Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:11][C:10]2[C:9](=O)[NH:8][C:7]([NH2:13])=[N:6][C:5]=2[N:4]=1.P(Cl)(Cl)([Cl:18])=O>>[NH2:13][C:7]1[N:6]=[C:5]2[C:10]([NH:11][C:3]([C:2]([F:15])([F:14])[F:1])=[N:4]2)=[C:9]([Cl:18])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc(C(F)(F)F)[nH]c2c(=O)[nH]1
Product: Nc1nc(Cl)c2[nH]c(C(F)(F)F)nc2n1

Procedure:
A suspension of 8-trifluoromethylguanine (Pfleiderer and Shanshal, Liebigs Ann. Chem., 726, 201-215 (1969)) (2.0 g, 9.1 mmol) in phosphorous oxychloride (20 mL) was refluxed for 3 h. Excess phosphorous oxychloride was evaporated under reduced pressure. The resulting residue was mixed with ice-water (100 g), and the pH was adjusted to 3-4 with a concentrated aqueous NaOH solution. The resulting solution was mixed with MeOH (100 mL) and approximately half (i.e., 100 mL) of the aqueous methanol solution was loaded on a 3×80 cm Sephadex LH-20 column eluted with methanol/water (1:1) at 1 mL/min. Column eluent was continuously monitored at 280 nm and fractions (10 mL) were collected. The remainder of the reaction mixture in MeOH/H2O was chromatographed separately under identical conditions. The desired product eluted in fractions 73-85. Evaporation of solvent from the pooled fractions 73-85 from both chromatographic runs afforded analytically pure 2-amino-6-chloro-8-trifluoromethylpurine: yield, 0.94 g (43%); mp>225° C. dec.; UV (pH 1) 1max 245 nm (e=0.501×104), 314 (0.746×104); (pH 6.9) 270 (0.265×104), 315 (0.612×104); (pH 13) 272 (0.269×104), 314 (0.612×104); 1H NMR d 7.19 (s, 2 H, NH2, exchange with D2O), 14.25 (br s, 1 H, NH, exchanges with D2O); MS (EI) calcd. m/z for C6H3N5F335Cl 237.0029, found 237.0011; calcd. m/z for C6H3N5F337Cl 239.0000, found 238.9987; Anal. (C6H3N5F3C) C, H, N, F, Cl.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])([C:10]([OH:13])([CH3:12])[CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:22][O:23][C:24](OC)(OC)OC>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:9])[C:10]([CH3:12])([CH3:11])[O:13][C:22]([O:23][CH3:24])=[N:17][S:14]2(=[O:15])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(C)(O)C(C)(c1cccc(Br)c1)S(N)(=O)=O
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A suspension of 1.10 g of 2-(3-bromophenyl)-3-hydroxy-3-methylbutane-2-sulfonamide in 10 ml of tetramethoxymethane was admixed with 2 ml of acetic acid and stirred at 100° C. for 5 hours. After the removal of the solvent under reduced pressure, the crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (0.61 g) with a molecular weight of 362.2 g/mol (C13H16BrNO4S).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C@H:8]([C:12]([N:14]1[CH2:36][CH2:35][CH2:34][C@H:15]1[C:16]([NH:18][C@@H:19]([CH:31]([CH3:33])[CH3:32])[CH:20]([C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[OH:21])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10].[C:37]([O:41][C:42]([CH2:44][N:45]1[C:50](=[O:51])[CH:49]=[CH:48][N:47]([CH2:52][C:53](O)=[O:54])[C:46]1=[O:56])=[O:43])([CH3:40])([CH3:39])[CH3:38].Cl.N=C=N>O>[C:37]([O:41][C:42]([CH2:44][N:45]1[C:50](=[O:51])[CH:49]=[CH:48][N:47]([CH2:52][C:53]([NH:7][C@H:8]([C:12]([N:14]2[CH2:36][CH2:35][CH2:34][C@H:15]2[C:16]([NH:18][C@@H:19]([CH:31]([CH3:32])[CH3:33])[CH:20]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[OH:21])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:54])[C:46]1=[O:56])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)ccn(CC(=O)O)c1=O
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C)C(O)c1nc2ccccc2o1
Agent: Cl
Agent: N=C=N
Solvent: O
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Cn1ccc(=O)n(CC(=O)OC(C)(C)C)c1=O)C(C)C)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To pyridine (20 ml) containing L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-hydroxyethyl]-L-prolinamide (1.0 g) are added 2-(3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetic acid (0.7 g) obtained in Example 4 and 1-ethyl-3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 g), and the mixture is stirred at room temperature for 15 hours. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 1 mol/liter hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give the desired 2-(3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetyl-L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-hydroxyethyl]-L-prolinamide (1.5 g) as powders.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][NH:56][CH2:55]1>CN(C=O)C>[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][N:56]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:55]1
Reactant: Clc1ccccc1OC1CNC1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2ccccc2Cl)C1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 26.7 %

Procedure:
DIPEA (141 mg, 1.09 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (67 mg, 0.27 mmol) in DMF (3 mL) followed by HOBt (39 mg, 0.28 mmol) and EDCI (56 mg, 0.28 mmol). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (60 mg, 0.27 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Partitioning with cold water and ethyl acetate and concentration of the organic layer after drying over sodium sulfate afforded a residue which was purified by column chromatography (using silica gel 60-120 and 100% EtOAc as eluent) to afford 30 mg (26.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(2-chloro-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 411, 98.45%. 1H NMR (300 MHz, DMSO-d6): δ 8.34 (d, 1H), 8.28 (d, 1H), 8.12 (t, 1H), 7.72 (d, 1H), 7.44 (m, 3H), 7.38 (m, 1H), 7.26 (m, 1H), 6.8 (m, 1H), 6.7 (d, 1H), 5.1 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:15]([O-])=[O:16].[Na+].[OH-].[Na+]>O.ClCCl>[N:15]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(N=O)CC1

Procedure:
In a 500 mL round-bottomed flask, 6N aqueous HCl (30 mL) was cooled to −10° C., and tert-butyl piperazine-1-carboxylate (10 g) was added. Sodium nitrite (4.5 g) dissolved in 35 ml water was added slowly. NaOH (10 g in 20 mL water) was used to neutralize the solution. Dichloromethane (3×50 mL) was used to extract the product. After drying over Na2SO4 and filtration, the solution was concentrated. The crude product was added to a silica gel column (Analogix, SF65-400 g,) and purified by eluting with 0-30% ethyl acetate in hexane.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCC1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(C(NCC2CCCN2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
Pyrrolidin-2-ylmethylamine (527 mg) in dichloromethane (10 mL) was treated with triphenylmethyl chloride (1.47 g) and triethylamine (1.5 mL), stirred for 3 hours, treated with dichloromethane, washed with water, saturated NaHCO3, and water, and concentrated. The concentrate was flash chromatographed on silica gel with a gradient of 3%-10% methanol in 99:1 dichloromethane/triethylamine. 1H NMR (DMSO-d6) δ 7.4 (m, 6H), 7.3 (m, 6H), 7.2 (m, 3H), 3.2 (m, 1H), 2.8-2.5 (m, 2H), 2.0 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H), 1.5 (m, 2H), 1.2 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.C1C[O:15]CC1>O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([OH:10])=[O:15])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Reactant: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of the 2,4-dichloropyrimidine-5-carbonyl chloride (24 mmol) in THF (24 mL) is added H2O (0.64 mL) at room temperature. The reaction mixture is stirred at room temperature for 0.83 h and then diluted with H2O. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude titled compound; 1H NMR (CDCl3) δ 6.80 (brs, 1H), 9.18 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].Br[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C@H:21]2[CH2:25][CH2:24][C@:23]3([CH2:29][CH2:28][N:27]([CH3:30])[C:26]3=[O:31])[N:22]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:16]=1[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C@H:21]3[CH2:25][CH2:24][C@:23]4([CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[N:22]3[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:16]=2[CH3:39])[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: Cc1c(Br)ccnc1[C@H]1CC[C@]2(CCN(C)C2=O)N1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(F)c(-c2ccnc([C@H]3CC[C@]4(CCN(C)C4=O)N3C(=O)OC(C)(C)C)c2C)c1
Temperature: 140 °C
Yield: 28.9 %

Procedure:
To a microwave vial containing a solution of (5-ethoxy-2-fluoro-phenyl)boronic acid (121.99 mg, 0.6600 mmol) in MeCN (3 mL) and water (0.6000 mL) was added tert-butyl (2R,5R)-2-(4-bromo-3-methyl-2-pyridyl)-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (which may be prepared as described in Description 98) (225.1 mg, 0.5300 mmol), sodium carbonate (112.41 mg, 1.06 mmol) and bis(triphenyl-phosphine)palladium (II) dichloride (18.39 mg, 0.0300 mmol). The microwave vial was sealed and heated at 140° C. for 20 minutes. The reaction was concentrated in vacuo, and the residue was purified on silica (25 g, SNAP cartridge), eluting with EtOAc in isohexane from 0% to 100%. Fractions containing desired product were combined and concentrated in vacuo to give tert-butyl (2R,5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-3-methyl-2-pyridyl]-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D100) (74.2 mg, 0.1534 mmol, 28.9% yield) as a colourless oil;
Reaction SMILES: [CH3:1][C:2]1[S:22][C:5]2[NH:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH:25](Br)([CH3:27])[CH3:26].O>CN(C)C=O>[CH3:1][C:2]1[S:22][C:5]2[N:6]([CH:25]([CH3:27])[CH3:26])[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(s1)N(C(C)C)c1ccccc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (3.12 g) in dry dimethylformamide (50 ml) was added sodium hydride (0.63 g, 50% dispersion). The reaction mixture was stirred for 30 minutes at room temperature, then 30 minutes at 60-70° C. The reaction was cooled to 40° C., isopropyl bromide (1.13 ml) added and left for one hour. Water was added and the reaction extracted with ethyl acetate, washed with water, dried and evaporated under reduced pressure. Chromatography using 2% methanol/dichloromethane and flash silica gave the title compound, m.p. 120-121° C. Similarly prepared from the same starting material were:
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=2)[CH2:5][CH2:4]1)=O.[N:22]([C:24]1[C:25]([NH2:32])=[N:26][C:27]([NH2:31])=[N:28][C:29]=1[NH2:30])=O.C(OCC[O-])C.[Na+].[OH-].[Na+]>C(OCCO)C.CCOCC>[N:6]1([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]3[N:22]=[C:24]4[C:25](=[N:32][C:18]=3[NH2:19])[N:26]=[C:27]([NH2:31])[N:28]=[C:29]4[NH2:30])=[CH:20][CH:21]=2)[CH2:5][CH2:4][NH:3][CH2:8][CH2:7]1
Reactant: N#CCc1ccc(NCCCN2CCN(C=O)CC2)cc1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: CCOCC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCCO
Solvent: CCOCC
Product: Nc1nc(N)c2nc(-c3ccc(NCCCN4CCNCC4)cc3)c(N)nc2n1
Reaction time: 2.5 h
Yield: 64.8 %

Procedure:
A mixture of 4-[3-(4-formyl-1-piperazinyl)propylamino]benzylcyanide (1.15 g, 4.0 mmol), 5-nitroso-2,4,6-triamino-pyrimidine (0.56 g, 3.6 mmol) and 0.2N sodium-(2-ethoxy-ethoxide) in 2-ethoxyethanol (18 ml) was stirred under reflux for 3 hours, then NaOH (0.14 g, 3.5 mmol) was added and stirring under reflux was continued for further 2.5 hours. After cooling the mixture was diluted with 100 ml of ether. The separated precipitate was collected, washed with ether, then with water and dried to afford the title compound (0.92 g) as a yellow powder, yield: 64.8%. The above product was dissolved in a hot solution of L(+)-tartaric. acid (0.75 g, 5 mmol) in water (6 ml) and after cooling the mixture was diluted with methanol (6 ml). The separated crystals were collected, washed with methanol and dried to give the ditartrate of the title compound, mp. 170°-178° C. Yield of the salt formation: 51.9%.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[OH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:22](=[O:23])[CH:21]([OH:20])[C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: O=C(O)C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(C(O)c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 54F (0.05 g, 0.168 mmol) and 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (0.035 g, 0.160 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.070 g, 0.185 mmol) and N-methylmorpholine (0.056 mL, 0.505 mmol). The resulting mixture was stirred at room temperature for 90 minutes and was then partitioned between water and ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane. The title compound was obtained as a colorless solid (73 mg, 94%). 1H NMR (300 MHz, CDCl3) δ ppm 0.87-0.99 (m, 4 H) 1.23-3.25 (m, 9H) 3.48-3.73 (m, 2 H) 4.57-4.84 (m, 2 H) 5.20-5.37 (m, 2 H) 7.45-7.64 (m, 4 H) 7.87-8.05 (m, 2 H); MS (ESI) m/z 463 (M+H)+.
Reaction SMILES: [BH3-]C#N.[Na+].C(OC([NH:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:20])=[O:16])=O)(C)(C)C.[CH2:35]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH3:48])[CH:41]=O)[CH3:36].CO>C(O)(=O)C>[NH2:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:41][C:40]2[CH:43]=[CH:44][C:45]([O:46][CH2:47][CH3:48])=[C:38]([O:37][CH2:35][CH3:36])[CH:39]=2)[CH2:27][CH2:28]1)=[O:20])=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: CCOc1ccc(C=O)cc1OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1OCC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
NaBH3CN (0.25 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 3,4-diethoxybenzaldehyde (0.15 mol), methanol (1.2 mL) and acetic acid (0.050 mL), and the obtained mixture was stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. Dichloromethane (2 mL) and phenyl isocyanate (0.10 mL) were added to the obtained residue, and the resulting mixture was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (5 mL). The obtained product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL); and a 4 M dioxane solution of HCl (0.125 mL) was added to the resulting solution. The obtained mixture was stirred at room temperature overnight and concentrated. The resulting residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3,4-diethoxybenzyl)piperidine (Compd. No. 2065) (21.2 mg, 84%). The purity was determined by RPLC/MS (97%). ESI/MS m/e 505.2 (M++H, C26H34F2N4O4).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1OCOCC[Si](C)(C)C)CCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 5-hydroxy-6-methoxy-indan-1-one (21.1 g, 0.118 mol, see preparation in J. Org. Chem. 57, 1992, 589-594) and N,N-diisopropylethylamine (21.6 mL, 0.124 mol) in CH2Cl2 (200 mL) was added SEMCl (21.3 mL, 0.121 mol). The mixture was stirred at room temperature for 2 hours and diluted with NaHCO3 solution. After separation, the organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc/hexane (3:7 to 1:1) to give 26.3 g (72%) of the desired product as brown oil. MS (ESI) m/z: 309.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm −0.01 (s, 9H) 0.96 (t, J=8.25 Hz, 2H) 2.66 (t, J=5.70 Hz, 2H) 3.03 (t, J=5.70 Hz, 2H) 3.80 (t, J=8.25 Hz, 2H) 3.90 (s, 3H) 5.36 (s, 2H) H) 7.20 (s, 1H) 7.22 (s, 1H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=1.[CH:19]1([C:22]#[N:23])[CH2:21][CH2:20]1.C1(C)C=CC=CC=1>O>[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)[CH:13]=1
Reactant: N#CC1CC1
Reactant: Fc1cc(Br)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2cc(Br)ccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
LiHMDS (1M in toluene, 17.6 mL, 17.6 mmol, 3.1 eq) is added dropwise to a cold (−5° C.) mixture of 4-bromo-2-fluoro-pyridine [Marsais, F. et al, Journal of Organic Chemistry, (1992), 57, 565-573] (1 g, 5.7 mmol), cyclopropanecarbonitrile (1.25 mL, 17 mmol, 3 eq), 4 Å molecular sieves and toluene (20 mL). The reaction mixture is allowed to warm to rt, stirred for 16 h, poured into H2O and filtered. The filtrate is diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 9:1), to afford 620 mg of the title compound as a white solid: ESI-MS: 223.1/225.1 [M+H]+; tR=4.22 min (System 1); TLC: Rf=0.25 (Hex/EtOAc, 9:1).
Reaction SMILES: [N+](=[CH:3]P(=O)(OC)OC)=[N-].CC(C)([O-])C.[K+].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:25]=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:28]1([CH2:27][C@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[C:25]#[CH:3])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COP(=O)(C=[N+]=[N-])OC
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a solution of dimethyl diazomethylphosphonate (0.60 g, 4.0 mmol) (prepared as described by Brown, D. et al., J. Org. Chem. 1996, 61(7), 2540-1 which is hereby incorporated by reference in its entirety and for all purposes as if specifically set forth herein) in 20 mL of THF at −78° C. was added potassium tert-butoxide (4.0 mL, 4.0 mmol). The mixture was stirred for 15 minutes and (S)-(−)-2-(tert-butoxycarbonylamino)-3-phenylpropanal (0.50 g, 2.0 mmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-015684)), was added in 2 mL of THF. The mixture was stirred for 10 minutes and then warmed to −35° C. and stirred for 1 hour. The reaction was then quenched with 10 mL of aqueous NH4Cl and stirred for 15 minutes. The biphasic mixture was diluted with 10 mL of water and partitioned in a separatory funnel. The aqueous portion was then extracted three times with 10 mL of EtOAc. The combined organic layers were washed with 25 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (2.5% to 20% EtOAc/hexanes) afforded (S)-tert-butyl 1-phenylbut-3-yn-2-ylcarbamate (0.18 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.23 (m, 5H), 4.81-4.75 (m, 1H), 4.40-4.29 (m, 2H), 3.16 (dd, J=5.3 Hz, 14.2 Hz, 1H), 3.03 (dd, J=9.2 Hz, 5.1 Hz, 1H), 1.42 (s, 9H).