Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:30][CH2:31][C@H:32]1[O:38][CH:35]([O:36][CH3:37])[CH2:34][C@@H:33]1[OH:39])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>O1CCCC1>[CH2:3]([O:39][C@@H:33]1[C@@H:32]([CH2:31][O:30][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:38][CH:35]([O:36][CH3:37])[CH2:34]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC1C[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC1C[C@H](OCc2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 1.3 g (0.054 mole) of sodium hydride, 10.8 g (7.5 ml, 0.063 mole) of benzyl bromide and 50 ml dry tetrahydrofuran or other aprotic solvent under a dry nitrogen atmosphere were added slowly a solution of 14.8 g (0.038 mole) of crude methyl 2-deoxy-5-O-tritylribofuranoside in 100 ml of dry tetrahydrofuran. After the addition was completed (0.5 hr), the mixture was stirred at ambient temperature for 4 hrs., then at 65°-70° C. for an additional 2 hrs. The mixture was cooled, vacuum filtered through filter-aid, then heated at reflux for 2 hrs. with 15 ml (0.2 mole) of pyridine to consume the excess benzyl bromide. The mixture was again cooled and vacuum filtered through filter-aid. The solvent was removed from the filtrate under reduced pressure. Toluene (2×150 ml) was then added and evaporated. The residue (24.3 g.) was taken up in ethyl acetate (200 ml), washed with saturated NaCl solution (150 ml), then with DI water (150 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated under vacuum. The red-orange oil that remained was used directly in subsequent coupling reactions. An analytical sample was prepared by chromatography on silica gel eluting with 10% ethyl acetate in hexane. The light-yellow oil thus prepared showed the following: 1H NMR (CDCl3) δ2.05 (m, 2, CH2), 3.18 (s, 3, OCH3), 3.33 (s, 2, CH2), 3.6 to 4.4 (m, 2, OCH), 4.42 (d, 2, CH2), 4.9 to 5.1 (m, 1, anomeric CH), 7.1 to 7.7 (m, 20, ArH); IR (neat) 3090 cm-1 (w), 3060 (m), 3035 (m), 2920 (m), 1598 (w), 1490 (m), 1448 (s), 1362 (m), 1080 (s), 762 (m), 748 (m), 705 (s), 633 (m).
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.[CH3:46][O:47][C:48]([C:50]1[O:51]C2C=CC(N)=CC=2[CH:54]=1)=[O:49]>>[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]5[O:51][C:50]([C:48]([O:47][CH3:46])=[O:49])=[CH:54][C:22]=5[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: COC(=O)c1cc2cc(N)ccc2o1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2o1

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 2-methoxycarbonyl-5-aminobenzofuran were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.68 (bs, 1H), 8.13-8.10 (m, 2H), 7.63-7.54 (m, 3H), 7.27 (bs, 1H), 7.10 (d, 1H, J=8.7 Hz), 6.80 (d, 1H, J=8.1 Hz), 4.21 (s, 4H), 3.88 (s, 3H); LCMS: ret. time: 23.22 min.; purity: 95%; MS (m/e): 437 (MH+).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Cl:23])=[CH:21][CH:22]=1.[CH3:35][C:36]([O:39][C:40]([N:42]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:43]1[NH:44][C:45]([C:49](O)=[O:50])=[C:46]([Br:48])[N:47]=1)=[O:41])([CH3:38])[CH3:37].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:58][C:55]([O:54][C:52]([N:42]([C:43]1[NH:44][C:45]([C:49]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:18]=2[F:34])=[O:50])=[C:46]([Br:48])[N:47]=1)[C:40]([O:39][C:36]([CH3:35])([CH3:37])[CH3:38])=[O:41])=[O:53])([CH3:56])[CH3:57]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)O)[nH]1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
EDC (0.022 g, 0.116 mmol) and HOBT (0.016 g, 0.116 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.033 g, 0.106 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-bromo-1H-imidazole-5-carboxylic acid (0.043 g, 0.106 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. Saturated sodium bicarbonate was added and the reaction mixture was extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. Chromatography (MeOH:dichloromethane) gave the desired product (0.030 g, 34%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.B>>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N:14]1[CH2:15][CH2:16][S:17](=[O:21])(=[O:20])[CH2:18][CH2:19]1
Reactant: CCOc1cc(C(=O)O)cc(N2CCS(=O)(=O)CC2)c1Cl
Agent: B
Product: CCOc1cc(CO)cc(N2CCS(=O)(=O)CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-5-ethoxy-benzoic acid (0.17 g, 0.51 mmol, 1.0 equiv) was added borane (1.02 mL, 1.02 mmol, 2.0 equiv; 1 M solution in THF) and the reaction mixture stirred at rt overnight. The reaction was quenched by addition of a few drops of methanol, ethyl acetate was added (50 mL) and the organic phase washed with a 1 M solution of NaOH (3×20 mL). The organic phase was dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material used in the next step without further purification. Yield: 0.089 g (58%). 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.0 Hz, 3H), 3.13-3.16 (m, 4H), 3.42-3.45 (m, 4H), 4.04 (q, J=7.0 Hz, 2H), 4.56 (s, 2H), 6.64 (br s, 1H), 6.67 (br s, 1H).
Reaction SMILES: [Mg].[CH2:2]([N:4]([CH2:9]C)[CH2:5][CH2:6][CH2:7]Cl)C.BrC(Br)C.[CH3:15][N:16]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:21]=2[N:20]=[CH:19][C:18]2=[CH:27][CH:28]=[CH:29][N:17]12.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:2][N:4]([CH2:5][CH2:6][CH2:7][C:19]1[C:18]2[N:17]([CH:29]=[CH:28][CH:27]=2)[N:16]([CH3:15])[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:21]=2[N:20]=1)[CH3:9]
Reactant: CCN(CC)CCCCl
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCCC1=Nc2cnccc2N(C)n2cccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To magnesium turnings (1.9 g) in 10 ml of diethyl ether and 10 ml of tetrahydrofuran, was added a solution of 11.66 g of 3-diethylaminopropyl chloride in 10 ml of tetrahydrofuran. The reaction was initiated by the addition of 1 ml of dibromoethane and the application of heat. After stirring at 70° C. for four hours, the reaction mixture cooled to room temperature and treated, dropwise, with a solution of 7.7 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 50 ml of tetrahydrofuran. The mixture was then stirred at room temperature for two hours, poured into an iced ammonium chloride solution, and extracted with ethyl acetate (3×). The combined extracts were washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. High pressure liquid chromatography of the concentrate (silica gel; elution with 15% methanol/dichloromethane) afforded 10-[3-(N,N-dimethylamino)propyl]-5-methyl-5H-pyrido[3,4-f]pyrrolo-[1,2-b] [1,2,5]triazepine as an oil. The oil was dissolved in ethanol and acidified with an ethanol solution of fumaric acid. Diluting with diethyl ether precipitated 3.05 g of the corresponding sesquifumarate salt, mp 170°-172° C.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)C.C[O-].[Na+].[CH3:20][N:21]([CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([NH:29][NH2:30])=O)[CH3:22].Cl.CC(O)C>C(O)C.CCOCC>[ClH:1].[CH3:20][N:21]([CH3:22])[CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:26]([C:27]2[N:16]=[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=3)[NH:30][N:29]=2)[CH:25]=1
Reactant: CCOC(=N)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)Cc1cccc(C(=O)NN)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Solvent: CCOCC
Product: CN(C)Cc1cccc(-c2n[nH]c(-c3ccc(C(F)(F)F)cc3)n2)c1
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
To an ethanolic suspension of 4-trifluoromethyl-benzimidic acid ethyl ester hydrochloride salt (761 mg, 3.0 mmol, 1.5 eq.) was added sodium methoxide (162 mg, 3 mmol) in ethanol (20 ml.) and the resulting mixture stirred for 30 min.at r.t. 3-dimethylaminomethyl-benzoic acid hydrazide (386 mg, 2.0 mmol) in ethanol was then added at 20° C., followed by heating to reflux for 16 hrs. Upon cooling, the product mixture was filtered, solvent was evaporated and the residue subjected to preparative reversed-phase HPLC purification using a YMC ODS-AQ column (20×50 mm) and a (0.1% trifluoroacetic acid) water-acetonitrile gradient (25 ml/min. flow rate). The pure fractions were concentrated and the product obtained was converted to the hydrochloride salt in ether by addition of excess 5N HCl/iPrOH solution (1 ml) followed by solvent evaporation and high vacuum drying to afford the title compound (79 mg, 0.21 mmol, 10% yield) as a white foam. MS: m/e=347.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][CH:8]([CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:42])[NH:7][C@@H:8]([CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:9]([N:11]1[CH2:12][CH2:13][C:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)([C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:15][CH2:16]1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc([N+](=O)[O-])cc2)(C(=O)NC2CCCCC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(N)cc2)(C(=O)NC2CCCCC2)CC1

Procedure:
To a solution of {2-[4-Cyclohexylcarbamoyl-4-(4-nitro-benzyl)-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (9.77 mmol; 5.85 g) (prepared as in Example 1, substituting 4-nitrobenzylbromide for 4-biphenylmethyl bromide and cyclohexylamine for cyclohexylmethylamine), in tetrahydrofuran (20 mL) and ethanol (40 mL) was added 10% palladium on carbon (2 g), and the resulting mixture was hydrogenated under 50 psi of hydrogen pressure overnight at room temperature. The catalyst was removed via filtration, and the filtrate was evaporated to yield (S)-{2-[4-(4-aminobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester. MS (ESI) m/z 569.40 [M+H]+.
Reaction SMILES: [Br:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](=O)[CH3:13].N1CCCCC1>C(Cl)Cl>[CH:12](=[C:4]([C:3](=[O:10])[CH:2]([Br:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)C(C)Br
Reactant: CC=O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC=C(C(=O)OCC)C(=O)C(C)Br

Procedure:
A solution of 100 g (0.45 mol) of ethyl 4-bromo-3-oxovalerate in 100 ml of absolute methylene chloride is cooled to -20° C. under nitrogen, and 50 g (1.12 mol) of acetaldehyde are added. 1 g of piperidine, dissolved in 10 ml of methylene chloride, is then added dropwise at -20° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>C1COCC1.CCOC(C)=O>[CH:11]([C@@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@@H:7]([C@H:25]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)[OH:26])[C:6]([O:9][CH3:10])=[N:5]1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 22.1 %

Procedure:
To a mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (5.2 mL, 29 mmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-054672)) and THF (50 mL) at −78° C. was added n-butyllithium (2.5 M solution in hexane, 12 mL, 31 mmol). The mixture was stirred for 15 minutes. The colorless solution turned light brown. A solution of 4-(trifluoromethyl)benzaldehyde (5.1 mL, 38 mmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B4-3644)) in THF (50 mL) was added dropwise through a dropping funnel at −78° C. The mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc and washed with a mixed solution of aqueous Na2HPO4 and KH2PO4 solution (pH=8). The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was separated into two isomers by silica gel chromatography: 0-2%-10% CH3CN—CH2Cl2. The product was obtained as light yellow oil (2.3 g, 22%). LCMS (API-ES) m/z: 359 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[NH:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:2][N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])#[N:7]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: N#Cc1cccc(CCl)c1
Product: CC(C)(C)OC(=O)N(Cc1cccc(C#N)c1)C(=O)OC(C)(C)C

Procedure:
) 3-(Chloromethyl)benzonitrile (30 g; 197.9 mmol) and di-tert-butyl iminodicarboxylate were reacted in analogy to Lila et al., Synth. Comm. 28, 23, 1998, 4419, to give di(tert-butyl) 3-cyanobenzylimidodicarbonate. 65 g of a reddish oil were obtained and were employed without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=S)=[CH:25][CH:24]=1.C(N=C=NC(C)C)(C)C>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[NH:15][C:11]3=[N:10][C:9]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[CH:13]=[C:12]3[N:14]=2)=[CH:25][CH:24]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: Fc1cnccc1-c1cc2nc(Nc3ccc(Cl)cc3)[nH]c2nc1-c1cccnc1
Temperature: 50 °C
Yield: 46.9 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.050 g, 0.179 mmol) and 1-chloro-4-isothiocyanatobenzene (0.045 g, 0.267 mmol) in ethanol (1 mL), 1,3-diisopropylcarbodiimide (0.042 mL, 0.267 mmol) was added. The mixture was heated at 50° C. for 2 h. After cooling at room temperature, the solid precipitated was filtered off to give the title compound (0.035 g, 47% of yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:39]3[CH:38]=[CH:37][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:41][CH:40]=3)(=[O:44])=[O:43])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(S(C)(=O)=O)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-(methylsulfonyl)benzenesulfonamide: 1H-NMR (CDCl3) δ 8.16-8.08 (4H, m), 7.47-7.20 (9H, m), 6.04 (1H, br.s), 3.46-3.41 (2H, m), 3.10 (3H, s), 2.87-2.82 (2H, m), 2.33 (3H, s), 2.22 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:14]([O:16]CC)=[O:15])=[CH:7][N:6]=[C:5]2[N:23](COCC[Si](C)(C)C)[CH:24]=[CH:25][C:4]=12.C(O)(C(F)(F)F)=O.O[Li].O.Cl>C(Cl)Cl.C1COCC1.O.CO>[CH3:1][O:2][C:3]1[C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:14]([OH:16])=[O:15])=[CH:7][N:6]=[C:5]2[NH:23][CH:24]=[CH:25][C:4]=12
Reactant: CCOC(=O)c1ccc(C)c(/C=C/c2cnc3c(ccn3COCC[Si](C)(C)C)c2OC)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(/C=C/c2cc(C(=O)O)ccc2C)cnc2[nH]ccc12
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of (E)-ethyl 3-(2-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzoate (298 mg, 0.64 mmol) in CH2Cl2 (2 mL) was added TFA (0.24 mL, 3.19 mmol). The reaction mixture was stirred for 1 hour and the organic solvent was concentrated under reduced pressure. To a solution of the resulting mixture in THF (2 mL) and MeOH (2 mL) was added LiOH.H2O (535 mg, 0.42 mmol) in water (2 mL). The reaction mixture was stirred for 8 hours at room temperature. To a reaction mixture was added 1N HCl solution to produce solid. The solid product was filtered and dried with nitrogen gas flow. The title product (128 mg, 65% yield) was used without further purification. MS m/z: 309 [M+1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P:18](=[N:31][C:32](N1C=CN=C1)=[O:33])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P:18](=[N:31][C:32](=[O:33])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1cccnc1
Reactant: Cc1ccccc1P(=NC(=O)n1ccnc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1P(=NC(=O)OCc1cccnc1)(c1ccccc1)c1ccccc1

Procedure:
A 760 mg portion of 3-pyridinemethanol, 35 ml of 1,2-dimethoxyethane, 340 mg of 50% sodium hydride in oil and 2.7 g of 1-[[[(2-methylphenyl)diphenylphosphoranylidene]amino]carbonyl]-1H-imidazole were reacted as described in Example 8, giving 2.05 g of the desired product, mp 142°-143° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][CH:12]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl>CCOCC.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:3]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][CH:12]([CH:18]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[OH:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)C)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(C)(C)C)cc1)C(O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a suspension (80 ml) of zinc chloride (6.59 g, 48.3 mol) in ether was added sodium borohydride (3.66 g, 96.6 mol) at room temperature and the mixture was stirred as it as for 2 hrs. A solution of ethyl 2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (8.61 g, 24.15 mmol) in ether (40 ml) was added, and the mixture was stirred at room temperature for 15 min. The reaction was stopped with 1N hydrochloric acid, and the reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1, 5:1) to give ethyl (2RS,3RS)-2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate (8.00 g, 92%) as a colorless transparent oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:16])[C:14]#[CH:15])[CH2:9]1)=O)(C)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:50][C:51]1[C:56]([Cl:57])=[CH:55][CH:54]=[C:53]([Cl:58])[C:52]=1O.C1(O)C=CC=CC=1.Cl.CCO>C1(C)C=CC=CC=1>[Cl:50][C:51]1[C:56]([Cl:57])=[CH:55][CH:54]=[C:53]([Cl:58])[C:52]=1[O:16][CH:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:14]#[CH:15]
Reactant: C#CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Oc1c(Cl)ccc(Cl)c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1
Product: C#CC(Oc1c(Cl)ccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-3-(1-hydroxyprop-2-ynyl)pyrrolidine-1-carboxylic acid t-butyl ester (21.0 mg, 93.2 μmmol) and DIAD (22.0 μL, 112 μmmol) was dissolved in toluene (65 μL, 610 μmmol) at room temperature. PPh3 (29.3 mg, 112 μmmol) and 2,3,6-trichlorophenol (20.2 mg, 102 μmmol) were dissolved in toluene (0.1 mL, 1 mmol) and heated at 100° C. The t-butyl ester mixture was slowly added into the phenol mixture at 100° C., and stirred for 1 hour. The mixture was then removed from the heat and stirred at room temperature overnight. The mixture was then concentrated and the resulting residue was treated with 1.25M HCl in EtOH (0.6 mL, 0.8 mmol) at room temperature overnight. The mixture was concentrated and the residue was redissolved in a mixture of 50% AcOH/H2O (1.4 mL) and MeCN (0.2 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (21.2 mg, 99% purity). MS m/z: [M+H]+ calcd for C13H12Cl3NO, 304.00; found 304.0.