Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ClCCl.CCN(CC)CC.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[CH:30])[CH3:26]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:30]#[C:29][CH:28]([O:31][CH2:32][CH3:33])[O:27][CH2:25][CH3:26])=[CH:7][N:6]=1
Reactant: C#CC(OCC)OCC
Reactant: Clc1ncc(Br)c(NC2CCCC2)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1cnc(Cl)nc1NC1CCCC1)OCC
Temperature: 60 °C
Yield: 54.3 %

Procedure:
To a stiffed solution of (5-bromo-2-chloro pyrimidin-4-yl)-cyclopentyl-amine (1.00 g, 3.62 mmol) and PdCl2(dppf).dichloromethane (148 mg, 0.181 mmol) in THF (10 mL) is added Et3N (0.757 mL, 5.43 mmol) and 3,3-diethoxy-propyne (0.778 mL, 5.43 mmol) sequentially at room temperature. The mixture is degassed under a stream of N2 and stirred at room temperature for 10 minutes before CuI (29 mg, 0.154 mmol) is added. The reaction vessel is evacuated and back-filled with N2 (×3) and heated at 60° C. for 48 hours. The mixture is allowed to cool, diluted with EtOAc, filtered and partitioned between H2O and ethyl acetate. The phases are separated and the aqueous layer is further extracted with EtOAc (×3), combined organic extracts are dried (MgSO4), filtered and concentrated. The residue is purified by SiO2 chromatography, eluting with a gradient of 5% EtOAc/petrol to 20% EtOAc/petrol to give [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-cyclopentyl amine (636 mg, 54%). MS (ESI) m/z 324.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:23])(=[O:22])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[C:6](N)[CH:5]=1.N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7]([S:10](=[O:22])(=[O:23])[NH:11][C:12]3[C:13]2=[CH:14][CH:15]=[C:16]2[C:21]=3[N:20]=[CH:19][CH:18]=[CH:17]2)=[CH:6][CH:5]=1)=[O:25]
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 18.6 %

Procedure:
In a similar fashion using route 16 general procedure 61, 3-amino-4-(quinolin-8-ylsulfamoyl)-benzoic acid methyl ester (Intermediate 277) (340 mg, 0.95 mmol), t-butyl nitrite (0.17 ml, 1.4 mmol), AcOH (3.4 ml) and THF (3.4 ml), gave the title compound (60 mg, 18%) after purification by column chromatography with DCM/MeOH (99.8:0.2) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([OH:11])[C:6]([CH3:12])=[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:4]=1[OH:24]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(O)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.1 %

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methylbenzoquinone (33.8 g) was dissolved in dichloromethane (250 ml). Trityl chloride (30 g) followed by triethylamine (10 g) was added, and the mixture was stirred at room temperature overnight. Then water (250 ml) containing sodium hydrosulfite (40 g) was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound (80.4 g).
Reaction SMILES: [CH:1]1([CH2:12][OH:13])[C:9]2[C:4](=[C:5]([CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)[C:16]([O-])=[O:17].[Tl+].C(O)(C(F)(F)F)=O.[Cl-].[Li+].[O-2].[Mg+2]>[Pd](Cl)Cl.CCOC(C)=O.C(Cl)Cl.CO>[OH:13][CH2:12][CH:1]1[C:9]2[CH:8]=[CH:7][C:6]3[C:16](=[O:17])[O:11][CH2:10][C:5]=3[C:4]=2[CH2:3][CH2:2]1
Reactant: O=C([O-])C(F)(F)F
Reactant: OCc1cccc2c1CCC2CO
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1OCc2c1ccc1c2CCC1CO
Reaction time: 16 h

Procedure:
To a flask charged with 2,3-dihydro-1H-indene-1,4-diyldimethanol (210 mg, 1.2 mmol) and a stir bar was added thallium trifluoroacetate (770 mg, 1.4 mmol) and TFA (2 mL) at 0° C. The mixture was allowed to stir for 16 hours. LC showed no SM left at that point. The volatiles were removed under reduced pressure, and the residue was dissolved in DCM and concentrated twice to affect azeotropic removal of all TFA. After pumping the residue under high vacuum for 20 minutes, palladium chloride (21 mg, 0.18 mmol), lithium chloride (75 mg, 1.8 mmol), magnesium oxide (190 mg, 4.7 mmol), and MeOH (10 mL) were added to the flask. The mixture was treated under an atmosphere of CO for 2 hours. To this mixture was added DCM and EtOAc to precipitate all the inorganic solids. The crude solution was filtered through a celite pad, and the filtrate was collected, adsorbed onto silica gel, and purified by MPLC to afford 6-(hydroxymethyl)-1,6,7,8-tetrahydro-3H-indeno[4,5-c]furan-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:14])[C:10]=2[NH:15][C:16]2[S:26][C:19]3[CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][C:18]=3[C:17]=2[C:27]([O:29]C(C)(C)C)=[O:28])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:14])[C:10]=2[NH:15][C:16]2[S:26][C:19]3[CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][C:18]=3[C:17]=2[C:27]([OH:29])=[O:28])=[CH:4][CH:3]=1
Reactant: CCN1CCc2c(sc(Nc3c(Nc4ccc(Cl)cc4)c(=O)c3=O)c2C(=O)OC(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2c(sc(Nc3c(Nc4ccc(Cl)cc4)c(=O)c3=O)c2C(=O)O)C1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a stirred mixture of compound O3 (293 mg, 0.600 mmol) in methylene chloride (12 mL) and toluene (3 mL) at room temperature under nitrogen was added trifluoroacetic acid (6.91 g, 60.6 mmol) dropwise over 2 min. After addition, the reaction mixture was stirred for another 2 h. The reaction mixture was diluted with toluene (20 mL) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with ammonium hydroxide/methanol/methylene chloride (1:14:85) to afford compound O4 as yellow solid (120 mg, 46%): MS (M−H) 430.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH:20]([CH2:23][OH:24])[O:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][CH2:19][CH:20]([O:21][CH3:22])[CH:23]=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: COC(CO)CO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(C=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oleyl 2-O-methyl-rac-glycerate (Compound 76) To a solution of oxalyl chloride (87 (L, 1.0 mmol) in CH2Cl2 (7 mL) at −78° C. was added DMSO (71 (L, 1.0 mmol). After 20 min, alcohol Compound 42 (0.20 g, 0.91 mmol) was added followed, after another 20 min, by the addition of triethylamine (0.63 mL, 4.6 mmol). The reaction was warmed to room temperature over a 10 min period, filtered through a plug of silica-gel, which was washed with ethyl acetate (50 mL) and concentrated to give 3-O-t-butyldimethylsilyl-2-O-methyl-rac-glyceraldehyde Compound 73 (0.20 g, 100%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)[CH:8]=2)[N:3]=1.Cl.[O:34]([NH2:36])[CH3:35]>CO.N1C=CC=CC=1>[CH3:35][O:34][N:36]=[C:25]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
To a solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.090 g, 0.213 mmol) in MeOH (4.0 mL) was added methoxylamine hydrochloride, 98% (0.089 g, 1.063 mmol) followed by 3 drops of pyridine. The reaction mixture was brought up to reflux for 41 h until the conversion was completed, as determined by LCMS. The reaction mixture was cooled to RT and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA) to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone O-methyl oxime as a off-white solid. MS (ESI, pos. ion) m/z: 453 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([CH3:13])=[N:11][CH:12]=1.Cl.C(Cl)Cl>N1C=CC=CC=1>[Br:6][C:7]1[CH:8]=[C:9]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]([CH3:13])=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(Br)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ncc(Br)cc1NS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (97 μl) was added dropwise to 5-bromo-2-methyl-3-pyridinamine (Chempacific) (200 mg) in pyridine (5 ml). The reaction was stirred at room temperature for 20 min before addition of 2M HCl (aq) (5 ml) and extraction into DCM. The DCM was passed through a hydrophobic frit then dried under a stream of nitrogen. The residue was dissolved in DCM and washed through an aminopropyl cartridge (preconditioned with DCM) with DCM to give title compound, 77 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:38]2[CH:39]=[CH:40][C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:36][CH:37]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(C(C)(C)C)cc2)sc1C(=O)OCC
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester (1.0 g, 2.0 mmol), 4-tert-butylphenyl boronic acid (0.71 mg, 4.0 mmol), cesium carbonate (1.43 g, 4.4 mmol), and tetrakis(triphenylphosphine)palladium(0)(347 mg, 0.3 mmol) were suspended in 10 mL of 1,4-dioxane. The reaction was heated at reflux temperature overnight, cooled to room temperature and diluted with ethyl acetate. The organic mixture was successively washed with saturated sodium bicarbonate and brine solutions. The organic fractions were dried over anhydrous sodium sulfate and concentrated to an oil residue, which was then purified by column chromatography, eluting the title compound from silica gel with a gradient of (0-70%) ethyl acetate in hexanes to yield 1.11 g of a yellow oil. MS: (+) m/z 577.2 (M+Na+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]2[NH:21][CH:20]=[C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[C:15]=2[N:16]=[CH:17][N:18]=1.[H-].[Na+].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]2[N:21]([S:38]([CH3:37])(=[O:40])=[O:39])[CH:20]=[C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cn(S(C)(=O)=O)c3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
tert-Butyl 4-(4-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (3.1 mg, 0.0063 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), sodium hydride (55% in oil, 0.4 mg, 0.0095 mmol) and methanesulfonyl chloride (0.4 mL, 0.0057 mmol) were added under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction liquid was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=10:1) to give the titled compound (0.6 mg, 16.8%) as a pale yellow amorphous.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH2:10]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41](O)=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CS(N)(=O)=O>CN(C)C=O>[CH2:10]([C@H:17]1[CH2:21][O:20][C:19](=[O:22])[N:18]1[C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([NH:9][S:6]([CH:3]4[CH2:5][CH2:4]4)(=[O:8])=[O:7])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2C(=O)OC[C@@H]2Cc2ccccc2)c1
Agent: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(N2C(=O)OC[C@@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (301 mg, 7.5 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (930 mg, 7.7 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 0.77 mmol) and 1,1′-carbonyldiimidazole (310 mg, 1.9 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-((S)4-benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (86 mg, 20%) as a white solid: LC/MS m/e calcd for C31H33N3O5S (M+H)+: 560.65, observed: 560.1.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.Br[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:48]=1[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:46](=[O:57])[C:45]2([CH3:59])[CH3:58]>>[CH3:58][C:45]1([CH3:59])[C:44]2[C:48](=[C:40]([CH2:39][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])[CH2:3]3)[CH:41]=[CH:42][CH:43]=2)[N:47]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:56])[CH3:55])[C:46]1=[O:57]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)C3(C)C)cc1

Procedure:
Analogously to Method D, 0.600 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and 0.574 g of 7-bromomethyl-3,3-dimethyl-1-(2-trimethylsilanylethoxymethyl)-1,3-dihydroindol-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.16 (1:2 EtOAc-heptane); Rt=6.79.
Reaction SMILES: [F-].[Cs+].Br[C:4]1[CH:5]=[C:6]([F:21])[C:7]([NH2:20])=[C:8]2[C:13]=1[O:12][CH2:11][C:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[N:9]2.[CH3:22][C:23]1[C:27](B(O)O)=[C:26]([CH3:31])[O:25][N:24]=1>C(O)CCC.O.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.Cl[Pd]Cl>[CH3:22][C:23]1[C:27]([C:4]2[CH:5]=[C:6]([F:21])[C:7]([NH2:20])=[C:8]3[C:13]=2[O:12][CH2:11][C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:9]3)=[C:26]([CH3:31])[O:25][N:24]=1
Reactant: Nc1c(F)cc(Br)c2c1N=C(c1cccnc1)CO2
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: CCCCO
Solvent: O
Product: Cc1noc(C)c1-c1cc(F)c(N)c2c1OCC(c1cccnc1)=N2
Temperature: 100 °C
Yield: 59.1 %

Procedure:
4-(Di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1) (3.3 mg, 0.0047 mmol) and cesium fluoride (83 mg, 0.54 mmol), 8-bromo-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine (50 mg, 0.2 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (33 mg, 0.23 mmol) were stirred in 1-butanol (0.50 mL) and water (0.12 mL). The system was placed under vacuum and back-filled with nitrogen (repeated 3×) while stirring the suspension. The mixture was further degassed by bubbling nitrogen through the solution for 10 minutes. The mixture was heated at 100° C. for 1 hour. Extractive workup with ethyl acetate gave the desired compound 40 mg, 80%. 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.68 (m, 1H), 8.51 (m, 1H), 7.52 (m, 1H), 6.89 (m, 1H), 5.80 (s, 2H), 5.13 (s, 2H), 2.25 (s, 3H), 2.10 (s, 3H). LCMS calculated for C18H16FN4O2 (M+H)+: m/z=339.1. found: 339.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[OH-].[Na+].[Cl:14][C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[Cl:14][C:15]1[S:19][C:18]([S:20]([NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])(=[O:22])=[O:21])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: N[C@@H](CCC(F)(F)F)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of the crude 5,5,5-trifluoronorvaline (0.785 g, 4.59 mmol) and NaOH mixture dissolved in THF (10 ml) and 2N NaOH (10 mL) was added dropwise a solution of 5-chlorothiophene-2-sulfonyl chloride (1.32 g, 5.04 mmol) in THF (10 ml) over 30 min. After 60 min, the reaction mixture was allowed to warm gradually to 25° C. and stirred for 16 h. THF was removed in vacuo and the mixture was acidified to a pH of about 2 with 1N HCl. After 15 min, a precipitate began to crash out of the milky white solution. After 60 min, the mixture was cooled to 0° C. for 45 min and then filtered. The precipitate washed with 1N HCl (10 mL) to provide a white solid. The white solid gummed out. It was dissolved in EtOAc (100 mL). The aqueous was washed with EtOAc (3×50 mL) and the organic layers were washed with saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoronorvaline as a dark red oil (1.1 g, 68.3%). Mass Spectrum (−ESI): 350 (M−H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)[CH:5]=C.CSC>ClCCl.CO>[C:27]([O:26][C:24]([N:7]([CH2:4][CH:5]=[O:1])[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:10][CH2:9]1)=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: C=CCN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ozone (g) was bubbled into a solution of benzyl 4-[allyl(tert-butoxycarbonyl)amino]piperidine-1-carboxylate (2.75 g, 7.34 mmol) in dichloromethane (30 mL) and methanol (15 mL) at −78° C. for 17 min. Nitrogen (g) was then bubbled into the mixture for 30 min followed by the addition of dimethylsulfide (2.70 mL, 36.72 mmol). The reaction warmed to ambient temperature and stirred for 3 h. The mixture was concentrated and redissolved in ethyl acetate. The ethyl acetate layer was washed with water (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated to give the title compound (2.5 g). MS 277.09 (M+1-boc group)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)(C)(C)C.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.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+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:17]1([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][NH2:7])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: NCc1cccc(N2CCCC2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Slurry a mixture of (3-bromobenzyl)-carbamic acid tert-butyl ester (600 mg, 2.1 mmol, U.S. Pat. Appl. Publ. US 2003134885), pyrrolidine (450 mL, 5.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.21 mmol), BINAP (400 mg, 0.63 mmol) and cesium carbonate (960 mg, 2.94 mmol) in anhydrous toluene (10 mL). Degas under vacuum, fill the system with nitrogen and heat in a sealed flask at 90° C. for 18 h. Cool to room temperature, dilute with diethyl ether, filter, and concentrate in vacuo. Dissolve the resulting residue in DCM (10 mL) and add trifluoroacetic acid (5 mL). Stir at ambient temperature for 1 h and concentrate in vacuo. Purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (1:1), EtOAc and 2M ammonia in methanol. Purify again by SCX chromatography to give the title compound as a brown oil (300 mg, 85% overall). MS (ES+) m/z: 178 (M+H)+.