Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[NH:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([S:22][C:23]3[CH:24]=[C:25]([C:29]4([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[N:11]=1>>[CH3:3][N:4](/[CH:6]=[N:37]/[C:35]([C:29]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([S:22][C:19]3[CH:18]=[CH:17][C:16]([N:12]4[C:13](=[O:15])[NH:14][C:10]([CH3:9])=[N:11]4)=[CH:21][CH:20]=3)[CH:24]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:36])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C(N)=O)CCOCC4)c3)cc2)c(=O)[nH]1
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)/N=C/N(C)C)CCOCC4)c3)cc2)c(=O)[nH]1

Procedure:
N,N-Dimethylformamide dimethyl acetal (15 mL) was added to 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxamide (2.0 g, 4.88 mmol) (example 10) and the reaction mixture was refluxed for about 2 hours. The solvent was evaporated under reduced pressure to obtain a light brown paste. Yield: 3.0 g.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]2[C:12]([C:13](OC3CCCC3)=[O:14])=[C:11]([CH:21]([CH3:23])[CH3:22])[O:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH:1]1([O:6][CH2:7][C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH:21]([CH3:23])[CH3:22])[O:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)c1onc(COC2CCCC2)c1C(=O)OC1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1onc(COC2CCCC2)c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A solution of cyclopentyl 3-[(cyclopentyloxy)methyl]-5-(1-methylethyl) -4-isoxazolecarboxylate (0.093 g, 0.29 mmol) in THF (2.8 mL) was stirred in an ice bath as a 1.5M solution of diisobutylaluminum hydride in toluene (0.42 mL, 0.63 mmol) was added dropwise. The solution was allowed to stir at room temperature for 2 hours. The solution was cooled to 0° C. before an additional portion of diisobutylaluminum hydride (0.42 mL, 0.63 mmol) was added and the solution was allowed to stir at room temperature for one hour. A 10% aqueous solution of Rochelle's salt (30 mL) was added and the solution was allowed to stir for 20 hours. The solution was extracted with ethyl acetate and the organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 1:1 ethyl acetate:hexanes) to provide [3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.051 g, 74%). 1H NMR (400 MHz, DMSO-d6): δ 4.82 (t, J=5 Hz, 1H), 4.42 (s, 2H), 4.30 (d, J=5 Hz, 2H), 3.95 (m, 1H) 3.24 (septet, J=7 Hz, overlapping H2O), 1.64-1.55 (m, 6H), 1.46 (m, 2H), 1.21 (d, J=7 Hz, 6H).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][C@@H:53]3[CH2:55][C@H:54]3[C:56]([O:58]CC)=[O:57])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[C:35]([O:34][C:32]([N:9]1[CH2:10][CH2:11][C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[Cl:31])=[CH:15][CH:14]=2)[C@@H:7]([C:5]([N:4]([CH2:39][C:40]2[CH:41]=[C:42]([CH:43]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:45]=2)[O:51][CH2:52][C@@H:53]2[CH2:55][C@H:54]2[C:56]([OH:58])=[O:57])[CH:1]2[CH2:2][CH2:3]2)=[O:6])[CH2:8]1)=[O:33])([CH3:37])([CH3:36])[CH3:38]
Reactant: CCOC(=O)[C@@H]1C[C@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-{[(1R,2R)-2-(ethoxy-carbonyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 3 in ethanol (0.1 M) was added 1 M aqueous NaOH (3 eq.). The reaction was heated at 100° C. in a microwave (Biotage) for 5 min. The reaction was cooled to rt and concentrated in vacuo. The residue was suspended in 1 N aqueous HCl and EtOAc. The aqueous layer was extracted several times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as a foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]2=[N:8][CH:7]=1)=[O:5])C.O[Li].O.Cl.[Na+].[Cl-]>C1COCC1.CO.O>[F:18][C:15]([F:16])([F:17])[C:14]1[C:9]2[N:10]([C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:13]=1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Agent: Cl
Agent: [Cl-]
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a solution of the above 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (3.06 g, 7.61 mmol) in THF (45 mL), MeOH (5 mL) and water (11.3 mL) at 23° C. was added LiOH·H2O (479 mg, 11.41 mmol) and the mixture was stirred at 23° C. for 3 h. Poured into icewater, adjusted pH with 1 N HCl (about 11.41 mL) to pH 2-3, saturated with solid NaCl, extracted with EtOAc, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a light brown solid (2.87 g, 101%). MS (ISN) 373 [(M−H)−]; mp 248° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][NH:16][C:12]=3[C:11](=[O:17])[NH:10][C:9]2=[S:18])[CH2:2]1.[CH:19](O)=O.[BH3-]C#N.[Na+]>CO>[CH3:19][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][NH:16][C:12]=3[C:11](=[O:17])[NH:10][C:9]2=[S:18])[CH2:2]1
Reactant: O=CO
Reactant: O=c1[nH]c(=S)n(CC2CCCNC2)c2cc[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCCC(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
1-Piperidin-3-ylmethyl-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one (Example 7) (0.092 g, 0.35 mmol) was dissolved in methanol (2 mL) and formic acid (37% aq., 0.059 mL, 0.7 mmol) was added. After 5 minutes of stirring at r.t. a precipitate had formed. NaCNBH3 (0.026 g, 0.42 mmol) was added and the mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo and the residual solid was purified by preparative HPLC, obtaining the title compound (0.022 g, 22%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:14]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:24](N(OC)C)=[O:25])[C:13]([C:30]#[N:31])=[C:12]([CH3:32])[NH:11][C:10]=1[CH3:33])#[N:8]>C1COCC1>[CH:24]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH:14]3[C:13]([C:30]#[N:31])=[C:12]([CH3:32])[NH:11][C:10]([CH3:33])=[C:9]3[C:7]#[N:8])[CH:16]=2)[NH:20][N:19]=1)=[O:25]
Reactant: CON(C)C(=O)c1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C=O)c3c2)C(C#N)=C(C)N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Lithium aluminum hydride (45 mg, 1.2 mmol) was added portion-wise to a cooled solution of 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-N-methoxy-N-methyl-1H-indazole-3-carboxamide (340 mg, 0.94 mmol) in THF (20 mL). After 30 min, the mixture was heated up to 60° C. After 2 hr, the reaction was quenched by the slow addition of ethyl acetate at 5° C. and 0.4 N NaHSO4. The organic layer was washed with brine, dried with Na2SO4, and concentrated. The crude product was purified by column to give 4-(3-formyl-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (200 mg, 70%) (Cpd. No. 145, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=10.18 (s, 1H), 9.58 (s, 1H), 7.98 (d, 1H), 7.76 (d, 1H), 7.46 (d, 1H), 4.65 (s, 1H), 2.03 (s, 6H) ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:17]([C:26]([O:28][CH2:29][CH:30]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C@H:18]([C:23](O)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.C1C=CC2N(O)N=NC=2C=1>[NH:17]([C:26]([O:28][CH2:29][CH:30]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C@H:18]([C:23]([NH:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
The obtained wet crystals of Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in chloroform (13 mL), Fmoc-Leu-OH (373 mg, 1.06 mmol) and HOBt (14.3 mg, 106 μmol) were added at room temperature, and EDC.HCl (223 mg, 1.16 mmol) was further added under ice-cooling. The mixture was warmed to room temperature, stirred overnight, and concentrated under reduced pressure. Methanol (10 mL) was added to the residue, and the precipitate was collected by filtration to give Fmoc-Leu-Leu-OBzl (2-MeO-4-OC12OC22) (1.02 g, 93% yield relative to Bzl (2-MeO-4-OC12OC22)OH).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(CO)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
To a solution of 3-(piperidin-1-ylsulfonyl)benzoic acid (538 mg, 2.00 mmol) in dry THF (8 mL) under nitrogen was added a solution of borane-THF complex in dry THF (1.0 M, 8 mL, 8.00 mmol) and the mixture then stirred for 18 hours at room temperature. The reaction was then quenched by the addition of excess methanol and evaporated in vacuo. The residue was partitioned between ethyl acetate and 2N HCl, and the separated organic layer washed successively with water and saturated brine, before being dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified using automated flash column chromatography on silica gel (gradient of 0 to 60% ethyl acetate in petrol) to afford (3-(piperidin-1-ylsulfonyl)phenyl)methanol (320 mg, 1.25 mmol, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[C:8]2[C:16]([F:19])([F:18])[F:17].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C1COCC1>[CH2:24]([NH:26][C:27]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[C:8]2[C:16]([F:19])([F:17])[F:18])=[O:28])[CH3:25]
Reactant: Nc1ccccc1Cc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccccc1Cc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Temperature: 20 °C
Reaction time: 36 h
Yield: 62.2 %

Procedure:
A stirred THF (5 mL) solution of 6-(2-aminobenzyl)-4-trifluoromethyl-1H-quinolin-2-one (Preparation #2, 50 mg, 157 μmol) was treated dropwise with a solution of EtNCO (78 μL, 985 μmol) in anhydrous THF (1 mL) at 0° C. The reaction mixture was allowed to warm to 20° C., before being stirred for 36 h. The precipitate formed was collected, washed with THF, & dried to give the title compound (38 mg, 62%): δH ((CD3)2SO)=1.00 (t, 3H), 3.05 (q, 2H), 4.00 (s, 2H), 6.30 (t, 1H), 6.90–6.95 (m, 2H), 7.05 (d, 1H), 7.15 (t, 1H), 7.35 (d, 1H), 7.40 (d, 1H), 7.55 (s, 1H), 7.70–7.80 (m, 2H); m/z (ES+)=390.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C@@H:10](O)S([O-])(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[OH-].[Na+].Cl.[NH2:24][C@H:25]1[C:34]([CH2:37][CH3:38])([CH2:35][CH3:36])[C:33]2[CH:32]=[C:31]([OH:39])[CH:30]=[CH:29][C:28]=2[CH2:27][C@@H:26]1[O:40][CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC1OCCC1.CCOC(C)=O>[CH3:19][O:18][C:16](=[O:17])[C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][NH:24][C@@H:25]1[C@@H:26]([O:40][CH3:41])[CH2:27][C:28]2[C:33](=[CH:32][C:31]([OH:39])=[CH:30][CH:29]=2)[C:34]1([CH2:37][CH3:38])[CH2:35][CH3:36]
Reactant: COC(=O)C(CC1CCCCC1)C[C@@H](O)S(=O)(=O)[O-]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1NCC[C@H](CC1CCCCC1)C(=O)OC
Reaction time: 0.33 h
Yield: 101.9 %

Procedure:
To a slurry of sodium (S)-4-cyclohexyl-1-hydroxy-3-methoxycarbonyl-butane-1-sulfonate (158 mg, 0.5 mmol) in 2-MeTHF (2 mL) was added 2N NaOH (0.22 mL, 0.44 mmol). The reaction mixture was stirred for 20 min at which time all of the solids had dissolved. (6S,7S)-7-Amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ol hydrochloride (100 mg, 0.35 mmol) was added and the mixture was stirred at RT for 30 min. Sodium triacetoxyborohydride (425 mg, 2.0 mmol) was added in 4 portions over 3 h. Thirty minutes after the last addition, EtOAc (15 mL) was added and the mixture was washed with 5% aqueous sodium carbonate (2×5 mL) and saturated sodium chloride (5 mL). The organic layer was dried with Na2SO4 and concentrated to give the title compound (159 mg). (m/z): [M+H]+ calcd for C27H43NO4, 446.33. Found, 446.6.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][S:17][CH2:16][CH2:15]3)[N:11]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:10]2=[O:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][S:17][CH2:16][CH2:15]3)[N:11]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]2=[O:28])=[CH:5][C:4]=1[C:29]([F:30])([F:32])[F:31])#[N:2]
Reactant: CCOC(=O)CCCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C12CCSCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(N2C(=O)N(CCCC(=O)O)C3(CCSCC3)C2=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Using the procedure of Example 7, 440 mg of the product of Example 18, 20 ml of methanol and 2 ml of 2N sodium hydroxide were reacted and the mixture was stirred for 3 hours and 30 minutes at ambient temperature. 3 ml of 2N hydrochloric acid were added and purification was carried out on silica with methylene chloride-methanol: 95-5 as eluant to obtain 346 mg of the expected product (white crystals) melting at 197°-198° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].O=[CH:26][C@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28]>C(Cl)Cl.[Zn]>[Br:21][C:20]([Br:24])=[CH:28][C@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:26]
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](C=C(Br)Br)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of zinc (135 g, 2.08 mol), PPh3 (545 g, 2.08 mol) and CBr4 (682 g, 4.08 mol) in CH2Cl2 (2 L) was stirred at 0° C. for 1.5 hr. A solution of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (114 g, 0.66 mol) in DCM was added in one portion, and the reaction mixture was stirred at 0° C. for another 3 hr. The mixture was quickly passed though a silica gel, and the solvent was evaporated to give the crude (R)-tert-butyl 4,4-dibromobut-3-en-2-ylcarbamate. To a cooled (−78° C.) solution of the crude compound (R)-tert-butyl 4,4-dibromobut-3-en-2-ylcarbamate in THF (2 L) was added dropwise 2.5 M BuLi (0.75 L, 1.88 mol) under nitrogen. The reaction was quenched with water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over MgSO4, filtered and concentrated to give the crude compound N.2, (R)-tert-butyl but-3-yn-2-ylcarbamate, which was used without further purification. 1H NMR (CDCl3) δ 4.47 (br s, 1H), 2.24 (s, 1H), 1.49 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: C([O-])=O.[NH4+].[N+:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[NH:12]2)([O-])=O.C(#N)C>[Pd].CO>[NH2:5][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[NH:12]2
Reactant: COC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cc2c(N)cccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
Ammonium formate (63 g, 1.00 mol) was added cautiously to a suspension of the product of Example 2 (45.6 g, 0.207 mol) and 10% palladium on charcoal (5 g) in methanol (700 ml) under an argon blanket at 45° C. The mixture was stirred for 4 h, cooled to room temperature, and after 18 h filtered and evaporated in vacuo to give a dark brown semi-solid. This was taken up into acetonitrile (500 ml), filtered (to remove ammonium formate) and evaporated in vacuo to give a dark brown gum. Purification by column chromatography [silica; ethyl acetate-hexane (1:10 to 1:1)] gave the product (9.5 g) as a grey solid.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(F)cc1C(=O)OCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCc1ccc(F)cc1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-fluorobenzoate (1.19 g, 2.64 mmol) obtained from Example 8-(1) was reacted with anisole (1.5 g, 13.9 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-fluorobenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above was reacted with oxalyl chloride (1.68 g, 13.2 mmol) and N,N-dimethylformamide (15 μl), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-fluorobenzoyl chloride as a crude product.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20](OC)=[O:21])[CH:14]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:24]([OH:27])([CH3:26])[CH3:25]>>[Cl:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([O:27][CH:24]([CH3:26])[CH3:25])=[O:21])[CH:14]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)OC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A small piece of sodium was added to a solution of 4.0 g of 3-chloro-2-(4-chloro-3-methoxycarbonylphenyl)-5-trifluoromethylpyridine in 20 ml of anhydrous isopropanol, followed by stirring at 0° C. for 20 hours. The solvent was then removed. The residue was taken up in 50 ml of water. The aqueous phase was extracted three times with 50 ml of tert-butyl methyl ether each time. The combined organic phases were dried over sodium sulfate and concentrated. Yield: 2.5 g (58%) of a colorless oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl.Cl[CH2:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([CH:38]=1)=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][CH:33]=2>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:28][C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][CH:33]=3)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: COc1cccc2ncc(CCl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cnc2cccc(OC)c2c1)c1ccc(OC)c(OC)c1
Reaction time: 0.33 h
Yield: 35 %

Procedure:
To a solution of methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 (73 mg, 347 μmol) in dry THF (10 mL) at −66° C. in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added LiHMDS (1.0 N in TBME, 0.70 mL, 700 μmol) and the mixture was stirred for 20 min at that temperature. 3-(Chloromethyl)-5-methoxyquinoline hydrochloride CCH 34144B (84 mg, 344 μmol) was then added and the mixture was stirred for 2 h allowing the temperature to reach RT. The mixture was then quenched by carefully adding H2O (4 mL) and diluted with EtOAc (30 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (40 mL). Both organic phases were washed with brine (10 mL), then combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) provided methyl 2-(3,4-dimethoxyphenyl)-3-(5-methoxyquinolin-3-yl)propanoate 34144-5 as a pale yellow oil (46 mg, 35% yield).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[NH:24][S:23]3(=[O:29])=[O:28])=[C:18]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=2)[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH2:78]>CN(C=O)C>[NH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=1[NH:78][C:12](=[O:14])[C@@H:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25](=[O:27])[NH:24][S:23]2(=[O:28])=[O:29])=[C:18]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:17]=1
Reactant: O=C1CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)[C@H](Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-benzenesulfonylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid (110 mg, 0.2 mmol) in DMF (5 mL) is added diisopropylethylamine (0.038 mL, 0.22 mmol) and HATU (84 mg, 0.22 mmol). The mixture is stirred at RT for 10 min then a solution of 1,2-diaminobenzene (26 mg, 0.24 mmol) in DMF (1 mL) is added and stirring is continued for 48 h. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step