Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:33])[C:14]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(COS(C)(=O)=O)[C:15](OCC)=O)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:33])[CH:14]([CH2:15][S:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:11]
Reactant: CCOC(=O)C(COS(C)(=O)=O)(CC1CCCCC1)C(=O)OCC
Reactant: SCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CSCc1ccccc1)CC1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 18.4 %

Procedure:
Sodium (0.097 g, 4.2 mmol) was dissolved in ethanol (10 mL) and the resulting solution was cooled to 0° C. and treated with a mixture comprising benzyl mercaptan (0.493 mL, 4.2 mmol) and 2-cyclohexylmethyl-2-methylsulfonyloxymethyl-malonic acid diethyl ester (1.466 g, 4.02 mmol). The reaction was stirred at room temperature for 17 hours, 53° C. for 20 hours and 73° C. for 24 hours. The ethanol was removed by rotary evaporation, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid ethyl ester (0.237 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)n1ccc2c(Br)cccc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 4-bromo-1H-indole (36 g) in dimethylformamide (80 mL) was treated with a suspension of NaH (60% in mineraloil, 6.9 g) in dimethylformamide (200 mL) at 20° C. After stirring for 30 min the mixture was cooled to −10° C. an treated portionwise with t-butyldimethylsilyl chloride (38 g) followed by stirring for 1 h at room temperature. Standard work-up with ethyl acetate gave and oil which was purified by flash chromatography giving 4-bromo-1-(t-butyldimethylsilyl)-1H-indole (38 g) as a crystalline material.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of N-(4-{2-[(tert-butoxy)carbonylamino]-ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (96 mg, 0.22 mmol, Example 71) in CH2Cl2 (3 mL) was added TFA (3 mL). The mixture was stirred for 3 h at RT. The reaction mixture was concentrated and dried in vacuo to yield N-[4-(2-aminoethyl)phenyl]{2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide. MS (ES+):348 (M+H); (ES−):346 (M−H). Calc'd. for C20H21N5O—347.17.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:15]=[CH:16][CH:17]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[CH:15]=[CH:16][CH:17]=1)=[O:2]
Reactant: O=CO
Reactant: Nc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C

Procedure:
Formic acid (2.5 mL, 66.3 mmol) and acetic anhydride (5 mL, 52.9 mmol) were mixed, and stirred with heating at 50° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with tetrahydrofuran (50 mL), and cooled to 0° C. A solution of N-(3-aminophenyl)-3-(trifluoromethyl)benzamide (5.65 g, 20.2 mmol) in tetrahydrofuran (50 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 16 hr, during which the reaction temperature was allowed to gradually warm to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (50 mL) and ethyl acetate (250 mL). The solution was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated aqueous ammonium chloride solution (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-(formylamino)phenyl]-3-(trifluoromethyl)benzamide as a yellow amorphous substance. To a solution of N-[3-(formylamino)phenyl]-3-(trifluoromethyl)benzamide produced above in tetrahydrofuran (100 mL) was added a 1.9M solution (21 mL, 39.9 mmol) of borane-dimethylsulfide complex in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 hr. Since the starting materials were not completely consumed, a 1.9M solution (2 mL, 3.8 mmol) of borane-dimethylsulfide complex in tetrahydrofuran was added, and the mixture was further stirred at room temperature for 1 hr. Methanol (30 mL) and acetic acid (10 mL) were added to the reaction solution, the mixture was stirred at room temperature for 14 hr, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (250 mL), and the solution was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give the title compound (5.54 g, total yield of 2 steps 93%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:49][C:48]([O:50][C:51]3[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=3[F:58])=[CH:47][C:46]2=[O:59])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH:4]([N:13]1[CH2:49][C:48]([O:50][C:51]2[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=2[F:58])=[CH:47][C:46]1=[O:59])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2
Reactant: COC(=O)C(N)CC1CC2CCC1C2
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CC1CC2CCC1C2)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 140 °C
Yield: 21.4 %

Procedure:
In a round bottom flask was placed 2-amino-3-bicyclo[2.2.1]hept-2-yl-propionic acid methyl ester (206 mg, 1.04 mmol), N,N-diisopropylethylamine (390 μL, 2.24 mmol) and 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 390 mg, 2.24 mmol) in acetonitrile (10 mL). This mixture was then split into two 5 mL portions and placed in two sealed microwave reaction tubes and heated in a microwave reactor at 140° C. for 1 h. The contents of the two reaction tubes were combined, concentrated in vacuo and diluted with dichloromethane (20 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), a saturated sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 15% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (87 mg, 15%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>CO>[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(CNc2ccc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.121 mmol) and MP-CNBH3 (180 mg, 0.360 mmol) in methanol (1 ml) was added acetic acid (6 μl, 0.121 mmol) followed by 3-chlorobenzaldehyde (15 μl, 0.133 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to yield the desired product. RT: 3.09 min, MI: 539, Method: 2; 1H NMR (DMSO, 300 MHz): 8.47 (s, 1H), 7.90 (2H, d), 7.50-7.27 (m, 8H), 6.92 (d, 1H), 6.84 (d, 2H), 6.74 (d, 2H), 4.42 (s, 2H), 4.30 (t, 2H), 3.37 (t, 2H), 3.26 (s, 4H), 2.03 (s, 4H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:17][C:13]=1[C:14](O)=[O:15])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])\[CH3:25])[CH:19]=[CH:20][C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:40]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)O)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC/C=C(\C)CCC=C(C)C)ccc1OC/C=C(\C)CCC=C(C)C
Yield: 55 %

Procedure:
In a manner identical to Example 15, 2,5-digeranyloxybenzoic acid(2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.47 g(55%) of the aimed compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[OH-].[Na+].[CH2:13]([OH:16])[CH2:14][OH:15]>O>[OH:15][CH2:14][CH2:13][O:16][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: O=Cc1cccc(CBr)c1
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cccc(COCCO)c1
Temperature: 55 °C

Procedure:
A mixture of 1.99 g of 3-(bromomethyl)benzaldehyde, 0.80 g of sodium hydroxide and 8 ml of ethylene glycol was heated at 55° C. for 6 hours. After water was added, the mixture was extracted with chloroform and then washed with an aqueous saturated sodium chloride solution. After dried over anhydrous sodium sulfate and then concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography to obtain 0.79 g of oily 3-[(2-hydroxyethoxy)methyl]benzaldehyde [Compound No. (g)].
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([C:44](O)=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O.O1CCOCC1>[C:20]([O:24][C:25]([NH:27][C@H:28]([C:44]([N:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 2 h
Yield: 74 %

Procedure:
23 g (0.086 mol) of prolyl-arginine (2) are dissolved in 100 ml of water and to this solution under stirring there is added a solution of 53 g (0.1 mol) of pentafluorophenyl ester of tert.butyloxycarbonyl-Nε -benzyloxycarbonyl-lysine in 300 ml of dioxane. 2 hours thereafter the solvent is evaporated and the residue is dissolved in 150 ml of dimethylformamide and stirred at room temperature (20° C.) for 48 hours. Then dimethylformamide is evaporated to 1/3 of its volume and the solution is poured into one liter of ether. After 2 hours the resulting residue is filtered-off, washed on the filter with ether and dried in vacuum. After reprecipitation from a mixture ethylacetate-ethanol-ether (3:1:30) there are obtained 47 g (74%) of the product (3) having the following properties: M.p. 90° C., [α]D20 -39.0° (c 1.0; 10% CH3COOH); Rf =0.51 (A, "Eastman"), 0.82 (B, "Eastman"); EHis =0.34 (pH=2.4).
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:21]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:22]([F:24])[F:23])=[C:10]([CH:20]=1)[CH2:11][NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[C:34](O)(=[O:43])[C@@H:35]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[OH:36].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:22]([F:24])[F:23])=[C:10]([CH:20]=1)[CH2:11][NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:34](=[O:43])[C@@H:35]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[OH:36]
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)F)cc1
Reactant: O=C(O)[C@H](O)C1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@H](O)C2CCCCC2)C(F)F)cc1
Yield: 36.8 %

Procedure:
EDC (0.0469 g, 0.24 mmol was added to a stirred mixture of N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-L-prolinamide (0.0691 g, 0.16 mmol), (R)-hexahydromandelic acid (0.0258 g, 0.16 mmol) and HOAT (0.0111 g, 0.08 mmol) in DMF (2.0 mL). After 2 h the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 10-70% ethyl acetate/hexanes gradient) to give N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-[(2R)-2-cyclohexyl-2-hydroxyethanoyl]-L-prolinamide (0.0332 g) as a white solid; LC-MS m/z=564.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH:16]=O)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1C=CC=CC=1.B>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[N:1]1([CH2:16][C@@H:15]2[CH2:18][CH2:19][CH2:20][N:14]2[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: B
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
Part A. Morpholine (7.1 g, 7.1 mL, 82 mmol) was added to a stirring solution of N-BOC-(S)-prolinal (3.3 g, 17 mmol) in methylene chloride (83 mL) followed by zinc chloride (0.5 M in THF, 100 mL, 50 mmol). After stirring at ambient temperature for 5 h, borane-pyridine (ca. 8 M, 2 mL, 16 mmol) was added. After stirring at ambient temperature overnight, the reaction was evaporated in vacuo. Methanol was added to the residue and the solids were filtered. Evaporation of the filtrate afforded 13 g of crude product. Purification over silica gel afforded 3.9 g (87%) of 1,1-dimethylethyl (S)-2-(4-morpholinylmethyl)-1-pyrrolidinecarboxylate: 1H-NMR (CDCl3) δ 3.90 (1H, m), 3.69 (4H, m), 3.34 (2H, m), 2.57 (2H, m), 3.40 (2H, m), 2.18 (1H, m), 1.90 (4H, m), 1.74 (1H, m), 1.47 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.N[CH2:9][C@@H:10]1CC[CH2:12][N:11]1CC.C(=O)C>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[CH2:9][CH2:10][NH:11][CH3:12]
Reactant: CCN1CCC[C@H]1CN
Reactant: CC1CCC(C)N1
Agent: CC=O
Product: CNCCN1C(C)CCC1C

Procedure:
By using 2,5-dimethylpyrrolidine (200 mg) as a starting material, the title compound (0.17 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([C:19](OC)=[O:20])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]([CH2:19][OH:20])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 2.61 g (8.8 mmol) of 1-phenylmethyl-3-(SR)-carbomethoxy-4-(SR)-phenylpyrrolidine (from Example 1, Step A) in 100 mL of THF at -78 ° C. was treated with 9.2 mL of 1.5 M diisobutyl-aluminum hydride solution in toluene. The reaction was warmed to 0 ° C. and stirred for 1 h. The reaction was quenched with 50 mL of sat'd sodium potassium tartrate solution, diluted with 100 mL of ether and stirred at rt for 20 h. The layers were separated and the organic layer was washed with 75 mL of H2O, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 100 g of silica gel using 1:1 v/v, then 3:2 v/v EtOAc/hexanes as the eluant afforded 1.99 g (84%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): δ2.56-2.63 (m, 1H), 2.80 (dd, J=4.3, 9.4, 1H), 2.91-2.98 (m, 2H), 3.05 (dd, J=6.9, 9.6, 1H), 3.27 (dd, J=5.0, 10.7, 1H), 3.44 (dd, J=5.5, 10.8, 1H), 3.62 (q, J=9.0, 1H), 3.76 (ABq, J=24.2, 2H), 7.22-7.40 (10H). Mass Spectrum (NH3 -CI): m/z 268 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH:24]([CH3:28])[NH:23]1>CN(C)C=O.C(OCC)C>[CH3:21][CH:22]1[NH:23][CH:24]([CH3:28])[CH2:25][N:26]([CH2:12][C:10]([OH:11])([CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[C:13]([F:16])([F:15])[F:14])[CH2:27]1
Reactant: CC1CNCC(C)N1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)NC(C)C1)C(F)(F)F
Yield: 70.9 %

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (98.7 mg) and 2,6-dimethylpiperazine (77.2 mg) in dimethylformamide (1 mL) was heated at 100° C. for 5 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 1:98.5:0.5 methanol-methylene chloride-triethylamine) to give the title compound as a white solid (97.3 mg), m.p. 61° C.-62° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].C(O)(=O)C.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23]>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:27][C:26]2[C:28]([CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=[CH:31][C:25]=2[CH:22]([CH3:24])[CH3:23])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=C(C)C(c2ccccc2C=Nc2c(C(C)C)cccc2C(C)C)C(C)=C1C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (10.0 mmol) in ethanol (30.0 mL) were added dropwise acetic acid (1.0 mmol) and 2,6-diisopropylaniline (10.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, the solvent was distilled off under reduced pressure to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,6-diisopropylphenyl)amine (3.85 g, yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>CN(C)C=O.C(O)C>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1)[CH3:23]
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: CCO
Product: CCN(CC)C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and diethylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=359.
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[N:19]=[C:18]4[NH:20][C:21]([C:23]5[N:28]=[C:27]([C:29](OC)=[O:30])[CH:26]=[CH:25][CH:24]=5)=[N:22][C:17]4=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:33].C[Al](C)C>C1(C)C=CC=CC=1.O1CCOCC1>[N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[N:19]=[C:18]4[NH:20][C:21]([C:23]5[N:28]=[C:27]([C:29]([NH2:33])=[O:30])[CH:26]=[CH:25][CH:24]=5)=[N:22][C:17]4=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)n1
Reactant: N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: NC(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)n1
Temperature: 100 °C

Procedure:
To (R)-methyl 6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)picolinate (200 mg, 0.460 mmol) in toluene (5 mL) were added sequentially a freshly prepared saturated solution of ammonia in dioxane (10 mL) at −20° C., and trimethylaluminum (0.099 g, 1.348 mmol). The reaction vessel was sealed and was heated at 100° C. for 16 h. The mixture was cooled to room temperature and was partitioned between ethyl acetate, and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated twice with methanol:diethyl ether (1:10) to afford the title compound (40 mg). MS (ES+) (M+H) 420.2892; LCMS retention time 3.71 min (Method I1).