Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH2:7]([N:10]1[CH:14]=[C:13]([C:15](OC)=[O:16])[N:12]=[N:11]1)[CH2:8][CH3:9].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[OH:16][CH2:15][C:13]1[N:12]=[N:11][N:10]([CH2:7][CH2:8][CH3:9])[CH:14]=1
Reactant: CCCn1cc(C(=O)OC)nn1
Agent: O=S([O-])([O-])=S
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCn1cc(CO)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of aluminum lithium hydride (0.58 g) in THF (51.4 ml) was added dropwise a solution of methyl 1-propyl-1,2,3-triazole-4-carboxylate (2.6 g) in THF (26 ml) at 0° C. The mixture was stirred for 1 hour at room temperature, and an aqueous solution of saturated sodium thiosulfate was added to the mixture at 0° C. The mixture was filtered with Celite, and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-hydroxymethyl-1-propyl-1,2,3-triazole (1.9 g). To 4-hydroxymethyl-1-propyl-1,2,3-triazole (1.9 g) was added thionyl chloride (32 ml) at 0° C., and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, to give 4-chloromethyl-1-propyl-1,2,3-triazole (1.75 g).
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:27])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])=[N:13]2)=[O:8])[N:6]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>N1C=CC=CC=1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])[O:3][CH:4]=3)=[O:8])[CH3:27])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3coc(Br)n3)n2)ccc(C#N)c1Cl
Reactant: COCCN
Solvent: c1ccncc1
Product: COCCNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)co1
Temperature: 120 °C
Yield: 15.65 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide (0.180 g, 0.401 mmol) was added into a microwave vial with dry pyridine as a solvent. The mixture was bubbled with nitrogen. 2-Methoxyethylamine (0.129 ml, 2.407 mmol) was added and the mixture was heated with microwaves at 120° C. for 2 h. The product was purified by Flash-chromatography. Yield 15.65%. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 2.58 (s, 3H), 3.39 (s, 3H), 3.44 (t, 2H), 3.51 (t, 2H), 4.30 (dd, 1H), 4.40 (dd, 1H), 4.51-4.60 (m, 1H), 5.07 (t, 1H), 6.44 (d, 1H), 7.40 (d, 1H), 7.51 (d, 1H), 7.52-7.58 (m, 2H), 7.67 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[C:19]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=4[F:36])=[N:20][O:21][C:22]=3[CH:23]3[CH2:25][CH2:24]3)=[CH:12][C:11]=2[CH3:37])=[N:7][C:6]=1[CH3:38])=[O:4].[Li+].[OH-].Cl>CO.C1COCC1.O>[CH:23]1([C:22]2[O:21][N:20]=[C:19]([C:26]3[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:27]=3[F:36])[C:18]=2[CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:38])[N:7]=3)=[C:11]([CH3:37])[CH:12]=2)[CH2:25][CH2:24]1
Reactant: COC(=O)c1sc(-c2ccc(OCc3c(-c4c(F)cccc4C(F)(F)F)noc3C3CC3)cc2C)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2c(-c3c(F)cccc3C(F)(F)F)noc2C2CC2)ccc1-c1nc(C)c(C(=O)O)s1
Temperature: 55 °C
Yield: 98 %

Procedure:
To a solution of 2-(4-(5-Cyclopropyl-3-(2-fluoro-6-trifluoromethyl-phenyl)-isoxazol-4-ylmethoxy)-2-methyl-phenyl)-4-methyl-thiazole-5-carboxylic acid methyl ester (0.025 g, 0.046 mmol) in 1 mL of methanol and 1 mL of THF is added a solution of LiOH (0.011 g, 0.46 mmol) in water (11 mL). The reaction is heated to 55° C. for 30 minutes. The reaction is cooled, acidified with aqueous 1M HCl, and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered, and evaporated to yield the title compound (24 mg, 99%). ES/MS m/e 533.0 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Boc-L-Leucine methyl ester (22.7 g, 90 mmoles) in dry toluene (250 ml) under N2 was cooled to -78° and 25% di-isobutylaluminium hydride in toluene (130 ml, 225 mmoles) were added over 25 mins. keeping the temperature under -70°. The mixture was stirred for 15 mins. at -78° after completion of the addition, then MeOH (10 ml) was added cautiously. When effervescence ceased the mixture was poured into an ice-cold solution of Rochelle salt (100 ml of saturated solution +600 ml H2O). This mixture was shaken until an extractable solution was obtained. The toluene was separated and the aqueous phase re-extracted with ether (2×300 ml). Toluene and ether extracts were combined and dried (Na2SO4). The resulting oil was passed rapidly through a pad of silica gel in 15% EtOAc/petrol 40°-60°. The crude aldehyde was obtained as an oil, weight 18.68 g. Nmr showed aldehyde content to be b 85%, therefore yield of aldehyde: 15.9 g (83%).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:6]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([CH2:2][C@@H:3]([OH:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[CH:6]=1)=[N+:23]=[N-:24]
Reactant: O[C@H](CCl)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NC[C@@H](O)Cc1cccc(/C=C/c2c(Cl)cccc2Cl)c1

Procedure:
(S,E)-1-Chloro-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol was reacted with NaN3 following the method used in Example 74 to give (S,E)-1-azido-3-(3-(2,6-dichlorostyryl)phenyl)propan-2-ol. This material was used in the next synthetic step without purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[O:23][C:24]([CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[O:23][C:24]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)CCc1oc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Sc2nc(-c3ccccc3)c(CCC(=O)O)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-oxazolyl]propionate (250 mg), lithium hydroxide hydrate (61.4 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (1.5 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-oxazolyl]propionic acid (200 mg, yield 82%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 136–137° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:2]1.Cl[S:18]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)(=[O:20])=[O:19])=[CH:2]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CNCc2ccoc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2)Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
110 mg of 1-(furan-3-yl)-N-(4-methoxybenzyl)methanamine (example 5-27a) was mixed with methyl 4-(chlorosulfonyl)benzoate (example 5-10c) (117 mg, 0.5 mmol) and triethyl amine (100 uL) in DCM (5 mL). The mixture was stirred overnight at ambient temperature and concentrated. The residue was re-dissolved in ethyl acetate (20 mL), washed with 1N HCl (aq., 2 mL), followed by water (5 mL) and brine (5 mL) then dried over magnesium sulfate. The crude product was purified by preparative TLC (40% Ethyl Acetate/hexanes) to give methyl 4-(N-(furan-3-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate as a white solid. Saponification as in example 5-10 gave 4-(N-(furan-3-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid as a white crystalline solid (68 mg, 64% yield). MS (M−H, 400.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.72 (s, 3H), 4.13 (s, 2H), 4.26 (s, 2H), 5.99 (s, 1H), 6.87 (m, 4H), 6.87 (d, 2H, J=8.8 Hz), 7.13 (d, 2H, J=8.8 Hz), 7.39 (s, 1H), 7.49 (s, 1H), 7.95 (d, 2H, J=8.4 Hz), 8.09 (d, 2H, J=8.8 Hz).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[Cl:15])(=O)C.[S:16]([NH2:26])(=[O:25])([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:17].CN(C1C=CC=CN=1)C.N1C=CC=CC=1>CCOC(C)=O>[Cl:15][C:6]1[CH:7]=[C:8]([S:11]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([S:16](=[O:25])(=[O:17])[NH2:26])=[CH:19][CH:20]=2)(=[O:12])=[O:13])[CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc(S(N)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 4-acetamido-3-chlorobenzenesulphonyl chloride (2.68 g, 10.0 mmol), sulphanilamide (2.06 g, 12.0 mmol), dimethylaminopyridine (1.22 g, 10.0 mmol) and pyridine (2.40 ml, 10.0 mmol) in EtOAc (150 ml) was stirred at ambient temperature for 3 days. The solution was washed with 1.0M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in ethanol (100 ml) and 2M aqueous sodium hydroxide (22.1 ml) was added. The mixture was heated at reflux for 4 hours and then cooled to ambient temperature and evaporated to dryness. Water (25 ml) was added to the residue and the solution was neutralised to pH 7.0 by the addition of 1M aqueous hydrochloric acid. The aqueous solution was extracted with EtOAc, the EtOAc extracts washed with brine, dried and evaporated to give, as a solid, the title compound (2.34 g, 6.5 mmol). M.p. 197°-198°; NMR: 6.3 (s, 2H), 6.8 (d, 1H), 7.2 (s, 2H), 7.25 (d, 2H), 7.4 (dd, 2H), 7.55 (d, 1H), 7.65 (d, 2H); MS: 360.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH:6]=[C:5]2[C:15]([F:18])([F:17])[F:16].[F-].[Cs+].[CH:21](I)([CH3:23])[CH3:22]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([O:14][CH:21]([CH3:23])[CH3:22])[CH:6]=[C:5]2[C:15]([F:18])([F:16])[F:17]
Reactant: COc1cc2[nH]c(=O)cc(C(F)(F)F)c2cc1N
Reactant: CC(C)I
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cc2nc(OC(C)C)cc(C(F)(F)F)c2cc1N
Yield: 54 %

Procedure:
This compound was prepared according to General Method 12 (EXAMPLE 22) from 6-amino-7-methoxy-4-(trifluoromethyl)-1H-quinolin-2-one (500 mg, 1.9 mmol), CsF (1.18 g, 7.7 mmol), isopropyl iodide (1.31 g, 7.7 mmol) in 8 mL DMF to afford 308 mg (53%) of 6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline, a light yellow oil, and 190 mg (29%) of 2-isopropyloxy-7-methoxy-6N-(isopropyl)amino-4-(trifluoromethyl)quinoline, after flash chromatography (7:3 hexanes:EtOAc). Data for 6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline: Rf 0.51 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.18 (s, 1H), 7.13 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.3), 4.11 (broad s, 2H), 4.01 (s, 3H), 1.40 (d, 6H, J=6.3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2CC[C@H](N)C2)CC1
Reaction time: 2 h

Procedure:
To a 50 mL round-bottomed flask was added N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)-amino]phenyl}-piperidyl)-2-oxoethyl]{(3S, 1R)-3-[(tert-butoxy)carbonylamino]-cyclopentyl)-carboxamide (Step a) (323 mg, 0.5 mmol) followed by a 50% soln of TFA in CH2Cl2 (20 mL). After stirring for 2 h, the solvent was removed in vacuo. Purification by preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min]provided the title compound (TFA salt) as a white foam (145 mg). MS (ESI, pos. ion) m/z: 547 (M+1); (ESI, neg. ion) 545 (M−1). Calc'd for C27H35ClN4O4S: 546.21. Anal. Calcd for C27H35ClN4O4S.1.2C2HF3O2: C, 51.63; H, 5.49; N, 8.19. Found: C, 51.69; H, 5.49; N, 8.14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:12]=[CH:13]/[C:14]([N:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][O:18][C:17]2=[O:27])=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO[CH2:30][N:31]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][Si](C)(C)C.C(O)(C(F)(F)F)=O.C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:37]([N:31]1[CH2:32][C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[CH:3]=2)[C@H:13]([C:14]([N:16]2[C@H:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][O:18][C:17]2=[O:27])=[O:15])[CH2:30]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)c(F)c1)N1C(=O)OC[C@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H](c2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
To a solution of 338 (2.10 g, 5.54 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.98 mL, 7.75 mmol) dissolved in toluene (25 mL) and cooled to 0° C. A solution of TFA (0.0427 mL, 0.554 mmol) and benzene (1 mL) was added slowly over 15 min and the mixture was stirred for 4 h. The mixture was washed sequentially with satd. aq. NaHCO3, twice with water, dried, filtered and evaporated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20-40% EtOAc) to afford 1.62 g (57.1%) of (R)-3-((3S,4R)-1-benzyl-4-(3-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one (340) as white foamy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[S:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[S:38][C:34]([CH3:33])=[CH:35][N:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cnc(C2(N)CC2)s1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)s5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine (0.07 g, 1 eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA (0.19 ml, 3 eq) were dissolved in dichloromethane and the above solution was stirred at room temperature for 18 h. Then water was added to the mixture and the organic layer was separated. The organic layer was washed with water and the product was purified by Prep. HPLC. Yield: 65 mg (25%)1H NMR (400 MHz, CDCl3): δ 1.43-1.46 (m, 2H), 1.74-1.77 (m, 2H), 2.32 (s, 3H), 2.37 (s, 3H), 3.01-3.03 (d, J=5.2 Hz, 3H), 4.04 (s, 3H), 5.89 (m, 1H), 6.91 (s, 1H), 7.16 (t, 2H), 7.27 (m, 2H), 7.51 (d, J=4 Hz, 1H), 7.66 (s, 1H), 8.00 (m, 2H), 8.13 (s, 1H), 8.7 (s, 1H). LCMS: (ES+) m/z=570.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.ClCCl.[C:20](#[N:22])C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:20]#[N:22])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1
Reactant: Fc1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: CC#N
Solvent: ClCCl
Product: N#Cc1c(-c2cncc(F)c2)[nH]c2ccccc12

Procedure:
2-(5-Fluoro-pyridin-3-yl)-1H-indole (Example 92) is processed according to the method described in Example 140, using a mixture of dichloromethane and acetonitrile instead of dichloromethane, to give 2-(5-fluoro-pyridin-3-yl)-1H-indole-3-carbonitrile. MS (ESI) m/z 238.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:19])[CH3:18].[H-].[Na+]>CN1C(=O)N(C)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[N:10]([CH2:15][CH2:16][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:19])[CH3:18])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(F)cc2)n[nH]1
Reactant: CC(C)(CCCl)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN1CCCN(C)C1=O
Product: Cc1nc(-c2ccc(F)cc2)nn1CCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
5.88 g (33 mmol) 3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazole are dissolved in 40 mL DMPU and reacted as described for intermediate product 1c) with 11.04 g (50 mmol) of tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate, 1.59 g (40 mmol, 60%) sodium hydride and 2.21 g (6 mmol) tetrabutylammonium iodide.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][P:7](=[O:18])([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][CH2:29][C:30]2[C:31]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]([C:42]([F:45])([F:44])[F:43])=[CH:24][N:23]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[CH3:41][N:36]([S:37]([CH3:40])(=[O:39])=[O:38])[C:31]1[C:30]([CH2:29][NH:28][C:26]2[C:25]([C:42]([F:45])([F:43])[F:44])=[CH:24][N:23]=[C:22]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:6][P:7](=[O:18])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)[N:27]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CCCCOP(=O)(Cc1ccc(N)cc1)OCCCC
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1)OCCCC
Temperature: 105 °C
Yield: 73 %

Procedure:
A mixture of dibutyl (4-aminobenzyl)phosphonate (18 mg, 0.06 mmol), N-[3-({[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfonamide XLIa (20 mg, 0.05 mmol), TFA (12 uL, 0.15 mmol) and TFE (0.5 mL) was heated at 105° C. under nitrogen in a microwave reactor for 40 minutes. The resulting mixture was concentrated in vacuo and the residue purified by preparative HPLC (MDP) to afford 24 mg of dibutyl [4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate trifluoroacetate (Example 26, yield 73%).
Reaction SMILES: C([C@@:3]([C:12]([O-])=O)([OH:11])[C@@:4]([CH2:9][CH3:10])(O)[C:5]([O-:7])=O)C.[C:15]([NH:34][C@@H]1CC(CO)=CC1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OO)(C)(C)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:15]([NH:34][C@H:10]1[CH2:12][C@H:3]2[C@:4]([CH2:5][OH:7])([O:11]2)[CH2:9]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCC1=CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: OC[C@@]12C[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H]1O2
Temperature: -35 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A reactor was charged with (+)-diethyl-L-tartrate (2.23 L, 13.0 mol) and methylene chloride (10.5 L). Stirring was started and the mixture was cooled to −30 to −40° C. Titanium (IV) isopropoxide (3.93 L, 13.4 mol) was slowly added while maintaining the internal temperature between −30 to −40° C. A solution of [(4S)-4-(tritylamino)cyclopent-1-en-1-yl]methanol (4.2 kg, 11.8 mol) in methylene chloride (19 L) was slowly added to the reaction mixture, while maintaining the temperature between −30 to −40° C. After stirring for 20 minutes, t-butyl hydroperoxide (5-6 M in decane, 3.3 L, 16.3 mol) was slowly added while maintaining the temperature between −30 to −40° C. Upon completion of the addition, the reaction mixture was analyzed by HPLC, which confirmed the formation of the product and presence of 3% (AUC) of the starting material. The reaction mixture was carefully quenched into a 100-L reactor containing a cold aqueous solution (0 to 5° C.) of iron (II) sulfate heptahydrate (10.5 kg) and tartaric acid (6.3 kg) in DI water (42 L). After stirring for 15 minutes, the organic phase was separated and filtered through a pad of diatomaceous earth. The pad was washed with methylene chloride (2×2 L), and the filtrate was transferred into a 100-L reactor. A cold solution (0 to 5° C.) of solid sodium hydroxide (3.36 kg) in brine (42 L) was slowly added to the gently stirred reaction mixture. After 1 h, the organic phase was separated, dried over anhydrous sodium sulfate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give a brown oil. This was purified via silica-gel chromatography using five columns. Each column was performed as follows. A 20 cm diameter glass column was loaded with a slurry of silica gel (5 kg) in 30% ethyl acetate/heptane with 0.5% triethylamine added. Crude product (˜1.2 kg) was adsorbed onto silica gel (1.5 kg) and loaded on the column. Polarity was gradually increased from 30% to 40% ethyl acetate/heptane with 0.5% triethylamine. Combined purified material from all columns afforded the title compound (3.93 kg, 89% yield) as an amber oil. 1H NMR (300 MHz, CDCl3, δ) 7.54-7.50 (m, 5H), 7.32-7.18 (m, 10H), 3.80-3.76 (d, J=12.5 Hz, 1H), 3.65-3.61 (d, J=12.5 Hz, 1H), 3.31 (s, 1H), 3.03-2.92 (m, 1H), 1.77-1.69 (m, 2H) and 1.37-1.13 (m, 2H).