=2[F:33])[CH2:8]1
Reactant: CCOC(=O)NC1CCN(c2c(F)c(C)c3c(=O)c(C(=O)OCC)cn(C4CC4)c3c2C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(F)c(N2CCC(N)C2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 29.5 %

Procedure:
To ethyl 7-(3-ethoxycarbonylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5, 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (130 mg) is added 5% aqueous potassium hydroxide solution (3.2 ml) and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is made acidic with acetic acid and then made weak alkaline with potassium carbonate. The resultant is extracted with dichloroethane and the extract is dried, followed by distillating the solvent under reduced pressure. To the residue is added diethyl ether and the precipitated crystals are filtered to give 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5, 8-dimethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg), m.p. 96°-98° C., as pale yellow needles.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]([NH:9][NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)=O)[CH3:2].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[O:20][C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[N:10][N:9]=1)[CH3:2]
Reactant: CCOC(=O)CCC(=O)NNC(=O)c1ccc(F)c(F)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCc1nnc(-c2ccc(F)c(F)c2)o1
Temperature: 25 °C

Procedure:
To a solution of 4-[N′-(3,4-difluorobenzoyl)hydrazino]-4-oxo-butyric acid ethyl ester (590 mg, 1.96 mmol) and pyridine (474 μL, 5.88 mmol) in methylene chloride (25 mL) at −78° C. was added dropwise triflic anhydride (397 μL, 2.35 mmol) and the reaction was allowed to warm up to rt overnight. The reaction mixture was diluted with methylene chloride (100 mL), washed with 0.1 M HCl and brine, dried over sodium sulfate and concentrated to provide 3-[5-(3,4-difluorophenyl)-[1,3,4]oxadiazol-2-yl]propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 7.89-7.77 (m, 2H), 7.31 (m, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(NC1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)CNCC1C=CC=CC=1)CCC.[CH2:32]([C:39]1[C:53]([S:54](=[O:57])(=[O:56])[NH2:55])=[CH:52][C:42]([CH2:43][NH:44]CC2C=CC=CC=2)=[CH:41][C:40]=1[O:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([C:39]1[C:53]([S:54](=[O:57])(=[O:56])[NH2:55])=[CH:52][C:42]([CH2:43][NH2:44])=[CH:41][C:40]=1[O:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCCOc1cc(CNCc2ccccc2)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: CCCCNc1cc(CNCc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: CCCCOc1cc(CN)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
By replacing in Example 296 (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)benzylamine with an equimolar amount of (4-benzyl-3-n-butoxy-5-sulfamylbenzyl)benzylamine (prepared as described in Example 184) and following the hydrogenation procedure described, crude 4-benzyl-3-n-butoxy-5-sulfamylbenzylamine is obtained. The crude amine is dissolved in ethanol (50 ml) and a saturated solution of dry hydrogen chloride in ethanol (2 ml) is added to precipitate, after cooling, 4-benzyl-3-n-butoxy-5-sulfamylbenzylamine hydrochloride. After filtration and recrystallization from ethanol it is obtained as a hydrate with a melting point of 176°-179° C.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[CH:33]=[CH:34][C:35](=[O:38])[NH:36][N:37]=5)=[CH:31][C:26]=4[N:25]=[CH:24]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=c1ccc(-c2ccc3c(c2)ncn3CCNCC(O)COc2ccc(CCOCC3CCC3)cc2)n[nH]1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[S:16][CH2:15][C@H:14]2[C@:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])([CH2:10][O:11][C@@H:12]([CH2:17][OH:18])[CH2:13]2)[N:8]=1.[N+:26]([O-])([OH:28])=[O:27].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:6][C:7]1[S:16][CH2:15][C@H:14]2[C@:9]([C:19]3[CH:24]=[C:23]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:21][C:20]=3[F:25])([CH2:10][O:11][C@@H:12]([CH2:17][OH:18])[CH2:13]2)[N:8]=1
Reactant: NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CO)C[C@H]2CS1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@@H](CO)C[C@H]2CS1
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (2.5 ml) was added dropwise to a solution of [(4aR,6R,8aS)-2-amino-8a-(2-fluorophenyl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-6-yl]methanol (700 mg) in TFA (5 ml) in an ice bath. Then, fuming nitric acid (specific gravity: 1.52, 103 μl) was added dropwise at the same temperature, followed by stirring for one hour. The reaction mixture was poured into ice and made basic with a 5 N sodium hydroxide solution, followed by stirring at room temperature for two hours. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](Cl)[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)CC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[NH:18][N:19]=[C:12]([NH2:13])[C:11]3=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(N)cc2)nc1Cl
Reactant: NN
Solvent: CCCO
Solvent: O
Product: Nc1ccc(-c2ccc3c(N)n[nH]c3n2)cc1
Temperature: 130 °C
Yield: 98.4 %

Procedure:
In an appropriately sized microwave reactor, 0.97 mmol (222 mg) of 6-(4-aminophenyl)-2-chloronicotinonitrile is suspended in 3.3 ml of 1-propanol. 0.28 ml (0.290 g, 5.80 mmol, 6 eq.) of hydrazine hydrate is added. The suspension is heated for 45 minutes at 130° C. in a microwave oven. The mixture is filtered and the solid is dried so as to obtain a green solid (215 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:15]1[CH:16]=[N:17][CH:18]=[C:13]([C:12]([F:21])([F:11])[F:20])[CH:14]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cncc(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4-difluorobenzaldehyde and 5-(trifluoromethyl)pyridin-3-ol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC>CN(C)C=O>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: Cn1ccc2ccccc21
Temperature: 130 °C
Yield: 227.6 %

Procedure:
Indole (10 g, 85.4 mmole), potassium carbonate (5 g), N,N-dimethylformamide (70 mL) and dimethyl carbonate (11 mL, 0.13 mol) were mixed together and refluxed (˜130° C.) for 2 h. At this point TLC analysis of the reaction showed two compounds, the N-methylated indole along with a significant amount of starting material. The reaction mixture was cooled down to ˜50° C. and a second portion of dimethyl carbonate (5.5 mL, 0.065 mol) was added. The mixture was heated at reflux for another 7 h until TLC analysis indicated total consumption of starting indole. The reaction mixture was cooled down to room temperature and it was slowly diluted with water (150 mL). The resulting mixture was extracted with tert-butyl methyl ether (150 mL) and the separated organic layer was washed with water (2×100 mL). The solvent was evaporated in vacuao to furnish 10.8 g of 1-methylindole as light yellow oil (96.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])[N:10]=2)[N:7]=1.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[CH2:12][OH:13])[N:10]=2)[N:7]=1
Reactant: CC(C)(C(=O)O)c1cn2nc(Cl)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(C)(CO)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
0.719 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionic acid was dissolved in 15 ml of tetrahydrofuran; 0.535 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 60 minutes. To this mixture, 1.15 g of tetra-n-butylammonium borohydride was added under ice cooling conditions, followed by stirring at room temperature for 1 hour. 2 ml of 5 N hydrochloric acid was added to the reaction mixture, followed by concentration under reduced pressure. The residue was adjusted to pH 7 by the addition of aqueous sodium carbonate and extracted with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated; the crystal obtained was collected by filtration to yield 0.488 g of the title compound.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[NH4+].[Cl-]>C1COCC1>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[C:11]([F:10])([F:20])[F:21])[OH:15]
Reactant: BrCCC1OCCO1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCC1OCCO1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.7 %

Procedure:
Method 6 General Experimental: Magnesium (230.0 mmol, 5.6 g) in THF (200 ml), under an argon atmosphere, was treated with 2-(2-bromoethyl)-1,3-dioxolane (200.0 mmol, 23.5 ml), slowly, keeping the internal temperature below 35° C. with the aid of an ice bath. After completion of the addition, the mixture was held at room temperature for an additional 1 h. 2-Trifluoromethyl benzaldehyde (100 mmol, 13.2 ml) in THF (100 ml) was cooled to −78° C. under an argon atmosphere, then treated with the freshly formed Grignard reagent prepared above. After completion of the addition, the solution was allowed to warm to room temperature, then held at room temperature overnight. The reaction mixture was then poured into saturated aqueous NH4Cl (200 ml), and extracted with ethyl acetate (2×150 ml). The combined organics were washed with brine (2×75 ml), then concentrated under reduced pressure to give 32.8 g of 3-[1,3]dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-ol, which may be used without further purification. 1H NMR (CDCl3) δ 7.78 (1H, d, J=7.7), 7.62-7.52 (2H, m), 7.34 (1H, t, J=7.6), 4.92 (1H, t, J=4.0), 4.00-3.81 (5H, m), 1.90-1.80 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].Cl.N[CH2:22]C(OCC)=O>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][CH3:22])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: COc1cc(N)c(C(=O)c2ccccc2)cc1OC
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc(C(=O)c2ccccc2)c(N)cc1OC
Yield: 46.1 %

Procedure:
Heat under reflux for 36 hours under an inert atmosphere a mixture of 4.5 g (17.6 mmol) of (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa), 5 g (36 mmol) of ethyl glycinate hydrochloride, and 30 ml of anhydrous pyridine. Add four 2.5 g (18 mmol) fractions of ethyl glycinate hydrochloride, every 6 hours. Allow to equilibrate to room temperature. Evaporate to dryness. Add 200 ml of water. Extract three times with 300 ml of dichloromethane. Dry the organic fractions on Na2SO4 Purify by chromatography (AcOEt 3/hexane 1/3% triethylamine). Recrystallize in EtOH/EtO2. One obtains 2.2 g of the abovenamed product in the form of colorless crystals. Yield: 43%. M:248–250° C. 1H-NMR (CDCl3, 200 MHz): d 3.71 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.31 (s, 2H, CH2), 6.64 (s, 1H Ar), 6.70 (s, 1H Ar), 7.27–7.59 (m, 5H Ar), 9.40 (s, 1H exchangeable, —NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[O:38])=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(=O)Cc1ccc(OCc3ccccc3)cc1)C2
Yield: 81.2 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.1 g) and 4-benzyloxyphenylacetyl chloride (1.3 g) according to an analogous synthetic method to Preparation Example 87, the title compound (1.6 g) was obtained.
Reaction SMILES: [CH2:1]1[O:13][CH:4]([CH2:5][CH2:6][CH2:7][CH:8]([C:10]([OH:12])=[O:11])[NH2:9])[O:3][CH2:2]1>P([O-])([O-])([O-])=O>[CH2:2]1[O:3][CH:4]([CH2:5][CH2:6][CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])[O:13][CH2:1]1
Reactant: NC(CCCC1OCCO1)C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: N[C@@H](CCCC1OCCO1)C(=O)O
Reaction time: 12 h
Yield: 36.6 %

Procedure:
In a 200 mL microjar, 4.73 g of D,L-allysine ethylene acetal and 4.1 mg of catalase (derived from bovine liver, Sigma) were dissolved in 100 mL of 10 mM phosphate buffer (pH 8.3). Then, 2.37 g of immobilized D-amino acid oxidase (of the Trigonopsis origin, Boehringer Mannheim) was added and the reaction was conducted with stirring and 0.5 mL/min. aeration at 25° C. for 12 hours. This reaction mixture was filtered and the filtrate was subjected to HPLC analysis. The substrate residue rate was 50%. The filtrate was also concentrated under reduced pressure, added methanol, and stirred under cooling with ice bath, and the precipitated L-allysine ethylene acetal was collected by filtration and dried to provide 1.73 g of pure L-allysine ethylene acetal. By HPLC analysis, the chemical purity of this product was found to be 99% (Finepak SIL C18-5, Nippon Bunko), and the optical purity was 100% e.e. (CROWNPAK CR(+), Daicel).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O
Temperature: 0 °C

Procedure:
A mixture of 4.7 g (9.7 mmols) of ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1-butyl}-aminocarbonylmethyl]-benzoate and 14.7 ml of 1N sodium hydroxide was stirred in 47 ml of ethanol for 2 hours at 60° C., then neutralized with 14.7 ml of 1N hydrochloric acid and cooled to 0° C. The mixture was filtered to remove the precipitated colorless crystals, and the crystals were washed with ice water and with a little ice cold ethanol and then dried at 100° C./1 Torr.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.C(O)(=O)C.ClCCCl>CCCCCC>[C:1]1([C:7]2[N:8]=[C:9](/[CH:12]=[N:14]/[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(CO)cc1
Reactant: O=Cc1nc(-c2ccccc2)cs1
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OCc1ccc(/N=C/c2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A mixture of 4-phenyl-1,3-thiazole-2-carbaldehyde (1.10 g, 5.81 mmol), (4-aminophenyl)methanol (615 mg, 5.0 mmol), acetic acid (0.4 mL) and 1,2-dichloroethane (10 mL) was stirred at room temperature for 30 min. The reaction mixture was diluted with hexane. The precipitated solid was collected by filtration, washed with hexane, and dried to give the title compound (1.30 g, yield 88%) as yellow crystals.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.CN(C)[CH:20]=[O:21]>O1CCCC1>[CH:1]1([CH2:7][N:8]2[C:12]([CH:20]=[O:21])=[CH:11][CH:10]=[N:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: c1cnn(CC2CCCCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccnn1CC1CCCCC1
Temperature: -78 °C
Yield: 67.6 %

Procedure:
To a solution of pyrazole (1.00 g, 14.7 mmol) in of dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 450 mg, 11 mmol). After 5 min, bromomethylcyclohexane (2.4 mL, 17 mmol) was added by syringe and the mixture was maintained overnight. The reaction mixture was quenched with methanol, diluted with water, and extracted with ether (2×). The combined organic layers were dried over magnessium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 500 mg (27%) of 1-cyclohexylmethyl-1H-pyrazole. To a solution of 1-cyclohexylmethyl-1H-pyrazole (490 mg, 3.00 mmol) in tetrahydrofuran (10 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (1.5 mL, 3.8 mmol). The reaction mixture was maintained at −78° C. for 1 h and was treated with dimethylformamide (1.0 mL, 13 mmol). The reaction mixture was allowed to warm to rt, maintained overnight, and was quenched with methanol. The reaction mixture was diluted with water and was extracted with ether (2×). The combined organic layers were dried over magnessium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 390 mg (68%) of 2-cyclohexylmethyl-2H-pyrazole-3-carbaldehyde.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[N:32][CH:33]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:2]3[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][N:9]4[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]4([CH3:18])[CH3:17])=[CH:4][CH:3]=3)=[N:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CC1(C)CCCC(C)(C)N1CCOc1ccc(I)cc1
Product: CC1(C)CCCC(C)(C)N1CCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-ethyl]-2,2,6,6-tetramethyl-piperidine (260 mg, 0.67 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (155 mg, 0.73 mmol).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:35][C:36]1[S:37][C:38]2[C:43]([N:44]=1)=[CH:42][CH:41]=[C:40]([O:45][C:46]1[C:47]([Cl:67])=[CH:48][C:49]([F:66])=[C:50]([NH:52][C:53](=[O:65])[C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([C:63]#[N:64])([CH3:62])[CH3:61])[CH:55]=3)[CH:51]=1)[N:39]=2>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:67][C:47]1[C:46]([O:45][C:40]2[N:39]=[C:38]3[S:37][C:36]([NH:35][C:8](=[O:10])/[CH:7]=[CH:6]/[C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[N:44][C:43]3=[CH:42][CH:41]=2)=[CH:51][C:50]([NH:52][C:53](=[O:65])[C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([C:63]#[N:64])([CH3:62])[CH3:61])[CH:55]=2)=[C:49]([F:66])[CH:48]=1
Reactant: O=C(O)/C=C/c1ccco1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)/C=C/c5ccco5)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a solution of (2E)-3-furan-2-ylprop-2-enoic acid (24 mg, 0.173 mmol) in pyridine (1.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (65.7 mg, 0.173 mmol), and the mixture was stirred at room temperature for 10 min. N-{5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (80 mg, 0.166 mmol) produced in Example C52(v) was added to the obtained solution, and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (37.2 mg, 87%) as a colorless powder.