Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(C)C[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=O.C(N(CC)CC)C.[OH:23][C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=1[CH:31]=[CH:32][C:33]([OH:35])=[O:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C=O)C>[CH3:14][C:7]([O:34][C:33](=[O:35])[CH:32]=[CH:31][C:25]1[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=1[OH:23])([CH:6]=[CH2:4])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12]
Reactant: CC(N)CC(=O)C1C(C)C=CCC1(C)C
Reactant: O=C(O)C=Cc1ccc(O)cc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)C=Cc1ccc(O)cc1O
Reaction time: 1 h

Procedure:
To a solution of 3-amino-1-(2,6,6-trimethyl-cyclohex-3-enyl)-butan-1-one (2.38, 11.3 mmol, 10) and triethylamine (2.30 g, 22.6 mmol) in anhydrous THF (150 mL) stirred for 5 min at 22° C. is added 3-(2,4-dihydroxyphenyl)-acrylic acid (2.04 g, 11.3 mmol). To this heterogeneous solution is added BOP Reagent (5.00 g, 11.3 mmol; Aldrich #22,608-4) in DMF (10 mL), and the subsequent homogeneous reaction mixture is stirred for 1 h. The reaction mixture is partitioned between ether (200 mL) and water (400 mL); the organic layer is removed and washed with ether (200 mL). The combined organic layers are washed sequentially with saturated sodium bicarbonate solution (200 mL) and brine (200 mL). The organic layer is dried over anhydrous magnesium sulfate, vacuum filtered and concentrated to give 3-(2,4-dihydroxy-phenyl)-acrylic acid 1,5-dimethyl-1-vinyl-hex-4-enyl ester as an oil that is purified by flash chromatography to give 11 as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2O)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])[CH3:3].FC(F)(F)C(O)=O.[C:31]([O:35][CH3:36])(=[O:34])[CH2:32][SH:33]>>[CH3:3][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[S:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[CH:8]=[C:7]([C:19]([CH3:22])([CH3:20])[CH3:21])[C:6]=1[OH:23])([CH3:1])[CH3:4]
Reactant: COC(=O)CS
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 15 (2.0 g, 0.0059) was added to trifluoroacetic acid (5 ml). After several minutes methyl thioglycolate (0.63 g) was added, and the reaction mixture was stirred at room temperature for 2 hours. The trifluoroacetic acid was evaporated with a gentle flow of nitrogen gas. The residue was dissolved in diethyl ether (50 ml) and washed twice with 2 ml of 0.25 N NaOH, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The product was purified by silica gel chromatography to give a colorless oil. The structure was supported by NMR, infrared and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([NH2:13])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]#[N:13]
Reactant: NC(=O)Cc1cc(F)c(F)cc1Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
The compound (143 mg, 0.572 mmol) of Step 1 was dissolved in THF. Pyridine (0.138 mL, 1.71 mmol) was added thereto, trifluoroacetic anhydride (0.119 mL, 0.858 mmol) was added thereto at −5° C. to 0° C., and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. After diluted with ethyl acetate, the resultant was washed with 1 N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure to thus obtain the title compound without purification.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[N:46]1([S:51](C2C=CC(N)=CC=2)(=[O:53])=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([S:51]([N:46]5[CH2:50][CH2:49][CH2:48][CH2:47]5)(=[O:53])=[O:52])=[CH:22][CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: O=S(=O)(c1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1)N1CCCC1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)aniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.11 (bs, 1H), 9.76 (bs, 1H), 8.19 (d, 1H, J=3.9 Hz), 7.82 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=8.7 Hz), 7.27 (d, 1H, J=2.4 Hz), 7.08 (dd, 1H, J=2.4 and 8.7 Hz), 6.85 (d, 1H, J=8.7 Hz), 4.23 (s, 4H), 3.10-3.06 (m, 4H), 1.64-1.58 (m, 4H); LCMS: ret. time: 22.68 min.; purity: 93%; MS (m/e): 472 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.C[Si]([C:31]#[CH:32])(C)C>C(N(CC)CC)C.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:31]#[CH:32])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: C#C[Si](C)(C)C
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: C#Cc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A solution of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (50 mg, 0.11 mmol) in triethylamine (2 mL) containing CuI (2.1 mg, 0.011 mmol) was degassed with bubbling nitrogen for 10 min. Pd(PPh3)4 (13 mg, 0.011 mmol) was added followed by trimethylsilylacetylene (5 equiv). The reaction vessel was sealed and heated in the microwave at 130° C. for 30 min. The cooled mixture was diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue dissolved in 2 mL methanol. The solution was treated with potassium carbonate (100 mg) and the suspension stirred for 2 hr at room temperature. The reaction mixture was concentrated, diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue purified by reverse phase HPLC to give 133. MS: (ESI+) 394.1.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH:10](O)[CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]3[CH2:25][OH:26])[CH:7]=[CH:6][C:5]=12.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH:10]3[O:26][CH2:25][C@@H:13]4[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17][N:12]4[CH2:11]3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc3nonc3c2)[C@H](CO)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2CC(c3ccc4nonc4c3)OC[C@@H]2C1
Temperature: 100 °C

Procedure:
To a 20 mL size microwave tube containing a stir bar was added tert-butyl (3S)-4-[2-(2,1,3-benzoxadiazol-5-yl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (0.80 g, 2.1 mmol), cyanomethylene tri-n-Butylphosphorane (0.92 g, 3.8 mmol) and anhydrous toluene (15 mL). The tube was degassed and purged with N2 followed by heating at 100° C. for 12 h. The solution was concentrated to dryness and the organic residue was then purified over silica gel with the solvent systems of 30% Acetone in DCM to furnish the title compound: 1H-NMR (CDCl3, 500 MHz), δ 7.854-7.832 (m, 2H), 7.428 (d, J=9 Hz, 1H), 4.754 (d, J=10.5 Hz, 1H), 4.041-4.015 (m, 3H), 3.774-3.733 (m, 2H), 3.517 (t, J=11 Hz, 1H), 3.011 (d, J=11.5 Hz, 1H), 2.782 (d, J=9.5 Hz, 1H), 2.335-2.240 (m, 3H), 1.510 (s, 9H).
Reaction SMILES: C(N)CCC.C(OC1C2N=NN(CC)C=2[C:12](C(O)=O)=[C:11]([CH3:23])[N:10]=1)C.[CH2:24]([O:26][C:27]([C:29]1[C:30]2[N:41]([CH2:42][CH3:43])[N:40]=[N:39][C:31]=2[C:32](OCC)=[N:33][C:34]=1[CH3:35])=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[C:30]2[N:41]([CH2:42][CH3:43])[N:40]=[N:39][C:31]=2[C:32]([NH:10][CH:11]([CH3:23])[CH3:12])=[N:33][C:34]=1[CH3:35])=[O:28])[CH3:25]
Reactant: CCOc1nc(C)c(C(=O)O)c2c1nnn2CC
Reactant: CCOC(=O)c1c(C)nc(OCC)c2nnn(CC)c12
Solvent: CCCCN
Product: CCOC(=O)c1c(C)nc(NC(C)C)c2nnn(CC)c12

Procedure:
The following additional compounds are obtained by the procedure of Example 2 by substituting the appropriate amine for the butylamine and another product of Example 1 for the 4-ethoxy-1-ethyl-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[F:19][C:20]([F:30])([F:29])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH2:22]>>[F:30][C:20]([F:19])([F:29])[CH:21]([NH:22][C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: NC(c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1ccc(C2CC2)c(OCC(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and 2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine (CAN 35272-15-2) as starting materials, MS (EI): m/e=420.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[CH3:28][O:29][CH2:30]Cl>ClCCl.C(OCC)(=O)C>[C:12]1([CH2:11][CH2:10][CH:9]([O:18][CH2:28][O:29][CH3:30])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COCCl
Reactant: OC(CCc1ccccc1)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCOC(CCc1ccccc1)CCc1ccccc1
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A solution of 101 mg (0.42 mmol) of 1,5-diphenyl-3-pentanol, 0.18 ml (1.0 mmol) of ethyldiisopropylamine, and 0.063 ml (0.84 mmol) of chloromethyl methyl ether in 1 ml of dichloromethane was allowed to stand for 16 h. The resulting solution was taken up in ethyl acetate, washed sequentially with 10% aqueous citric acid, water, and saturated sodium bicarbonate, dried over Na2SO4, and concentrated in vacuo. Flash chromatography using 10% ethyl acetate in hexane gave 109 mg (92%) of the desired compound (Rf 0.51, 25% ethyl acetate in hexane) as an oil. 1H NMR (CDCl3) δ1.88 (m, 4H), 2.70 (m, 4H), 3.44 (s, 3H), 3.64 (pentet, J=6 Hz, 1H), 4.70 (s, 2H), 7.15-7.3 (m, 10H). Mass spectrum (M+NH4)+ =302.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][O:17]C(=O)C)=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCCCc1ccc(COC(C)=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CCCCCCCc1ccc(CO)o1
Yield: 76.3 %

Procedure:
8-(5-Acetoxymethyl-2-furyl)-octanoic acid methyl ester (25.00 g, 0.084 moles), 6% aqueous potassium carbonate (200 g), and methanol (750 ml) were stirred at room temperature for 30 minutes. The solution was concentrated to 1/5 of the volume by distillation from a water bath (40° C) under reduced pressure (60 mm Hg). The residue was diluted with water (400 ml) and extracted with two 500-ml portions of ether. The combined ethereal extracts were washed with water (300 ml) and dried over magnesium sulfate. Evaporation of the solvent from a water bath (60° C) under reduced pressure, at last under 15 mm Hg, left a tea-coloured, oily residue (17.31 g), which after distillation gave 16.30 g (76%) of the title compound, b0.1 141° C, nD25 1.4815.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:5][CH:4]([NH2:27])[CH2:3]1.CCN(C(C)C)C(C)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.CO>C(Cl)Cl>[CH3:1][CH:2]1[CH:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:5][CH:4]([NH:27][S:40]([CH:37]2[CH2:39][CH2:38]2)(=[O:42])=[O:41])[CH2:3]1
Reactant: CC1CC(N)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1CC(NS(=O)(=O)C2CC2)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of 3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (0.27 g, 0.7 mmol) and DIEA (0.18 mL, 1.05 mmol) in DCM (5 mL) was added cyclopropanesulfonyl chloride (0.098 g, 0.7 mmol) drop-wise. The resulting mixture was stirred at ambient temperature for about 1 h. Another 0.18 mL of DIEA and 0.098 g of cyclopropanesulfonyl chloride were added and the reaction was continued for about 3 h. The solvent was removed and the residue was partitioned between saturated aqueous ammonium chloride and EtOAc (20 mL each). The organic layer was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concd. The residue was purified by silica gel chromatography (100% DCM for 5 min, then to 6% MeOH in DCM over next 30 min) to yield N-(3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)cyclopropanesulfonamide (0.18 g, 52% yield) as an off-white solid. LC/MS (Table 1, Method a) Rt=2.45 min; MS m/z 490 (M+H)+.
Reaction SMILES: [Si]([O:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[S:25][CH:26]=[C:27]([C:29](=[O:31])[NH2:30])[N:28]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:29]([C:27]1[N:28]=[C:24]([N:21]2[CH2:22][CH2:23][C@H:19]([OH:18])[CH2:20]2)[S:25][CH:26]=1)(=[O:31])[NH2:30]
Reactant: CC(C)(C)[Si](O[C@H]1CCN(c2nc(C(N)=O)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1csc(N2CC[C@H](O)C2)n1
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
To a solution of (3S)-3-t-butyldiphenylsilyloxy-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidine (3.1 g, 6.86 mmol) (obtained as described in Reference Example 20(6)) in anhydrous tetrahydrofuran (90 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (8.24 ml, 8.24 mmol) in an ice bath, and the mixture was stirred for 1.5 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→10% methanol in ethyl acetate as the eluant to afford (3S)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (1.42 g, yield 98%) as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12]>O>[CH:1](=[CH:12][CH2:11][CH2:10][CH2:9][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: O=Cc1ccccc1
Solvent: O
Product: NCCCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.3 %

Procedure:
To a stirred mixture of 20 g of water and 21.2 g of benzaldehyde, butylamine (14.6 g) was added under an nitrogen atmosphere. After being stirred for 45 minutes at room temperature, the agitation was stopped and the reaction mixture was allowed to stand for at least 15 minutes. The lower aqueous layer was then separated from the reaction mixture. The upper layer was collected and dried over anhydrous magnesium sulfate to give 22.0 g of product. 1H NMR (300 Hz, CDCl3, ppm): 8.25 (1H, s), 7.69 (2H, m), 7.39 (3H, m), 3.60 (2H, t, J=7.0 Hz), 1.68 (2H, p, J=7.3 Hz), 1.39 (2H, hex. J=7.7 Hz), 0.94 (3H, t, J=7.3 Hz)).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:58][CH2:59][CH:60]([OH:65])[C:61]([F:64])([F:63])[F:62].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[F:2][C:3]1[C:4]([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:18]([C:22]([NH:58][CH2:59][CH:60]([OH:65])[C:61]([F:64])([F:63])[F:62])=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(OCc2ncccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: NCC(O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ncccc2F)c2nc(C)c(C(=O)NCC(O)C(F)(F)F)n2c1
Reaction time: 0.83 h

Procedure:
120 mg (0.34 mmol) of 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid hydrochloride from Example 121A, 169 mg (0.44 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) and 176 mg (1.37 mmol) of N,N-diisopropylethylamine were initially charged in 2.2 ml of DMF, the mixture was stirred for 50 min, 66 mg (0.51 mmol) of rac-3-amino-1,1,1-trifluoropropan-2-ol were then added and the mixture was stirred at RT for 1.5 h. A few drops of water and TFA were added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated, and dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue. The aqueous phase was extracted three times with dichloromethane, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 49 mg (32% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: ClCc1ccc(Cl)nc1
Product: CCNCc1ccc(Cl)nc1

Procedure:
Using 6-chloro-3-pyridylmethyl chloride and 70% aqueous ethylamine solution, the reaction according to Reference Example 11 was carried out to give the title compound as a brown oil.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][C:8]1([OH:19])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1)(C)(C)C.Cl.[OH-].[Na+].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>O1CCOCC1>[C:12]([N:10]1[CH2:9][C:8]([CH2:7][C:6]([OH:20])=[O:5])([OH:19])[CH2:11]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)CC1(O)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(O)(CC(=O)O)C1
Temperature: 70 °C
Yield: 94 %

Procedure:
To a stirring solution of tert-butyl-2-(N-Boc-3-hydroxy-azetidin-3-yl)-acetate (0.86 g, 2.99 mmol) in dioxane (18 mL) was added 3M HCl (5 mL), and the mixture was heated at 70° C. for 1 h. The reaction mixture was then cooled to 0° C. and it was basified with 2 M NaOH (8 mL), followed by addition of BOC2O (1.0 g, 4.6 mmol). The reaction mixture was allowed to warm to room temperature for 2 h, and was then concentrated to half its total volume on the rotary evaporator. Isopropanol (3 mL) and chloroform (12 mL) were then added and the mixture was cooled to 0° C. and slowly acidified to pH 3 with 1M HCl. The organic layer was then separated, dried over Na2SO4, and concentrated to dryness to yield 2-(N-Boc-3-hydroxy-azetidin-3-yl)-acetic acid (0.65 g, 2.81 mmol, 94.0% yield).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH2:41][CH3:42])=[C:36]([CH:39]=1)[CH:37]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:37][C:36]2[CH:39]=[C:32]([Br:31])[CH:33]=[CH:34][C:35]=2[O:40][CH2:41][CH3:42])[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CCOc1ccc(Br)cc1C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(Br)cc1CN1CCC(CNC(=O)CNC(=O)c2cc(F)c(F)cc2N)CC1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-bromo-2-ethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.030 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. for 13 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×3). Product was eluted off using 2 N NH3 in CH3OH (5 ml) and concentrated. To the resulting material were added dichloromethane (1 mL) and trifluoroacetic acid (TFA) (0.50 mL) and the solution was stirred at room temperature for 10 min. The reaction mixture was concentrated, and the residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL: and concentrated. Preparative TLC (SiO2, ethyl acetate/methanol=10/1) gave 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compound No. 2052) (10.2 mg, 38%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 539.2 (M++H, C24H29BrF2N4O3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].C(O)C.C[O-].[Na+].Br[CH2:17][C:18]([OH:20])=[O:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CBr
Reactant: Sc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=C(O)CSc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-dichlorothiophenol, 50.0 gm, was added to 50 ml of ethanol. 63.8 ml of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 3 hours. Afterwards, 20 ml of bromoacetic acid was added and the system then heated to reflux. The system was continued at reflux for 16 hours. The reaction was then stopped and the solvent removed by stripping. The resulting material was dissolved with basic aqueous solution water and then washed with methylene chloride. Concentrated HCl was next added to the aqueous solution to acidify it. The product was extracted with methylene chloride. The methylene chloride solution was stripped and triturated with hexane. The product was then filtered, washed with water and air dried to yield 55.3 gm of the 2,6-dichlorothiophenoxyacetic acid.