Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O:4][C@@H:5]1[C@H:10]([O:11][C:12]([CH3:14])=[O:13])[C@@H:9]([O:15][C:16]([CH3:18])=[O:17])[C@@H:8]([O:19][C@:20]2([CH2:35][OH:36])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][C:28]([CH3:30])=[O:29])[C@@H:21]2[O:31][C:32]([CH3:34])=[O:33])[O:7][C@@H:6]1[CH2:37]O)=O.[C:39]([OH:42])(=[O:41])[CH3:40]>C(C(C)=O)C(C)C>[CH3:40][C:39]([O:42][CH2:37][C@H:6]1[O:7][C@H:8]([O:19][C@@:20]2([CH2:35][OH:36])[O:24][C@@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][C:28]([CH3:30])=[O:29])[C@H:21]2[O:31][C:32]([CH3:34])=[O:33])[C@H:9]([O:15][C:16]([CH3:18])=[O:17])[C@@H:10]([O:11][C:12]([CH3:14])=[O:13])[C@@H:5]1[OH:4])=[O:41]
Reactant: CC(=O)O
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CO)O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)CC(C)C
Product: CC(=O)OC[C@H]1O[C@H](O[C@@]2(CO)O[C@@H](CO)[C@@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O
Yield: 75 %

Procedure:
2,3,4,3',4'-penta-O-acetyl sucrose (2 g) was dissolved in methyl isobutyl ketone (20 ml) and acetic acid (1 ml) was added. The reaction of the mixture was heated under reflux (about 126°) for 3 hours. On cooling, the product crystallized to give a yield of 1.5 g (75%) of 2,3,6,3',4'-penta-O-acetyl sucrose.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: c1nc[nH]n1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(-n2cncn2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 26.2 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.7 g), 60% sodium hydride in oil (0.5 g, degreased with hexane), 1,2,4-triazole (0.70 g) and dimethylformamide (50 ml), the title compound (0.51 g) was obtained as an amorphous solid, MS, m/z: 390.3 (M+H)+, 779.3 (2M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:10]([CH2:14][CH3:15])([OH:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:5]1[N:6]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:10]([CH2:14][CH3:15])([OH:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(O)(CC)CC)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(C(O)(CC)CC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 52.1 %

Procedure:
Following a procedure similar to that described in Example 18(a), but using 0.75 g of ethyl 2-butyl-4-(1-ethyl-1-hydroxypropyl)imidazole-5-carboxylate (prepared as described in Preparation 13), 0.12 g of sodium hydride (as a 55% w/w dispersion in mineral oil) and 1.51 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, there were obtained 1.05 g of the title compound as an amorphous solid.
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[C:13]2[S:14][C:15]3[C:20]([C:21]4([CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH2:29])[CH2:23][CH2:22]4)[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.Cl>CN(C)C=O.O>[OH:7][C:8]1[C:13]2[S:14][C:15]3[C:20]([C:21]4([CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH2:29])[CH2:23][CH2:22]4)[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: C=CCN1CCC2(CC1)c1ccccc1Sc1c(OC)cccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCC2(CC1)c1ccccc1Sc1c(O)cccc12
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A solution of ethanethiol (1.49 ml.) in dry dimethylformamide (30 ml.) in an atmosphere of nitrogen is treated portionwise with sodium hydride (800 mg. of a 60% dispersion in mineral oil), with stirring at 20°-25° C. After 15 mins. the internal temperature is raised to 100° C. and the 4-methoxy-1'-allylthioxanthene-9-spiro-4'-piperidine (1.685 g.) is added in one portion. The solution is heated at 100° C. for 45 mins., cooled to ambient temperature, poured into water (300 ml.), acidified with concentrated HCl, the mixture filtered and the filtrate rebasified with solid sodium carbonate and extracted three times with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried over MgSO4 and then evaporated, to give 4-hydroxy-1'-allylthioxanthene-9-spiro-4'-piperidine m.p. 224° C. on recrystallisation from methanol/dimethylformamide/water.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][O:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13]>CC(C)=O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:11]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCC1CO1
Solvent: CC(C)=O
Product: CO[Si](CCCOCC1CO1)(OC)OC
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
In a 10-liter flask provided with stirrer, reflux condenser, internal thermometer and 2 dropping funnels, one filled with 2.85 kg of allyl glycidyl ether and the other with 3.05 kg of trimethoxysilane, 500 ml of allyl glycidyl ether or gamm-glycidyloxypropyltrimethoxysilane was heated to 130° C. Then 1 ml of an 0.01 molar solution of the mesityl oxide-platinum dichloride complex in acetone was added and the reaction was allowed to take place with rapid stirring and the simultaneous feeding in of the two reactants, within about 20 minutes. The internal temperature was kept between 130° C. and 140° C. by slight external cooling and by regulating the feed. This was followed by vacuum distillation producing 5.4 kg of γ-glycidyloxypropyltrimethoxysilane boiling at BP0.05 81° C. (nD20 : 1.4290, d420 : 1.073).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:25])[NH:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH3:24][C@@H:19]([NH:18][C:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH2:8])=[CH:15][CH:14]=1)=[O:25])[C:20]([F:23])([F:21])[F:22]
Reactant: C[C@@H](NC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)Cc1ccc(CN)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Dissolve (R)—N-(tert-butoxycarbonyl)-4-[(1-methyl-2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzylamine (155 mg, 0.43 mmol) in DCM (8 mL). Add 4M hydrogen chloride in dioxane (0.85 mL) and stir at room temperature overnight. Concentrate in vacuo and partition the hydrochloride salt between saturated aqueous NaHCO3 and EtOAc. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound (105 mg, 91%). MS (ES+) m/z: 261 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Yield: 92 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-(1H-tetrazol-5-yl)ethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 92% of theory, C27H27N9O (493.6) ##EQU44##
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([N:23]2[C:28](=[O:29])[NH:27][C:26](=[O:30])[CH:25]=[N:24]2)[CH:10]=[C:11]([Cl:22])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([N:23]2[C:28](=[O:29])[NH:27][C:26](=[O:30])[CH:25]=[N:24]2)[CH:10]=[C:11]([Cl:22])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.), stirred solution of chlorosulfonic acid (1 mL) was added 2-[3,5-dichloro-4-(4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (0.6 g). After 30 min, the resulting brown solution was poured over ice and the resulting mixture was allowed to stir at ambient temperature for 30 min, the solids filtered and dried in vacuo to afford the title compound of Step A as a colorless solid, 0.7 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[C:35]([O:41][CH3:42])[CH:34]=1.[OH-].[Na+]>C1COCC1.CO>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([OH:43])=[O:31])=[CH:34][C:35]=1[O:41][CH3:42])=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)-quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-3-methoxy-benzoic acid methyl ester following the procedure of Example 478 then hydrolysis using sodium hydroxide in THF:MeOH (1:2) at RT for 12 hr, the reaction mixture was acidified and concentrated. The crude residue was purified by reverse phase HPLC to provide the desired compound: mp 100-110° C.; MS (ES) m/z 555.8; HRMS: calcd for C32H22F3NO5+H+, 558.15228; found (ESI, [M+H]+), 558.154.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])=[CH:25][CH:26]=1
Reactant: CCOP(=O)(COc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(COc1ccc(CCN)cc1)OCC

Procedure:
4-(2-t-Butoxycarbonylaminoethyl)phenoxymethylphosphonic acid, diethyl ester (2.856 g, 9.95 mMol) in methylene chloride (300 ml) and trifluoracetic acid (16 ml) was stirred at room temperature for 5 h. The solution was concentrated under reduced pressure and product dried under in vacuo. The trifluoacetic acid salt was neutralized with aqueous sodium carbonate and extracted with dichloromethane containing a small proportion of methanol (5×100 ml). The combined organic layers were dried over sodium sulfate and evaporated to dryness to give the title compound as a pale yellow gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)[CH3:2].C([BH3-])#N.[Na+].S(=O)(=O)(O)O.[CH3:35][C:36]([CH3:38])=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH:36]([CH3:38])[CH3:35])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N(c2ccc3c(c2)C(C)(C)OC3(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
To a solution of 4-[(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 79, 0.1 g, 0.32 mmol) and sodiumcyanoborohydride (0.12 g, 1.92 mmol) in 2 mL of acetone and 2 mL of acetic acid, sodiumcyanoborohydride (0.1 g, 1.58 mmol) was added followed by a drop of sulfuric acid. After half an hour at room temperature, another drop of sulfuric acid was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was taken up in ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash column chromatography on silica gel, using 5% ethyl acetate in hexane as the eluent, to afford the title compound (0.007 g, <10%). 1H NMR (300 MHz, CDCl3): δ 7.83 (d, 2H, J=9.0 Hz), 7.14 (d, 1H, J=7.9 Hz), 7.00 (dd, 1H, J=7.8, 1.8 Hz), 6.81 (d, 1H, J=1.7 Hz), 6.52 (d, 2H, J=9.2 Hz), 4.39 (heptet, 1H, J=6.6 Hz), 4.30 (q, 2H, J=7.11 Hz) 1.56 (s, 6H), 1.51 (s, 6H), 1.34 (t, 3H, J=7.1 Hz), 1.17 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:24]=[CH:25][C:26]([S:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:27][CH:28]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Reactant: Brc1ccc(SCCN2CCCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(SCCN5CCCC5)cc4)nnc3c2)c1
Yield: 21.3 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.625 g, 2.08 mmol, 1 equiv), 1-[2-(4-bromo-phenylsulfanyl)-ethyl]-pyrrolidine (0.894 g, 3.12 mmol, 1.5 equiv), cesium carbonate (2.04 g, 6.25 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.24 g, 0.417 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.19 g, 0.208 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (12 mL), outfitted with reflux condenser and heated to reflux for 16 hours. The reaction was then filtered and the solvents were removed. The residue was taken up in minimum amount of DCM (ca. 5 mL) and precipitated out with excess hexanes. The resulting precipitate was collected and dried. 0.5 g of this crude product was taken on and purified by ISCO silica gel chromatography to afford product as an orange solid (0.224 g, 22% yield). MS (ESI+): m/z=506.1, LC retention time: 2.91 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:13]([O:18][CH2:19][CH:20]1[O:22][CH2:21]1)(=[O:17])[C:14]([CH3:16])=[CH2:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[C:13]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]([O:11][CH3:12])[O:2][CH3:1])=[CH:5][CH:6]=1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: COC(OC)c1ccc(O)cc1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Product: C=C(C)C(=O)OCC(O)COc1ccc(C(OC)OC)cc1
Temperature: 80 °C

Procedure:
In a 500 ml. 4-neck flask fitted with a mechanical stirrer, thermometer, condenser and a vented nitrogen bubbler were placed 84 g. 4-dimethoxymethyl phenol (0.5 mole), 71 g. glycidyl methacrylate (GMA) (0.5 mole), and 1.5 g. benzyl tributyl ammonium chloride (0.005 mole). The apparatus was flushed with air for 5 minutes and the solution was then heated to 80° C. for 5 hours. The progress of the reaction was followed from disappearance of the GMA. Gas chromatographic analysis of the reaction mixture indicated 95% reaction. The solution was cooled and dissolved in 250 ml. methylene chloride and washed three times with lN sodium hydroxide (100 ml.) and then with water until the washings were neutral. The organic layer was dried over magnesium sulfate and the solvent was removed at reduced pressure using a Rotovap. The oily residue was dried under high vacuum for 30 minutes. The yield was 133 g. (86%) product. H-1 NMR showed signals typical of GMA except the signal for the protons that were attached to the epoxide carbon at 2.8 and 3.3 ppm showed up as doublets and a quintet respectively. The spectrum also showed signals for the 4-dimethoxymethylphenyl group at ppms 7.8-6.9 and 3.4.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[NH2:27][C@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O>>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH2:27])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: C[C@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)(C)OC(=O)N1CCCC(N)C1

Procedure:
After two hours in reaction, 1.25 g of N-Boc-3-piperidinone, 1.7 g of D-glucose, 1.0 g of L-alanine, and 3.3 mg of pyridoxal phosphate were added. Further, after five hours in reaction, 1.25 g of N-Boc-3-piperidinone, 1.7 g of D-glucose, and 3.3 mg of pyridoxal phosphate were added. During the reaction, the reaction liquid was sampled. From the sample, N-Boc-3-aminopiperidine was extracted by the addition of ethyl acetate after basifying the sample with 6 N aqueous solution of sodium hydroxide. The amount of N-Boc-3-aminopiperidine produced was measured by analyzing N-Boc-3-aminopiperidine under the following GC conditions. Further, by the law of the art, N-Boc-3-aminopiperidine thus obtained was acted on by 3,5-dinitrobenzyl chloride to form a dinitrobenzyl derivative. After that, the dinitrobenzyl derivative was analyzed under the following HPLC conditions, whereby the optical purity thereof was measured. In the result, the amount of N-Boc-3-aminopyrrolidine produced after 23.5 hours in reaction was 3.13 g. The absolute configuration of N-Boc-3-aminopyrrolidine was (S), and the optical purity was not less than 99.9% e.e.
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(OCC)C>C(#N)C>[F:1][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: [F-]
Reactant: O=C(CBr)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=C(CF)c1ccccc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A suspension of potassium fluoride (3.091 g) and 18-crown-6-ether (0.341 g) in acetonitrile (25 mL) was stirred at 55° C. for 1 hour. α-Bromoacetophenone (5.12 g) was added to the reaction mixture, followed by stirring for 20 hours. Subsequently, diethyl ether was added to the reaction mixture, and then the insoluble matter that was formed was removed by filtration. Water was added for partitioning the filtrate. The organic layer was sequentially washed with water and saturated brine. Subsequently, the organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([O:32]C)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([OH:32])=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)O
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a stirred solution of methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (520 mg, 1.15 mmol) (obtained as described in example 1, preparation of starting materials) in methanol (10 ml), was added 2.5M aqueous sodium hydroxide (2 ml, 5 mmol) and the solution was stirred for 3 hours. The solution was evaporated and the residue was taken into water and was acidified to about pH4 with acetic acid and stirred for 15 minutes. The precipitate was filtered off, washed with water and dried to provide (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid, (435 mg, 86%); NMR spectrum (300 MHz) 1.69 (d, 3H), 5.36 (q, 1H), 5.75 (s, 2H), 6.94 (d, 1H), 7.14 (d, 1H), 7.27 (t, 1H), 7.35 (d, 1H), 7.71 (m, 4H), 8.12 (s, 1H), 8.43 (s, 1H), 8.52 (s, 2H), 10 76 (s, 1H), one exchangeable not observed; Mass spectrum MH+ 441.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.N1C=CC=N1.C(=O)([O-])[O-].[K+].[K+].[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>C(Cl)Cl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:26][C:2]1([CH3:1])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[O:20][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)(C)CCS3(=O)=O)c1O
Reactant: CCS(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)(C)CCS3(=O)=O)c1OS(=O)(=O)CC
Yield: 82 %

Procedure:
0.7 Gram (1.9 mmol) of the 4,4,5,8-tetramethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound Ic-1) corresponding to pyrazole derivative (I-H), obtained in Referential Production Example 5, was dissolved in 8 ml of methylene chloride. Then, a solution of 0.51 g (3.8 mmol) of potassium carbonate in 5 ml of water was added, and further, 0.49 g (3.8 mmol) of ethanesulfonyl chloride and 0.05 g (0.2 mmol) of benzyltriethylammonium chloride, corresponding to compound B-A-Hal, were added. The mixture was allowed to react at room temperature for 2 hours, and further refluxed under heat for 2 hours. The reaction mixture was allowed to cool, and then a methylene chloride layer was recovered and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant oil was purified by silica gel column chromatography to give 0.73 g (yield 82%) of 4,4,5,8-tetramethyl-6-(1-ethyl-5-ethanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound Ic-2).