Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][F:35]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:33][CH2:34][F:35])[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: FCCBr
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(CCF)CC3)c2)c2ccc(F)cc21
Yield: 100.7 %

Procedure:
Following the general method as outlined in Example 81, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 111 mg; 0.25 mmol) and 1-bromo-2-fluoroethane (64 mg; 0.50 mmol), 122 mg (100%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[O:18]C.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[OH:18]
Reactant: CCc1ccc(Cc2cc(Br)c(OC)cc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(Br)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of 1-bromo-4-chloro-5-(4-ethylbenzyl)-2-methoxybenzene (AS) (5.1 g, 15 mmol) in anhydrous CH2Cl2 (15 mL), the solution of BBr3 in CH2Cl2 (1M, 20 mL) was added dropwise at −5° C. After BBr3 was added, the reaction mixture was allowed to warm to room temperature and stirred for 2 h, after which TLC showed the reaction was complete. The reaction was quenched with saturated NaHCO3. The organic phase was separated and washed with water and brine. After drying with anhydrous Na2SO4, the organic portion was filtered and concentrated to give AT as an oil (4.49 g, yield 92%). 1H-NMR (CDCl3, 300 MHz) δ 7.22 (s, 1H), 7.13 (m, 4H), 7.07 (s, 1H), 5.42 (s, 1H), 3.99 (s, 2H), 2.54 (q, J=7.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:30])[NH:15][CH2:16][C:17]2[S:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:20][CH:21]=2)=[C:10]([NH2:31])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N[C:34]1N=C(N)C=CC=1C(O)=O.CI.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:32])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:30])[NH:15][CH2:16][C:17]2[S:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:20][CH:21]=2)=[C:10]([NH2:31])[N:9]=1)[CH3:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of (6-amino-5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-carbamoyl)-pyridine-2-yl)-carbamic acid tert-butyl ester described in Preparation Example A+-2 (125 mg, 0.27 mmol) and methyl iodide (43 mg, 0.29 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (12 mg, 0.29 mmol, 60% in oil) on an ice bath, and the solution was stirred for 1 hour at room temperature. NH silica gel was added to the reaction solution, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=4:1 then 2:1), and the title compound (87 mg, 0.19 mmol, 70.5%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]([C@H:18]1[C@@H:25]([O:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH2:24][C@H:22]2[NH:23][C@@H:19]1[CH2:20][CH2:21]2)=[O:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]([C@H:18]1[C@@H:25]([O:26][C:27](=[O:28])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][C@H:22]2[N:23]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=3)[C@@H:19]1[CH2:20][CH2:21]2)=[O:17]
Reactant: N#Cc1ccc(Br)c2ccccc12
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2c1ccc(C#N)c2ccccc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
Adapting a protocol by Wolfe and Buchwald (Tetrahedron Lett., 1997, 37, 6359-6362), 1-bromo-4-cyanonaphthalene (124 mg, 0.53 mmol, Cakmak O. et al., Collect. Czech. Chem. Commun. 2000, 65, 1791-1804), norcocaine (185 mg, 0.64 mmol), Pd2(dba)3 (23.8 mg, 0.026 mmol), rac-BINAP (24.7 mg, 0.040 mmol) and caesium carbonate (242 mg, 0.74 mmol) were placed in an argon flushed vial, toluene (1.0 mL) was added and the resulting mixture was stirred under argon atmosphere at 110° C. overnight. The crude was then concentrated in vacuo and purification by preparative TLC (ethyl acetate/n-heptane 1:4, 4× eluted) afforded the title compound (68 mg, 29%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22]([C:23](=[O:39])[CH:24]([NH:31]C(OC(C)(C)C)=O)[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:6]12)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22]([C:23](=[O:39])[CH:24]([NH2:31])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:6]12)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(N)C3CCCCC3)C12
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 16 (346 mg, 0.64 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 1 h, the solution was concentrated, diluted with EtOAc, and washed with saturated NaHCO3. The aqueous phase was back extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 17 (245 mg) as an orange-colored foam that was used without further purification. Mass spectrum, m/z [444.4] (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1([CH2:12][CH2:13][C:14]([OH:16])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[O:25][CH2:26][CH:27]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:29]1[C:28]2[CH:27]([CH2:26][O:25][C:24]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:14](=[O:16])[CH2:13][CH2:12][C:7]3([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:40])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: NCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C=CCOC(=O)C1(CCC(=O)O)CCCC1
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: C=CCOC(=O)C1(CCC(=O)NCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1
Reaction time: 0.17 h
Yield: 12.9 %

Procedure:
To a solution of 3-(1-(allyloxycarbonyl)cyclopentyl)propanoic acid (1.191 g, 5.26 mmol) in 40 ml DMF was added (9H-fluoren-9-yl)methyl 5-aminopentylcarbamate (2.049 g, 6.32 mmol), DIEA (4.60 mL, 26.3 mmol) and HATU (2.402 g, 6.32 mmol). After stirring for 10 minutes, DMF was removed under reduced pressure. The material was subjected to normal-phase purification using a gradient of 0-100% acetonitrile in DCM. Fractions containing the desired material were combined and solvent removed under reduced pressure to give crude allyl 1-(3-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)pentylamino)-3-oxopropyl)cyclopentanecarboxylate (360 mg, 0.676 mmol, 12.84% yield) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18]([S:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:17]2[C:12]([N:13]([CH:27]([CH3:29])[CH3:28])[C:14](=[O:26])[N:15]([CH3:25])[C:16]2=[O:24])=[CH:11]1.S([O-])(O[O-])(=O)=[O:31].[K+].[K+].OOS([O-])=O.[K+]>CO.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18]([S:19]([CH2:20][CH2:21][CH2:22][OH:23])=[O:31])=[C:17]2[C:12]([N:13]([CH:27]([CH3:29])[CH3:28])[C:14](=[O:26])[N:15]([CH3:25])[C:16]2=[O:24])=[CH:11]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)n1c(=O)n(C)c(=O)c2c(SCCCO)n(C3Cc4ccccc4C3)cc21
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)n1c(=O)n(C)c(=O)c2c(S(=O)CCCO)n(C3Cc4ccccc4C3)cc21
Reaction time: 0.25 h

Procedure:
6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)thio]-3-methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg) was dissolved in methanol (40 ml). Water (10 ml) and potassium peroxymonosulphate (commercially sold under the trade mark "OXONE") (185 mg) were added and the solution was stirred for 15 minutes. The reaction mixture was diluted with water and then extracted with ethyl acetate thrice. The extracts were combined, washed with brine, then dried, filtered and the solvent was evaporated. The resultant oil was triturated with isohexane, then recrystallised from ethyl acetate-isohexane mixtures to give the title compound (15 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-6-nitro-benzoic acid (5.6 g, 30.9 mmol, 1.0 eq, Aldrich) and acetone (100 mL) was added crushed K2CO3 (21.4 g, 154.6 mmol, 5 eq) and MeI (9.6 mL, 154.6 mmol, 5.0 eq). The reaction was heated to reflux for 15 h then cooled to RT, filtered and concentrated in vacuo. The filtrate was dissolved in EtOAc, washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give the desired compound as a reddish-brown oil which upon standing at RT crystallized to tan needles
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:28]([O:29][CH3:30])=[O:31]
Reactant: COC(=O)C1CCNC(Cc2cccc(F)c2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Methyl 2-(3-fluorobenzyl)piperidine-4-carboxylate (7.6 g, 30.24 mmol) was dissolved in DCM (200 mL) and DIPEA (6.32 mL, 36.29 mmol), then methyl carbonochloridate (3.3 mL, 41.91 mmol) was added. The solution was stirred at room temperature for 2 h. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3-fluorobenzyl)piperidine-1,4-dicarboxylate (9.30 g, 99%) as a brown oil. MS m/z 310 (M+H)+
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([OH:24])[N:17]=2)=[CH:12][CH:11]=1.C1COCC1>CO>[Br:1][C:23]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:17][C:18]([OH:24])=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(Br)c(-c2ccc(F)cc2)nc1O
Yield: 94.6 %

Procedure:
N-Bromosuccinimide (3.66 g) was added to a mixture of 6-(4-fluorophenyl)-2-hydroxynicotinonitrile (4.00 g), THF (30 mL), and methanol (30 mL), and the resultant mixture was stirred at room temperature for 10 minutes. The solvent was distilled off, and the obtained residue was suspended in a mixed solvent of water, ethyl acetate, and hexane. Then, the obtained solid was washed with hexane to obtain the title compound (5.18 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].Cl.[CH3:20][C:21]1[CH:25]=[C:24]([NH2:26])[S:23][N:22]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:26][C:24]1[S:23][N:22]=[C:21]([CH3:20])[CH:25]=1)#[N:18]
Reactant: Cc1cc(N)sn1
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C#N)sn1
Reaction time: 20 h
Yield: 17.6 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (75 mg, 0.280 mmol), 3-methylisothiazol-5-amine hydrochloride (50 mg, 0.332 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (17 mg).
Reaction SMILES: [Cl-].[O:2]=[C:3]([CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][P+:5]([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)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:29]([CH:24]([CH2:25][CH2:26][CH2:27][CH3:28])[C:3]([CH:4]=[P:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=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)=[O:2])[CH3:30]
Reactant: CCCCC(CC)C(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCC(CC)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
Crude 2-oxo-3-ethylheptyltriphenylphosphonium chloride (88 g.) was added to a solution of sodium carbonate (100 g.) in water (1 litre) and the mixture stirred vigorously for 24 hours. The mixture was then extracted with diethyl ether and the extracts dried over magnesium sulphate. The solvent was evaporated and the crude product (63.3 g.) recrystallised from petrol (b.p. 60°-80°C.) to give 2-ethylhexanoylmethylenetriphenylphosphorane, m.p. 105.5°-107.5°C. (Found: C, 80.2; H, 7.5. C27H31OP requires C, 80.5; H, 7.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@@H:7]([N:13]1[C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][O:15]C1C(C1C=CC=CC=1)C1C=CC=CC=1)[C@@H:8]([OH:12])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.O.C(O)=O>[C:1]([O:5][C:6](=[O:37])[C@@H:7]([NH:13][C@@H:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][OH:15])[C@@H:8]([OH:12])[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](O)[C@@H](C(=O)OC(C)(C)C)N1C(C(c2ccccc2)c2ccccc2)OC[C@H]1c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: CC(C)[C@H](O)[C@H](N[C@H](CO)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.5 %

Procedure:
A solution of (2S,3S)-2-((4R)-2-benzhydryl-4-phenyl-oxazolidin-3-yl)-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester (600 mg, 1.196 mmole, obtained from Reference Example 11) in a mixture of tetrahydrofuran : water: formic acid (3:1:1) was stirred at room temperature for 20 h. The volatile was removed in vacuo, and the residue was dissolved in aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3 times), and the extracts were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, methylene chloride:methanol:diethyl ether=90:2:10) to give (2S,3S)-3-hydroxy-2-((1S)-2-hydroxy-1-phenyl-ethylamino)-4-methyl-pentanoic acid tert-butyl ester as a white solid (211 mg, 55%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[CH2:8][CH2:7][O:6][CH:5]([CH2:11][NH:12][CH3:13])[C:4]=2[C:3]=1[C:14]([F:17])([F:16])[F:15].[H][H]>CO.[Pd]>[CH3:13][NH:12][CH2:11][CH:5]1[C:4]2[C:3]([C:14]([F:17])([F:15])[F:16])=[CH:2][S:10][C:9]=2[CH2:8][CH2:7][O:6]1
Reactant: [H][H]
Reactant: CNCC1OCCc2sc(Br)c(C(F)(F)F)c21
Agent: [Pd]
Solvent: CO
Product: CNCC1OCCc2scc(C(F)(F)F)c21

Procedure:
To a solution of 1-(2-bromo-3-(trifluoromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-N-methylmethanamine (5 mmol) in MeOH (5 mL) was added a catalytic amount of Pd/C. A vacuum was applied and the reaction vessel was back filled with hydrogen gas three times. The resulting mixture was stirred under atmospheric H2. After the reduction was completed, the reaction mixture was filtered and the filter cake was washed with methanol. The combined filtrate was concentrated and purified by column chromatography to give the desired product.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH:8]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]3)[CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][CH:8]2[CH2:9][CH2:10][C:11]3[C:6](=[C:5]4[C:14](=[CH:13][CH:12]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[O:7]2)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4ncccc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4CCc5ccc6ncccc6c5O4)CC3)c2c1
Temperature: 25 °C
Yield: 6.2 %

Procedure:
Toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.22 g, 1.67 mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (4.0 g, 1.8 mmole) were combined in 200 mL of DMSO and heated at 75–80° C. under nitrogen for 13 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated sodium bicarbonate solution. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate and concentrated to an oil in vacuum. This was column chromatographed on silica gel using first methylene chloride to elute impurities and then 5% methanol in methylene chloride to elute the product, 0.19 g of a yellow oil. The oil was recrystallized from isopropanol with the addition of 0.05 g of oxalic acid to give 0.043 g of the title compound as a yellow solid (m.p. 148° C.).
Reaction SMILES: [CH2:1](OS(C)(=O)=O)[CH2:2][C:3]#[CH:4].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CCOCC>[CH2:1]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCOS(C)(=O)=O
Reactant: C1COCCN1
Solvent: CCOCC
Product: C#CCCN1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of methanesulfonic acid but-3-ynyl ester (10.1 g, 68 mmol) and morpholine (12.5 mL, 143 mmol) was heated to 100° C. for 1 h. The mixture was diluted with Et2O (50 mL) and filtered. The solid residue was discarded, and the mother liquor extracted with 3N HCl. The aqueous layer was basified with NaOH, and back-extracted into EtOAc. Drying (Na2SO4), concentration, and distillation (short-path, b.p.=130° C. at ˜5 mm Hg) game the title compound as a colorless oil. 1H NMR (CDCl3) δ 3.72 (t, 4H), 2.60 (t, 2H), 2.48 (t, 4H), 2.39 (td, 2H), 2.00 (t, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[F:22].[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][N:30]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]4[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=3[F:22])[CH2:29]2)[CH2:25][CH2:24]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Ethyl 7-chloro-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylate (327 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (160 mg) and acetonitrile (5 mL) were mixed together. The reaction mixture was stirred at 80° C. for 1 hour and was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (30 ml), washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:acetone=2:1->1:1->dichloromethane:methanol=10:1). The eluted pale yellow solid was dissolved in ethanol (4 mL), followed by addition of a 10% aqueous solution of sodium hydroxide (4 mL), stirring at 60° C. for 70 min, and concentration under reduced pressure. The resulting residue was diluted with water (10 mL), neutralized with 1 mol/L hydrochloric acid (pH 7.5), and extracted with dichloromethane (2×30 mL). The dichloromethane extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:methanol=10:1) to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid as white crystals (141 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G49) (160 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (115 mg, 0.5 mmol) according to the general procedure K. Obtainedas a white solid (53 mg).