Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:23](=NOC)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=1[NH:49][NH2:50].C(O)(=O)C>COCCO>[CH2:33]([C:32]1[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][CH:17]=2)=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:49]([C:41]2[CH:42]=[C:43]([N+:46]([O-:48])=[O:47])[CH:44]=[CH:45][C:40]=2[Cl:39])[N:50]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=NOC)C(=O)OCC
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 105 °C
Reaction time: 20 h
Yield: 49.5 %

Procedure:
A mixture of 3.07 g (5.79 mmol) of ethyl 3-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanoate (from Step F), 5.00 g (22.3 mmol) of 2-chloro-5-nitrophenylhydrazine hydrochloride [prepared from 2-chloro-5-nitroaniline according to H. Stroh and G. Westphal, Chem. Ber., 96, 184 (1963)], 55 mL of glacial acetic acid, and 25 mL of 2-methoxyethanol was stirred under N2 at 105° C. for 20 hours. The cooled mixture was concentrated in vacuo and the residue was partitioned between 200 mL of 0.2N HCl and 200 mL of ethyl acetate. The organic layer was washed with H2O (200 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatography of the residue twice on silica gel (first column eluted with 2% MeOH in CH2Cl2, second column eluted with 1% MeOH in CH2Cl2) to provide 1.71 g (47%) of the title compound as a viscous, orange oil; homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 598 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.3 Hz, 3H), 1.06 (t, J=7.1 Hz, 3H), 1.34 (m, 2H), 1.59 (m, 2H, partially obscured by H2O peak), 2.62 (t, J=7.8 Hz, 2H), 4.10 (s, 2H), overlapping 4.14 (q, J=7.0 Hz, 2H), 4.24 (s, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.32 (dd, J=7.5, 1.3 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.49 (m, 1H), 7.58 (m, 1H), 7.66 (d, J=8.8 Hz, 1 H), 8.14 (dd, J=7.9, 1.3 Hz, 1H), 8.26 (dd, J=8.8, 2.7 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H).
Reaction SMILES: N.[C:2]([NH2:5])(=[O:4])[CH3:3].[C:6]([O:9][CH2:10][CH2:11]Cl)(=[O:8])[CH3:7]>[NH2-].[Na+]>[C:6]([O:9][CH2:10][CH2:11][NH:5][C:2](=[O:4])[CH3:3])(=[O:8])[CH3:7]
Reactant: CC(N)=O
Reactant: CC(=O)OCCCl
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: CC(=O)NCCOC(C)=O

Procedure:
To 150 ml of liquid ammonia in which 7.8 g of sodium amide had been dissolved, was added 12 g of acetamide and the reaction mixture was reacted at room temperature for 5 hours in a pressure-resistant reaction tube. Then, 57 g of 2-chloroethyl acetate was added to the reaction solution, followed by a further reaction for 3 hours at room temperature. After the completion of the reaction, ammonia was distilled off and 10% aqueous hydrochloric acid solution was added to the resulting residue so as to obtain an aqueous solution of pH 5. The aqueous solution was extracted twice with 100 ml of ethylacetate. The ethylacetate layers were dried with magnesium sulfate, followed by the distillation-off of ethylacetate. The residual substance was subjected to a distillation under reduced pressure but the intended product, N-acetoxyethylacetamide(138°-140° C./ 2 mmHg) did not come out.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([C:10]=1[OH:11])[C:7]([OH:9])=[O:8].[CH3:13][C:14]([CH3:16])=O.S(Cl)(Cl)=O>COCCOC.CN(C1C=CN=CC=1)C.O.C([O-])([O-])=O.[K+].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:14]([CH3:16])([CH3:13])[O:8][C:7](=[O:9])[C:6]=2[C:10]=1[OH:11]
Reactant: CC(C)=O
Reactant: O=C(O)c1c(O)ccc(Cl)c1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: CC1(C)OC(=O)c2c(ccc(Cl)c2O)O1
Temperature: 10 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 5-chloro-2,6-dihydroxybenzoic acid (Doyle, F. P. J. Chem. Soc., 1963, p. 497-506) (500 mg, 2.65 mmol) in DME (2 mL) was added DMAP (16.2 mg, 0.13 mmol) and acetone (200.2 mg, 3.45 mmol). The solution was cooled to 10° C. and thionyl chloride (448 mg, 3.77 mmol) was added over 10 min. The solution was allowed to overnight. The solution was diluted with water and neutralized with solid K2CO3 and the aqueous phase was extracted w/EtOAc. The combined organic layers were washed with water, brine and dried (Na2SO4). The crude residue was purified by column chromatography on silica gel to afford the product as yellow solid (162 mg, 27% yield). 1H NMR: 1.74 (s, 6H), 6.44 (d, 1H, J=8.0 Hz), 7.48 (d, 1H, J=8.0 Hz), 10.83 (s, 1H).
Reaction SMILES: C1(CC[N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])CC1.N1C2C(=CC=CC=2)C(=O)C1=O.O1C2C=CC(O)=CC=2OC1.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>>[Br:38][C:39]1[CH:40]=[CH:41][C:42]([OH:45])=[C:43]([C:8]2([OH:15])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6][C:7]2=[O:16])[CH:44]=1
Reactant: O=C1C(=O)N(CCC2CC2)c2ccccc21
Reactant: Oc1ccc(Br)cc1
Agent: O=C1Nc2ccccc2C1=O
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1Nc2ccccc2C1(O)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with isatin, 1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained (71%) as a yellowish solid: MS (ES+) m/z 319.4 (M+1), 321.4 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:13][N:14]([CH3:16])[CH:15]=1)[N:5]=2.[CH2:24]([NH2:27])[CH2:25][CH3:26]>O1CCOCC1.C(Cl)Cl>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:12]1[C:11]([C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:27][CH2:24][CH2:25][CH3:26])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:15][N:14]([CH3:16])[N:13]=1
Reactant: CCCN
Reactant: Cn1cc(-c2ccc3nc(Br)sc3n2)c(-c2ccccc2F)n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCNc1nc2ccc(-c3cn(C)nc3-c3ccccc3F)nc2s1
Temperature: 25 °C
Yield: 973.3 %

Procedure:
A solution of 2-bromo-5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridine (0.0294 g, 0.0755 mmol, 1.0 eq.) and n-propylamine (0.1 mL, 1.22 mmol, 16.1 eq.) in 1,4-dioxane (1.5 mL) was heated at 75° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-N-propylthiazolo[5,4-b]pyridine-2-amine as a light tan solid (0.270 g, 97% yield). LC/MS (MH)=368.16.
Reaction SMILES: [I-:1].[CH2:2]1[CH2:28][O:27][CH:5]([CH2:6][CH2:7][P+:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][O:3]1.[CH2:29]([Li])CCC.[I-].[PH4+].C1COC(CC=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CO1.CI>O1CCCC1.CCCCCC>[I-:1].[CH2:2]1[CH2:28][O:27][CH:5]([CH2:6][CH:7]([P+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:29])[CH2:4][O:3]1
Reactant: c1ccc([P+](CCC2COCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: [Li]CCCC
Agent: C(CC1COCCO1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [PH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(CC1COCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
1.51 g (3.0 mmol) of finely powdered (4-ethylenedioxybutyl)-triphenyl-phosphonium iodide are suspended in 10 ml of tetrahydrofuran and treated dropwise with a solution of 4.5 mmol of butyl-lithium in hexane. The solution turns red as the phosphonium iodide goes into solution as (4-ethylenedioxy-butylidene)-triphenyl-phosphorane. After approximately 10 minutes, 0.25 ml (4.5 mmol) of methyl iodide are added to this solution, which thereby becomes lighter, and the (4-ethylenedioxy-1-methylbutyl)-triphenyl-phosphonium iodide which is formed partially precipitates as an oil. After 10 minutes, 3.0 mmol of butyl-lithium in hexane are added dropwise and the solution thereby again becomes dark red.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[N:18]2[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)([C:22]([NH2:24])=[O:23])[CH2:20][O:21][C:16]3=[C:17]2[C:12](=[CH:13][CH:14]=[CH:15]3)[NH:11]1.C(#N)C>C(O)(=O)C>[Br:1][C:15]1[C:16]2[O:21][CH2:20][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)([C:22]([NH2:24])=[O:23])[N:18]3[C:10](=[O:9])[NH:11][C:12]([C:17]=23)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Solvent: CC#N
Solvent: CC(=O)O
Product: NC(=O)C1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a solution of 2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide, acetonitrile (5 mL) and acetic acid (3 mL) and cooled to 0° C. The reaction mixture was stirred for 1 h and then concentrated to remove residual acetic acid. The resulting residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.040 g. 60%). LCMS calculated for C15H12BrN4O3 (M+H)+: m/z=375.1, 377.1. found: 375.0, 376.9.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][C:13]([NH2:15])=[O:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C[O:19][C:20](=O)[C:21]([C:23]1[C:33]2=[C:34]3[C:29](=[CH:30][CH:31]=[CH:32]2)[C:28]([CH3:36])([CH3:35])[CH2:27][CH2:26][N:25]3[CH:24]=1)=O>>[CH3:35][C:28]1([CH3:36])[C:29]2[C:34]3=[C:33]([C:23]([C:21]4[C:20](=[O:19])[NH:15][C:13](=[O:14])[C:12]=4[C:7]4[C:6]5[C:10](=[CH:11][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:4][CH:5]=5)[NH:9][CH:8]=4)=[CH:24][N:25]3[CH2:26][CH2:27]1)[CH:32]=[CH:31][CH:30]=2
Reactant: NC(=O)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)C(C)(C)CC2
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5cc(C(F)(F)F)ccc45)C(=O)NC3=O)c3cccc1c32

Procedure:
Beginning with (6-(trifluoromethyl)indol-3-yl)acetamide and (6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1([F:25])[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.O=O.[OH:28]S([O-])=O.[Na+]>C1COCC1.CCOCC>[F:13][C:14]1([F:25])[CH2:15][CH2:16][C:17]([OH:28])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Reactant: O=S([O-])O
Agent: O=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(O)CCC(F)(F)CC1
Temperature: -78 °C

Procedure:
A solution of butyllithium (1.600 mL, 4.00 mmol) was added to cold (−78° C.) solution of diisopropylamine (0.565 mL, 4.00 mmol) in THF (5 mL) under nitrogen and the mixture was stirred at −78° C. 1 h. A solution of ethyl 4,4-difluorocyclohexanecarboxylate (384 mg, 2 mmol) in THF (2 mL) was added at −78° C. and the mixture was stirred for 1 h. The mixture was gradually warmed to −20° C. over 2 h and then recooled to −78° C. and connected to a balloon of oxygen and stirred at −78° C. for 1 h. The reaction mixture was added satd. NaHSO3 solution (5 mL) and allowed to warm to rt and stirred at rt overnight. The reaction mixture was diluted with ether and organic layer separated, washed with water, brine, dried (Na2SO4). Evaporation of the solvent afforded a light yellow oil which was purified by silica gel FCC (DCM) to afford ethyl 4,4-difluoro-1-hydroxycyclohexanecarboxylate as a colorless oil (143 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.28 (q, J=7.3 Hz, 2H), 2.23 (br. s, 1H), 2.19-1.99 (m, 6H), 1.83-1.73 (m, 2H), 1.33 (t, J=1.0 Hz, 3H).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23](O)=[O:24].N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:24]
Reactant: COc1ccc(C)cc1C(=O)O
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol), 2-methoxy-5-methylbenzoic acid (CAS number 25045-36-7; 53 mg, 0.32 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (61 mg, 0.40 mmol), EDC (76 mg, 0.40 mmol) and triethylamine (111 μl, 0.80 mmol) in dry DCM (1 ml) was stirred at room temperature for 24 hours. The reaction mixture was partitioned between DCM (3 ml) and water (2 ml), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Br:20])[CH:14]=1)[C:23]([CH3:25])([CH3:24])[CH:22]2[OH:26])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2ccc(F)c(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a mixture of 4-{[1-(3-bromo-4-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (1.6 g, 4.57 mmol) and ytterbium(III) triflate hydrate (0.28 g, 0.457 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.42 mL, 4.57 mmol) and water (82 mg, 4.57 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-4-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.93 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrFNO3 M+: 422.3, observed: 404.2.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>CO>[CH2:24]([O:23][C:21](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13][C@@H:12]([NH2:8])[CH2:11][OH:10])[CH3:25]
Reactant: CCOC(=O)c1ccccc1C=C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1ccccc1C=C[C@@H](N)CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-4-[2-(2-ethoxycarbonylphenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.3 g, 8.70 mmol) in methanol (50 mL) is added conc. HCl (4 mL) and stirred at RT for 18 h. The solvent is removed under reduced pressure and EtOAc and 2N NaOH, which is saturated by NaCl, is added. The aqueous phase is extracted with EtOAc and the organic phases are combined together, washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound as a white solid: (M+1)+=236.
Reaction SMILES: [CH2:1]([N:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:9]([C@H:11]1[C@H:16]([C:17](=[O:33])[N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14][C:13](=[CH:34][C:35]([O:37][CH2:38]C)=[O:36])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg]>CO>[CH2:40]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([C@H:11]1[C@H:16]([C:17](=[O:33])[N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14][C@@H:13]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:12]1)=[O:10])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)C=C1CC[C@@H](C(=O)N(Cc2ccccc2)Cc2ccccc2)[C@H](C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Mg]
Solvent: CO
Product: COC(=O)C[C@@H]1CC[C@@H](C(=O)N(Cc2ccccc2)Cc2ccccc2)[C@H](C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Reaction time: 5 h
Yield: 91.5 %

Procedure:
To a solution of Ethyl 2-[(trans)-3,4-bis(dibenzylcarbamoyl)cyclohexylidene]acetate (9.27 g, 15 mmol) in dry MeOH (75 mL) is added Magnesium ribbon (1.08 g, 45 mmol). The suspension was stirred for 5 hr. To this homogeneous solution is added a further batch of Magnesium ribbon (200 mg, 8.2 mmol). This mixture is stirred for 17 hr. The resulting solution is extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated. The residue is purified by silica chromatography (eluting with 20% ethyl acetate/10% dichloromethane in hexane) to give the title compound (8.27 g) as a foam. ESI-MS (m/z) 617 (MH)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH:10]=[CH:11][CH2:12][C:6]=2[CH:5]=1.CCO>[Pd].C1COCC1>[F:17][C:2]([F:1])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1C=CCc2cc(OC(F)(F)F)ccc2N1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CCCc2cc(OC(F)(F)F)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(trifluoromethoxy)-1H-benzo[b]azepin-2(5H)-one (10 g, 41.1 mmol) in 1:1 EtOH:THF (150 ml) was added Pd/C (1.0 g) and the mixture was stirred at room temperature under 30 psi H2 for 3 h. The resulting mixture was filtered and concentrated under reduced pressure to give a crude solid that was recrystallized from ethyl acetate to give the title compound.
Reaction SMILES: [O:1]1CCCC1.[O:6]1[CH2:8][CH:7]1[CH2:9][N:10]([CH2:20][CH:21]1[CH2:23][O:22]1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].S(=O)(=O)(O)O.[Cl-].[Na+]>C(OCC)(=O)C>[OH:22][CH2:23][CH:21]1[O:1][CH:7]([CH2:8][OH:6])[CH2:9][N:10]([S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH2:20]1
Reactant: C1CCOC1
Reactant: O=S(=O)(c1ccccc1)N(CC1CO1)CC1CO1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)N1CC(CO)OC(CO)C1
Reaction time: 144 h

Procedure:
Tetrahydrofuran (40 mL) was added to N,N-bis(2-oxiranylmethyl)benzenesulfonamide (from step (i) (alternative A) above; 10 g, 37.1 mmol), followed by dilute sulfuric acid (10 mL of 1 M), and the mixture stirred for 6 days (reaction is complete within 1 day). Solid sodium chloride (3 g) and ethyl acetate (40 mL) were added, and the mixture stirred for 1 hour. The organic phase was separated and washed with aqueous ammonium chloride (10 mL of 10%). The organic phase was concentrated under reduced pressure before toluene was added (50 mL). The mixture was concentrated again to leave the title compound as a crude oil (10.65 g). This material was employed directly in subsequent reactions without any further purification.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5([NH2:34])[CH2:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)[N:23]=3)[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CCO>[NH2:34][C:30]1([C:27]2[CH:26]=[CH:25][C:24]([C:22]3[N:23]=[C:18]4[CH:17]=[CH:16][C:15]([C:14]5[C:9]([OH:8])=[N:10][CH:11]=[CH:12][CH:13]=5)=[CH:20][N:19]4[C:21]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: NC1(c2ccc(-c3nc4ccc(-c5cccnc5OCc5ccccc5)cn4c3-c3ccccc3)cc2)CCC1
Solvent: CCO
Product: NC1(c2ccc(-c3nc4ccc(-c5cccnc5O)cn4c3-c3ccccc3)cc2)CCC1
Yield: 11.6 %

Procedure:
The crude product from Step 3 (167 mg) was dissolved in EtOH (7 mL) whereupon a precipitate formed which was filtered. The filtrate was hydrogenated using an H-Cube flow reactor (Pd/C cartridge, oven temperature 50° C.). The eluant was collected from the flow reactor in two fractions. The second fraction was concentrated in vacuo and triturated with DCM to give a solid which was filtered and dried to give a further portion of title compound (16 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>[Cl-].[Na+].O.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.O.C(O)C.C1(C)C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: OB(O)c1ccccc1F
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=c1ccc(-c2ccccc2F)c[nH]1
Temperature: 100 °C
Reaction time: 17 h
Yield: 5 %

Procedure:
5-Bromopyridin-2(1H)-one (1.04 g), (2-fluorophenyl)boronic acid (0.924 g), sodium carbonate (1.40 g), lithium chloride (0.560 g) and tetrakis(triphenylphosphine)palladium(0) (0.347 g) were suspended in a mixed solvent of toluene (26.4 mL), ethanol (6.6 mL) and water (6.6 mL), and the suspension was stirred at 100° C. for 17 hr under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with brine, extracted with ethyl acetate, diluted with THF, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane→ethyl acetate/methanol) to give the title compound (0.0563 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[C:4]([CH3:18])[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[F-].[Cs+]>COCCOC.O>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]#[N:10])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(C#N)Cc1cccnc1
Reactant: COCCCc1ccccc1B(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cccnc2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution 2-(4-bromo-2-methylphenyl)-3-pyridin-3-ylpropanenitrile (1 eq.) from step 1 and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 (1.2 eq.) in DME (0.1M) at room temperature was added palladium tetrakistriphenyl phosphine (Pd(PPh3)4; 0.05 eq.) and CsF (2.4 eq.). The mixture was refluxed for 2 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with water, brine, dried over Na2SO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 65% in 30 min) afforded the desired compound.