Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:16][CH2:17][CH2:18][CH2:19][Si:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])(=[O:15])[CH:13]=C>>[C:12]([O:16][CH2:17][CH2:18][CH2:19][Si:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[O:27][CH2:28][CH3:29])(=[O:15])[CH3:13]
Reactant: C=CC(=O)OCCC[Si](OCC)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCO[Si](CCCOC(C)=O)(OCC)OCC
Yield: 41 %

Procedure:
The same procedure as in Example 1 was followed to conduct a reaction, except that p-toluenesulfonic acid was used in place of Ti(OBu)4. After completion of the reaction, the reaction product was analyzed by GC. As a result, it was thus found that triethoxysilylpropyl acrylate as the objective compound had been obtained in a yield of 41% (in terms of triethoxysilylpropyl acetate).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.Cl.[NH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C.C(N(CC)CC)C>[C:20]([O:19][C:17](=[O:18])[CH2:16][NH:15][CH2:1][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cccc(C=O)n1
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(CNCC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of ethyl 6-formylpyridine-2-carboxylate (1.74 g) in dichloroethane (30.0 mL) were added tert-butyl glycinate hydrochloride (4.89 g), triethylamine (4.06 mL), and acetic acid (2.78 mL), and sodium triacetoxyborohydride (6.18 g) under ice-cooling. The reaction suspension was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and then sodium hydrogen carbonate was added thereto until the solution became basic. The reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 6-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}pyridine-2-carboxylate (2.83 g).
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][C:14]([CH3:24])=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([O:41][CH3:42])[CH:35]=1>[Cu]I.CS(C)=O>[F:40][C:37]1[CH:38]=[CH:39][C:34]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[C:14]([CH3:24])[CH:15]=3)=[CH:22][CH:21]=2)=[CH:35][C:36]=1[O:41][CH3:42]
Reactant: Cc1cnc(N)c(-c2ccc(O)cc2)c1
Reactant: COc1cc(Br)ccc1F
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: COc1cc(Oc2ccc(-c3cc(C)cnc3N)cc2)ccc1F
Temperature: 130 °C
Reaction time: 10 h
Yield: 44.6 %

Procedure:
Copper(I) iodide (95 mg) was added to a mixture of picolinic acid (61.5 mg), 4-(2-amino-5-methylpyridin-3-yl)phenol (500 mg), tripotassium phosphate (1590 mg), 4-bromo-1-fluoro-2-methoxybenzene (614 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 10 hr. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (361 mg) as pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[C:4]=1[F:10])[CH3:2].P(Cl)(Cl)([Cl:13])=O>C(N(CC)CC)C.ClCCl>[Cl:13][C:5]1[C:4]([F:10])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ncnc(O)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ncnc(Cl)c1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of the compound of part (iv) (40 kg), dichloromethane (120 L) and triethylamine (28.4 g) was slowly added phosphorus oxychloride (47.2 kg) over 3 hours maintaining the reaction temperature below 40° C. during the addition. The mixture was heated under reflux for 5 hours, cooled to 25° C. and cautiously quenched into 3N aqueous hydrochloric acid solution (176 L), maintaining the temperature below 20° C. during this operation. The layers were separated, the aqueous phase extracted with dichloromethane (50 L) and the combined organic layers washed with water (50 L). The organic layer was concentrated under reduced pressure to provide the product as an oil (40.69 kg).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[CH3:13][NH2:14]>CO>[CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:14][CH3:13])=[O:5]
Reactant: CN
Reactant: CCOC(=O)c1cccnc1C
Solvent: CO
Product: CNC(=O)c1cccnc1C
Temperature: 50 °C
Yield: 95 %

Procedure:
To ethyl 2-methylnicotinate (24.2 g) was added a solution of 40% methylamine in methanol (150 ml), which was then heated in a sealed tube at 50° C. overnight. The reaction mixture was evaporated, to give the title compound as a pale yellow solid (20.781 g, yield; 95%).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH3:10][O:11][C:12]([CH:14]1[CH2:18][C:17]([CH2:20][CH:21]=[CH2:22])(O)[CH2:16][N:15]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([CH:14]1[CH2:18][C:17]([CH2:20][CH:21]=[CH2:22])([F:7])[CH2:16][N:15]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:13]
Reactant: C=CCC1(O)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C=CCC1(F)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To a stirred solution of DAST (1.06 g, 6.58 mmol) in DCM (10 mL) at −78° C., 4-allyl-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (940 mg, 3.3 mmol) in dry DCM (10 mL) was added slowly. The mixture was then stirred at −78° C. for 1 h, then at −10° C. for an additional 1 h. DCM (50 mL) was added, quenched with NH4Cl (10%, 150 mL) and the organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained on removal of solvent was purified by silica gel column chromatography using 5% EtOAc in hexanes as eluent to obtain 4-allyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (330 mg, 34%).
Reaction SMILES: F[C:2]1[C:22]([F:23])=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.O>CS(C)=O>[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][N:27]([C:2]2[C:22]([F:23])=[CH:21][C:5]3[C:6]4[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=4[CH:12]=[N:13][C:4]=3[CH:3]=2)[CH2:26]1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Reactant: CC1(C)CCCNC1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2cnc3cc(N4CCCC(C)(C)C4)c(F)cc3c2c1=O
Temperature: 80 °C

Procedure:
A suspension of 2 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 3.23 cm3 of 3,3-dimethylpiperidine in 40 cm3 of dimethyl sulphoxide was heated at a temperature in the region of 80° C. for 72 hours. After cooling to about 200° C., 200 cm3 of water was added to the reaction mixture. The precipitate obtained was dewatered and washed with 25 cm3 of water. The solid was taken up in 100 cm3 of dichloromethane, the residual water was decanted off; the organic solution was dried over magnesium sulphate and concentrated under reduced pressure (5 kPa) at about 40° C. 2.67 g of a mixture containing ethyl 9-(3,3-dimethylpiperidin-1-yl)-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and ethyl 8-(3,3-dimethylpiperidin-1-yl)-9-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained. This mixture was purified by flash chromatography on silica gel (particle size 20-45 μm, diameter 10 cm, height 60 cm) at a pressure of 80 kPa, eluted with a mixture containing 99% dichloromethane and 1% methanol, and 70 cm3 fractions were collected. After concentration of fractions 16 to 39 under reduced pressure (5 kPa) at about 50° C., 0.85 g of ethyl 9-(3,3-dimethylpiperidin-1-yl)-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a yellow solid, which melted at around 218-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (12.50 g, 34 mmol) in dry CH2Cl2 (150 mL) was added Et3N (13.74 g, 18.3 mL, 136 mmol, 4 eq) at −5-0° C. Then a solution of MsCl (7.75 g, 5.16 mL, 68 mmol, 2 eq) in dry CH2Cl2 (50 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. Upon reaction completion water (100 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×80 mL), the combined organic layers was washed with 10% citric acid, sat. NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (15 g), which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C[C:18]1[CH:19]=[C:20]([N:25]2CC[NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[CH3:24]>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:24][C:23]3[CH:22]=[C:21]4[C:20](=[CH:19][CH:18]=3)[NH:25][CH2:26][CH2:27][NH:28]4)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: FC(F)(F)c1cccc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)c1

Procedure:
Example 11 was prepared according to Example 2 except that in Step A 1-(3-trifluoromethylphenyl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 88°-91° C.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH:1]1([NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCN1CCCC1
Reactant: O=C=NC1CCCCC1
Solvent: CC#N
Product: O=C(NCCCN1CCCC1)NC1CCCCC1

Procedure:
In an argon atmosphere 10 mmol of cyclohexylisocyanate was added slowly to 10 mmol of 1-(3-aminopropyl)pyrrolidine in 10 ml of acetonitrile. The product precipitated instantly as a pure white solid. The solvent was removed under reduced pressure and the product was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: F[C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@H:32]2[CH2:36][CH2:35][O:34][CH2:33]2)[CH:30]=1)[C:18]([NH:20][C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)=[O:19]>>[CH3:10][N:7]1[C:6](=[O:11])[C:5]2[CH:12]=[CH:13][C:2]([O:14][C:15]3[CH:16]=[C:17]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:18]([NH:20][C:21]3[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[O:19])=[CH:3][C:4]=2[O:9][CH2:8]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)cn1
Reactant: CN1COc2cc(F)ccc2C1=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3)OCN(C)C4=O)cc(O[C@H]3CCOC3)c2)cn1

Procedure:
The preparations of 7-fluoro-3-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one and 3-hydroxy-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide were described earlier.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[N:13]=[C:14]([NH:17][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[S:15][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2csc(N)n2)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1OC
Yield: 65 %

Procedure:
A mixture of 0.5 g of 4-(3,4-dimethoxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.33 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored solution was poured into 50 ml of 1N hydrochloric acid and extracted three times with 50 ml of methylene chloride each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was chromatographed on 35 g of Kieselgel 60 with diethyl ether as the eluent. The product-containing fractions were concentrated, dissolved in 40 ml of 50% ethanol by the addition of a small amount of 2N sodium hydroxide solution and precipitated with 2N hydrochloric acid at pH 6. 0.4 g of N-[4-(3,4-dimethoxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide was obtained as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH2:16])[CH2:12]2.[C:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:38]4[CH:50]=[CH:49][C:41]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:40](F)[CH:39]=4)[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)#[N:18]>CS(C)=O.O>[C:17]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[C:37]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:38]4[CH:39]=[CH:40][C:41]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[C:49]([NH:16][CH:11]5[CH2:10][CH:9]6[N:8]([CH3:7])[CH:13]([CH2:14][CH2:15]6)[CH2:12]5)[CH:50]=4)[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CN1C2CCC1CC(N)C2
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1C2CCC1CC(Nc1cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc1C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Yield: 27 %

Procedure:
0.89 g of potassium carbonate and 6 g of 8-methyl-8-azabicyclo[3.2.1]octan-3-amine are successively added to a solution of 1 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 100° C. for 1 hour and 40 minutes in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (92/8 as mixtures), so as to give 0.34 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]benzoate in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[Al].[Li]>C1COCC1>[F:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[CH2:4][OH:3])[CH:15]=1
Reactant: CCOC(=O)C(CC(C)(C)c1cc(F)ccc1OC)(OCOC)C(F)(F)F
Agent: [Al]
Agent: [Li]
Solvent: C1CCOC1
Product: COCOC(CO)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a chilled (ice-water bath) solution of the 3.47 g (8.75 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-2-methoxymethoxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester in 50 mL of anhydrous THF, 1.09 g (28.88 mmol) of lithium aluminum was added in several portions. After 3 hours, the mixture was cautiously quenched (dropwise) with water (total: 8 mL), diluted with 100 mL of EtOAc, dried over magnesium sulfate, filtered, concentrated in vacuo, and dried at 75° C. under high vacuum to afford 3.1 g (100%) of 4-(5-fluoro-2-methoxyphenyl)-2-methoxymethoxy-4-methyl-2-trifluoromethylpentan-1-ol as a clear oil which was used without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]2[C@@H:11](I)[C@H:7]([C@@H:8]([C:21]([O:23][CH3:24])=[O:22])[N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:21]([O:23][CH3:24])=[O:22])[N:9]2[C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](OC(C)=O)[C@@H]([C@H]2I)N1[C@H](C)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OC(C)=O)C2)N1[C@H](C)c1ccccc1

Procedure:
A solution of methyl (1S,3S,4S,6R,7S)-6-acetyloxy-7-iodo-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 42-3 (1.73 g) in methanol (20 mL) containing 20% Pd(OH)2 (173 mg) and triethylamine (0.6 mL) was stirred at room temperature for 1.5 hrs under 1 atm pressure with hydrogen.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6].Cl[C:14]1[N:15]=[C:16]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][S:20][C:18]=2[N:19]=1>>[OH:1][CH2:2][CH2:3][NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:14]2[N:15]=[C:16]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:17]3[C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][S:20][C:18]=3[N:19]=2)[CH2:8]1)=[O:6]
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reactant: O=C(NCCO)[C@H]1CCCNC1
Product: O=C(NCCO)[C@H]1CCCN(c2nc(NCc3ccccn3)c3c(-c4ccccc4)csc3n2)C1

Procedure:
(S)-Piperidine-3-carboxylic acid (2-hydroxy-ethyl)-amide was reacted with (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine as in Example 6 above to give (S)-1-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-yl}-piperidine-3-carboxylic acid (2-hydroxy-ethyl)-amide as a yellow foam (188 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([NH:12][OH:13])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N:18]=[C:19]=[S:20])(C)C.CO>C1COCC1>[OH:13][N:12]([C@H:10]1[CH2:11][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9]1)[C:19]([NH2:18])=[S:20]
Reactant: ON[C@H]1C[C@@H](c2ccc(F)cc2)C1
Reactant: C[Si](C)(C)N=C=S
Solvent: C1CCOC1
Solvent: CO
Product: NC(=S)N(O)[C@H]1C[C@@H](c2ccc(F)cc2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
To a stirred solution of cis-3-(4-fluorophenyl)cyclobutylhydroxylamine (1.81 g, 10 mmol) in THF (30 ml) was added trimethylsilylisothiocyanate (1.58 g, 12 mmol) at room temperature. After stirring for 3 hours at 70° C., MeOH (20 ml) was added. Volatiles were removed in vacuo, and the residue recrystallized from ethyl acetate/n-hexane/EtOH to afford 1.34 g (55.8% yield) of the title compound, m.p. 156-158° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37])#[N:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:33]2[CH:34]=[CH:35][C:36]([F:37])=[C:31]([C:29]#[N:30])[CH:32]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: N#Cc1cc(B(O)O)ccc1F
Product: CC(c1ccc(-c2ccc(F)c(C#N)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-cyano-4-fluorophenylboronic acid to give the title compound as a colorless solid. MS (m/e)=519.2 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:27][NH:28][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 80.5 %

Procedure:
1-Methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (30 mg) was prepared by following General Procedure F using 1-methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (36 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.2 ml). LCMS: m/z 373; and 1H NMR (DMSO-d6, 400 MHz): δ 9.63 (d, 1H), 8.24 (d, 1H), 7.84 (m, 1H), 7.71 (t, 1H) 7.52 (d, 1H), 7.22 (m 2H), 5.24 (m , 1H), 3.65 (s, 3H), and 2.81 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][NH2:11].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:11][CH2:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:23])[N:21]=2)[CH:18]=1
Reactant: Cc1cc(Cl)cc(Cl)c1CN
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: Cc1cc(Cl)cc(Cl)c1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using (2,4-dichloro-6-methylphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.