Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])[C:6]([CH:9]([F:11])[F:10])=[CH:7][CH:8]=1.[Cl:23][C:24]1[N:25]=[CH:26][N:27](COCC[Si](C)(C)C)[C:28]=1[C:29](O)=[O:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C.ClCCl.C(OCC)(=O)C>[Cl:23][C:24]1[N:25]=[CH:26][NH:27][C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([F:11])[F:10])=[C:5]([O:12][C:13]2[CH:14]=[C:15]([C:16]#[N:17])[CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:4]=1[F:22])=[O:30]
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)F)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)F)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 30.5 %

Procedure:
A solution of 3-{[3-(aminomethyl)-6-(difluoromethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.08 g, 0.245 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.068 g, 0.245 mmol), EDC (0.047 g, 0.245 mmol) and HOBT (0.037 g, 0.245 mmol) in DMF (4 ml) was stirred at RT under an atmosphere of nitrogen for 16 h then ethyl acetate (30 mL) and saturated aqueous NaHCO3 solution (30 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (30 mL), water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. A solution of this residue and TFA (0.019 ml, 0.246 mmol) in dichloromethane (10 ml) was stirred at RT under an atmosphere of nitrogen for 16 h. The solvent was removed under vacuum and the resulting oil was purified by Reverse Phase HPLC (MeCN/water+0.1% TFA). The desired compound was washed with saturated aqueous NaHCO3 solution (25 mL) and extracted with ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), brine (25 mL), dried over MgSO4, filtered and concentrated to give the title compound (0.034 g, 30%) as a white powder. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (s, 1H), 7.44-7.63 (m, 3H), 7.27 (d, 2H), 6.92 (t, 1H), 4.70 (s, 2H). LC/MS m/z 453.2 (M−H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][NH:22][CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17]>CN(C=O)C>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][N:22]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Reactant: Clc1ncccn1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(c1ncccn1)CC2
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2-chloro pyrimidine (1.2 eq) in DMF, N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example I (1.0 eq) was added and the reaction mixture was stirred at 100° C. for 15 h. Solvent was then evaporated under reduced pressure to afford crude product, which, on purification by column chromatography or preparative HPLC afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:36]=[N:35][C:34]([Br:37])=[CH:33][N:32]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:37][C:34]1[N:35]=[CH:36][C:31]([NH:30][C:13](=[O:14])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)=[N:32][CH:33]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 58, 267 mg, 0.75 mmol) in methylene chloride (10 mL) was treated with N,N-dimethylformamide (3 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.1 M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.90 mmol). The reaction mixture was stirred at 25° C. for 30 min and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (10 mL) and was treated dropwise with a solution of 2-amino-5-bromopyrazine (261 mg, 1.50 mmol, prepared according to Tetrahedron 1988, 44, 2977-2983) in tetrahydrofuran (10 mL) and pyridine (0.30 mL, 3.75 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then diluted with a 1N aqueous citric acid solution (25 mL) and then concentrated to remove tetrahydrofuran. The remaining aqueous residue was then extracted with a 3/2 solution of chloroform/methanol (2×25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 35/65 hexanes/ethyl acetate) afforded N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (193 mg, 50%) as a yellow foam: EI-HRMS m/e calcd for C20H21BrClN3O4S (M+H)+ 514.0198. found 514.0200.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][C:15](=O)OC)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][CH3:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(NC(=O)OC)ccc3n2CC2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2nc3cc(NC)ccc3n2CC2CC2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 92.9 %

Procedure:
To a suspension of methyl [1-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-1H-benzimidazol-5-yl]carbamate (0.781 g, 2.06 mmol) in THF was added LAH (0.32 g, 8.43 mmol) at 0° C. The mixture was stirred for 1 h at 0° C. and 2.5 h at reflux, cooled town to −78° C., and quenched with MeOH (5 mL) and H2O (5 mL). After adding Na2SO4 (10 g), the resulting mixture was stirred for 1 h at room temperature. After filtration and concentration, the residue was purified by MPLC using EtOAc on silica gel to give 641.7 mg (93%) of the title compound as an off-white solid. 1HNMR (CDCl3): δ 0.22 (m, 2H), 0.48 (m, 2H), 1.26 (m, 1H), 1.38 (t, J=7.0 Hz, 3H), 2.89 (s, 3H), 3.83 (d, J=6.6 Hz, 2H), 3.98 (q, J=7.0 Hz, 2H), 4.23 (s, 2H), 6.64 (dd, J=8.6, 2.2 Hz, 1H), 6.80 (d, J=8.6 Hz, 2H), 6.99 (d, J=2.1 Hz, 1H), 7.13 (m, 3H). MS (ESI) (M+H)+=336.42.
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[CH3:19][C:20]([O:23][C:24]([N:26]([C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:37]([SH:44])=[CH:36][C:35]=1[CH3:45])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])[CH3:21].C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH3:33][C:30]([O:29][C:27]([N:26]([C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:37]([S:44][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:36][C:35]=1[CH3:45])[C:24]([O:23][C:20]([CH3:19])([CH3:21])[CH3:22])=[O:25])=[O:28])([CH3:31])[CH3:32]
Reactant: Cc1cc(S)c(C(C)(C)C)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of tosyl bromide (17.1 g, 72.73 mmol) and NEt3 (7.36 g, 72.73 mmol) in CCl4 (250 mL) was cooled to 0° C. To this solution was added [5-(1,1-dimethylethyl)-4-mercapto-2-methylphenyl]-imidodicarbonic acid bis(1,1- dimethylethyl) ester obtained from Example FFFF in CCl4 (250 mL) dropwise over an 8 hour period. The mixture was then allowed to warm to room temperature overnight. Chloroform was added, and the solution was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The resulting material was flash chromatographed on silica gel, eluting with 4:1 CHCl3 :hexanes to afford the title compound. 1H NMR (CDCl3) δ 1.16 (s, 9 H), 1.40 (s, 18 H), 2.10 (s, 3 H), 2.40 (s, 3 H), 7.07 (s, 1 H), 7.19 (d, 2 H), 7.40 (s, 1 H), 7.44 (d, 2 H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH2:6][OH:7])[CH2:4][OH:5].[C:11]([O:16]C=C)(=O)[CH2:12][CH2:13][CH3:14]>>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH2:6][OH:7])[CH2:4][OH:5].[C:11]([O:5][CH2:4][C:3]([CH2:6][O:7][C:11](=[O:16])[CH2:12][CH2:13][CH3:14])([OH:8])[C:2]([F:10])([F:9])[F:1])(=[O:16])[CH2:12][CH2:13][CH3:14]
Reactant: C=COC(=O)CCC
Agent: OCC(O)(CO)C(F)(F)F
Product: CCCC(=O)OCC(O)(COC(=O)CCC)C(F)(F)F
Temperature: 25 °C
Reaction time: 42 h

Procedure:
In parallel reactions, a mixture of 2-(trifluoromethyl)-1,2,3-propanetriol (100 mg), Amano PS onto Sepabeads (100 mg), vinyl butyrate (0.3 ml) and solvent (as shown in table 1 below) (1 ml) was shaken at room temperature. The reactions were analysed by 19F NMR after 42 hours to give 2-(trifluoromethyl)-1,2,3-propanetriol (triol)/title compound/2-[(butanoyloxy)methyl]-3,3,3-trifluoro-2-hydroxypropyl butanoate (diester) peak ratios shown in table 1 below.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])(=[O:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cc([N+](=O)[O-])ccc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of 2-[2-(hydroxymethyl)-5-nitrophenyl]ethanol (2.95 g, 14.96 mmol, J. Org. Chem., 1998, 63, 4116-4119) and triethylamine (6.26 mL, 44.9 mmol) in dry CH2Cl2 (60 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (2.89 mL, 37.4 mmol) dropwise and stirred at 0° C. for 30 mins. The mixture is then diluted with CH2Cl2 (40 mL), washed with 1M aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of EtOAc/heptane (30/70-70/30). Pooling and concentration of those fractions with an Rf=0.18 by TLC (EtOAc/hexane, 50/50) provides 4.58 g (87%) of the title compound as a white solid, mp 88-89° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([O:14][C:15]([NH:17][C@H:18]([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([CH:48]1[C:52]2[C:53]([O:57][C:58]3[N:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=3)=[CH:54][CH:55]=[CH:56][C:51]=2[CH2:50][O:49]1)[CH3:47]>CN(C)C=O>[CH2:46]([CH:48]1[C:52]2[C:53]([O:57][C:58]3[N:63]=[CH:62][C:61]([NH:64][C:19]([C@H:18]([NH:17][C:15](=[O:16])[O:14][C:11]([CH3:10])([CH3:12])[CH3:13])[CH2:22][CH3:23])=[O:21])=[CH:60][CH:59]=3)=[CH:54][CH:55]=[CH:56][C:51]=2[CH2:50][O:49]1)[CH3:47]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCC1OCc2cccc(Oc3ccc(N)cn3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1OCc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c21
Temperature: 60 °C
Yield: 73.7 %

Procedure:
In a 8 ml vial 6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinamine (Intermediate 108, 10 mg) was dissolved in N,N-dimethylformamide (1 ml) to give a colourless solution. DIPEA (10.22 μl, 0.059 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (9.52 mg, 0.047 mmol) and, finally, TBTU (15.03 mg, 0.047 mmol) were added. The reaction mixture was shaken at 60° C. After overnight shaking, the reaction was completed. The reaction mixture was evaporated under vacuum to give the crude product as a yellow oil which was purified via Biotage SP1 (with Cyclohexane/EtOAc as eluents from 2:1 to 1:1 in 10 CV; then 2:1 for 5 CV; 10 g SNAP Silica column). The collected fractions afforded the title compound as a colourless oil (12.7 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.OC1C=CC=CN=1.[F:18][C:19]1[CH:24]=[C:23](F)[C:22]([F:26])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:23]2[CH:24]=[C:19]([F:18])[C:20]([N+:27]([O-:29])=[O:28])=[CH:21][C:22]=2[F:26])[CH:7]=[CH:6][N:5]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
Sodium hydride (60% by weight in mineral oil) (3.08 g, 77 mmol) was placed in a 500 mL round bottom flask flushed with argon. DMF (140 mL) was added and the mixture was cooled in an ice bath. 2-Chloro-4-hydroxypyridine (7.68 g, 59.3 mmol) was then added slowly over 45 minutes. After addition of the hydroxypyridine was complete 2,4,5-trifluoronitrobenzene (10.5 g, 59.3 mmol) was added as a solution in DMF (29 mL). The mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the majority of DMF in the mixture, and was then partitioned between ethyl acetate (300 mL) and 10% aqueous lithium chloride (150 mL). A precipitate formed which was removed via suction filtration and then the layers were separated. The organic layer was washed with additional 10% aqueous lithium chloride (2×150 mL), saturated aqueous sodium bicarbonate (150 mL) and brine (150 mL). The organic layer was dried over magnesium sulfate and evaporated to yield a dark red solid which was purified by silica gel chromatography (10 to 30% ethyl acetate/hexane) to give 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (13.56 g, 80% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.45 (dd, 1H), 8.39 (d, 1H), 7.87 (dd, 1H), 7.39 (d, 1H), 7.24 (dd, 1H); MS (ESI) m/z: 287.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].CO.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[C:79](C)([O-:81])C.[K+]>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]>[CH3:79][O:81][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: CO
Product: COc1ccc(C(=O)NC2C(C)(C)[C@@H]3CC[C@@]2(C)C3)cc1S(=O)(=O)N1CCOCC1
Temperature: 140 °C
Yield: 20 %

Procedure:
Into a 5 mL microwave flask 4-bromo-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2.4.AaBa, 0.3 g, 0.6 mmol) was dissolved in methanol (2 mL, 0.05 mol). Bis(dibenzylideneacetone)palladium(0) (0.02 g, 0.03 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.02 g, 0.03 mmol), and potassium tert-butoxide (0.5 mL, 4 mmol) were then added. The reaction was heated in the microwave oven at 140° C. for 1 h. The solvent was evaporated and prep-HPLC was performed to yield product 2K in 20% yield as a white, crystalline solid. MS analysis (m+1)=437.6.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH3:19]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 68.1 %

Procedure:
Powdered sodium hydroxide (1 g, 28.77 mmol) was added to a solution of 3-nitro phenol (2 g, 14.35 mmol) in DMF (15 ml) and cooled in an ice-bath. Ethyl bromoacetate (3.2 ml, 28.77 mmol) was added, and the reaction mixture was heated at 90° C. for 7 hr. The reaction mixture was cooled and quenched with ice water. The product was extracted with ethyl acetate, washed with water and dried. Concentration under reduced pressure gave (3-nitrophenoxy)-acetic acid ethyl ester (2.2 g, 68%) as oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:14]1[CH:15]=[CH:16][C:11]([O:17][CH3:18])=[CH:12][CH:13]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1ccccc1
Product: COc1ccc(C(=O)c2ccccc2F)cc1

Procedure:
The process of Example 1 was followed except for the following: in Step 4, 2-fluorobenzoyl chloride was used in place of 3-methylbenzoyl chloride and reacted with anisole in place of benzene to yield 2-fluoro-4'-methoxybenzophenone; in Step 5, 2-fluoro-4'-methoxybenzophenone was used in place of 3-methylbenzophenone to produce 1-(2-fluorophenyl)-1-(4-methoxyphenyl)-2-propyn-1-ol; and in Step 6, 1-(2-fluorophenyl)-1-(4-methoxyphenyl)-2-propyn-1-ol was used in place of 1-(3-methylphenyl)-1-phenyl-2-propyn-1-ol. The recovered product, about 4.0 grams, had a melting point of 144° to 146° C. A nuclear magnetic resonance (NMR) spectrum showed the recovered product to have a structure consistent with 7-(2-fluorophenyl)-7-(4-methoxyphenyl)-7H-2-methyl-2,3-dihydrofuro[3',2',:5,6]naphtho[2,1-b]pyran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[CH:9](Br)[CH3:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>C(#N)C.C(OCC)(=O)C>[OH:12][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[NH:13][CH:9]1[CH3:10]
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Reactant: CC(C)(N)CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1NC(C)(C)COC1(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 3′-chloro-2-bromo-propiophenone (61.2 g, 247 mmol) in acetonitrile (752 mL) was added 2-amino-2-methyl-1-propanol (56.5 g, 630 mmol). The reaction mixture was allowed to reflux for 8 hours, then slowly cooled to room temperature. The solution was concentrated in vacuo to provide a yellow solid. The crude material was dissolved in 600 mL of ethyl acetate and washed with water (300 mL×2). The ethyl acetate layer was dried (MgSO4), filtered, and concentrated in vacuo to give the product in 90% yield. 1H NMR (CDCl3) δ0.82 (d, J=6.6 Hz, 3H), 1.07 (s, 3H), 1.39 (s, 3H), 3.19 (q, J=6.5 Hz, 1H), 3.42 (d, J=11.2 Hz, 1H), 3.83 (d, J=11.2 Hz, 2H), 7.2-7.65 (m, 4H).
Reaction SMILES: [C:1]1(=O)N(CCCCNC2CC3C(=CC=CC=3OC)OC2)C(=O)C2=CC=C[CH:27]=[C:2]12.[C:29]1(=[O:55])[N:33]([CH2:34][CH2:35][CH2:36][NH:37][CH:38]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[O:48][CH3:49])[O:40][CH2:39]2)[C:32](=[O:50])[C:31]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:30]12>>[CH2:1]([N:37]([CH:38]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][C:45]=2[O:48][CH3:49])[O:40][CH2:39]1)[CH2:36][CH2:35][CH2:34][N:33]1[C:32](=[O:50])[C:31]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:30]2[C:29]1=[O:55])[CH2:2][CH3:27]
Reactant: COc1cccc2c1CC(NCCCN1C(=O)c3ccccc3C1=O)CO2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Product: CCCN(CCCN1C(=O)c2ccccc2C1=O)C1COc2cccc(OC)c2C1
Yield: 76 %

Procedure:
Using the procedure described in Example 2, but replacing the compound of Example 1 by the compound of Example 3, the expected product is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]=2[CH:20]=1)#[N:2].[CH:21]12[N:27]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([C:35]#[C:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH:29]=3)[CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22]2.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1.C(OCC)(=O)C>[CH:21]12[N:27]([C:28]3[CH:34]=[CH:33][C:31]([NH:32][C:12]([CH:10]4[O:11][C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=5[N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]4)=[O:14])=[C:30]([C:35]#[C:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH:29]=3)[CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22]2
Reactant: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1N
Reactant: CCOC(=O)N1CC(C(=O)O)Oc2ccc(C#N)cc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N1CC(C(=O)Nc2ccc(N3C4CCC3CC4)cc2C#CCN(C)C)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of 6-cyano-4-ethoxycarbonyl-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (30 mg, 0.11 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)aniline (29 mg, 0.11 mmol) in 2-methyltetrahydrofuran (300 μL) was added pyridine (35 μL, 0.43 mmol) followed by T3P (173 μL of 50% w/w, 0.27 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with ethyl acetate (10 mL) and washed with aqueous 10% NaHCO3 (2×5 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate/hexanes) provided ethyl 2-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-(dimethylamino)prop-1-ynyl)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (35 mg, 61% yield). LC/MS m/z 528.5 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.16 (s, 1H), 7.56 (dd, J=2.0, 8.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.96-6.92 (m, 2H), 5.17 (t, J=4.5 Hz, 1H), 4.23 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 4.10 (d, J=4.4 Hz, 2H), 3.44 (d, J=2.2 Hz, 2H), 2.23 (s, 6H), 1.62 (d, J=7.0 Hz, 4H), 1.38 (d, J=6.8 Hz, 4H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([S:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([S:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(CNS(=O)(=O)C2CC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CNS(=O)(=O)C2CC2)c1

Procedure:
N-Cyclopropylsulfonyl-3-nitrobenzylamine was dissolved in methanol (50 mL) and to the solution was added 10% Pd—C. The reaction mixture was reacted under hydrogen atmosphere (˜40 psi) for 2 h. The catalyst was filtered off over celite and washed with methanol. The filtrate was evaporated to give N-cyclopropylsulfonyl-3-aminobenzylamine. 1H NMR (DMSO-d6): δ 0.88 (d, J=6.6 Hz, 4H), 2.44 (m, 1H), 4.00 (d, J=6.3 Hz, 2H), 5.08 (br, 2H), 6.44 (t, J=9.0 Hz, 2H), 6.53 (s, 1H), 6.94 (t, J=7.8 Hz, 1H), 7.46 (t, J=6.6 Hz, 1H).