Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([OH:25])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([O:25][C:43]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:44])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)NCC(=O)c1ccc(OC(=O)COc2ccccc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)NCC(=O)c1ccc(OC(=O)COc2ccccc2)c(OC(=O)C2CCCCC2)c1

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with cyclohexanecarbonyl chloride there is obtained 3-(cyclohexanecarbonyloxy)-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(cyclohexanecarbonyloxy)-4-(phenoxyacetoxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[CH2:25][O:26][CH3:27])=[O:10]>Cl.O1CCOCC1.CO>[ClH:1].[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[CH2:25][O:26][CH3:27])=[O:10]
Reactant: COC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC[C@@H]1CNCC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cis(±)tert-butyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(methoxymethyl)piperidine-1-carboxylate (Intermediate 73; 192 mg, 0.45 mmol) was dissolved in 4N HCl in dioxane (10 ml) and 10 ml of MeOH. The mixture was stirred at room temperature for 3 h, concentrated to dryness and azeotroped with MeOH to remove excess HCl (5×20 ml) to yield the title compound which was used without purification. (crude mixture 195 mg). MS (ES)(MH+): 320 for C13H19Cl2N3O2.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC1(c2ccc(F)cc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 57 %

Procedure:
The 4-hydroxymethyl-4-(4-fluorophenyl)cyclohexanone is dissolved in 50 ml. of pyridine and 30 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is pured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed sucessively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness. The solid residue is recrystallized from ether to give 9.77 g. (57% yield) of 4-acetoxymethyl-4-(4-fluorophenyl)cyclohexanone, having a melting point of 80° to 84°C.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([O:15]CC3C=CC=CC=3)=[O:14])[C:8](=[O:27])[C:7]3=[CH:28][N:29]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:5]([C:6]=23)=[N:4][CH:3]=1.[CH3:40][Al](C)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.O1CCOCC1>[CH3:25][C:23]([CH3:24])([CH3:26])[C@@H:12]([N:9]1[C:8](=[O:27])[C:7]2=[CH:28][N:29]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:5]3[C:6]2=[C:11]([C:2]([CH3:40])=[CH:3][N:4]=3)[CH2:10]1)[C:13]([OH:15])=[O:14]
Reactant: C[Al](C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OCc2ccccc2)C(C)(C)C)C3=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cnc42)CN([C@@H](C(=O)O)C(C)(C)C)C3=O)cc1
Temperature: 120 °C
Yield: 439.1 %

Procedure:
(R)-Benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate (10 mg, 0.018 mmol), Pd(Ph3P)4 (10 mg, 0.009 mmol), and dioxane (1 mL) were combined in a 2 mL microwave vial. The mixture was purged with nitrogen, and trimethylaluminum (2.0M/toluene, 0.053 mL, 0.11 mmol) was added. The vial was sealed and the reaction mixture was heated in a Biotage Initiator™ microwave for 1 h at 120° C. The reaction was repeated three times with an increased amount of (R)-benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate (30 mg) in each reaction. The reaction mixtures were combined and the resulting mixture was concentrated and purified by preparative HPLC (30-70% AcCN/H2O with 0.035% TFA) to afford the title compound as a yellow oil (36 mg, 44%). 1H NMR (500 MHz, CD3OD) δ 1.21 (s, 9H), 2.30 (s, 3H), 2.36 (s, 3H), 4.94 (s, 1H), 5.07 (d, J=18.6 Hz, 1H), 5.21 (d, J=19.0 Hz, 1H), 7.36 (d, J=8.3 Hz, 2H), 8.04 (d, J=4.9 Hz, 2H), 8.10 (s, 1H), 8.22 (s, 1H). [M+H] calc'd for C23H25N3O5S, 456; found, 456
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:19]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:21]2=[O:39])=[CH:18][C:12]2[N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:17][N:13]1[C:12]2[CH:18]=[C:19]3[C:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][C:30]5[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=5)[C:21]4=[O:39])[CH2:2][O:8][C:9]3=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1
Reactant: CN1CCOc2cc(O)c(C3C(=O)N(Cc4ccc(C(F)(F)F)o4)c4ccccc43)cc21
Reactant: O=C(O)C(F)(F)F
Agent: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CN1CCOc2cc3c(cc21)C1(CO3)C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one trifluoroacetate salt to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one was obtained. To a suspension of 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one (0.59 g, 1.3 mmol) in methanol (8.5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (1.5 mL, 6.0 mmol) and the resulting solution was stirred at ambient temperature for 35 min. The solvent was removed and the residue was dried under reduced pressure. The residue was then precipitated by addition of hexanes, sonicated and the solvent was removed under reduced pressure. This process was repeated several times, until the solid formed a fine suspension in hexanes. The material was then collected by filtration and air-dried to afford 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one hydrochloride (0.60 g, 94%) as a pale gray powder: mp 105° C. (dec.) (hexanes); 1H NMR (300 MHz, DMSO-d6) δ7.33 (ddd, J=7.8, 7.5, 0.9 Hz, 1H), 7.22-7.17 (m, 3H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.74 (d, J=3.3 Hz, 1H), 6.48 (s, 1H), 6.25-6.19 (m, 1H), 5.10 (d, J=16.2 Hz, 1H), 5.02 (d, J=16.2 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.65 (d, J=9.3 Hz, 1H), 4.33-4.22 (m, 2H), 3.27-3.18 (m, 2H), 2.68 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 157.2, 153.2, 147.9, 141.9, 139.6 (q, J=42.0 Hz), 131.3, 129.0, 123.9, 123.4, 121.5, 119.0 (q, J=267 Hz), 114.2 (q, J=2.8 Hz), 112.4, 109.9, 109.3, 98.8, 79.9, 62.7, 57.1, 48.8, 48.6, 41.5, 36.6; MS (ES+) m/z 457.1 (M+1); Anal. Calcd. for C24H19FN2O4.HCl: C, 58.49; H, 4.09; N, 5.68. Found: C, 58.85; H, 3.74; N, 5.37.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH2:16][CH3:17])[C:6]=2[CH:5]=1)[CH3:2].F[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH2:16][CH3:17])[C:6]=2[CH:5]=1)[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1)[CH3:2]
Reactant: CCNc1ccc2c(c1)C(CC)=CCC2(C)C
Reactant: O=C(O)c1ccc(F)nc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC1=CCC(C)(C)c2ccc(N(CC)c3ccc(C(=O)O)cn3)cc21
Temperature: 125 °C
Yield: 4.2 %

Procedure:
To a mixture of 0.35 g (1.5 mmol) ethyl-(8-ethyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 167 and 0.32 g (2.2 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (22 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:12]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[C:4]=3[CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-chlorophenyl boronic acid according to Procedure A. White solid: mp 150-151° C. 1H-NMR (CDCl3) δ 8.52 (s, 1H, D2O exchangeable), 7.50 (s, 1H), 7.31-7.44 (m, 4H), 7.16 (d, 1H, J=1.5 Hz), 6.89 (d, 1H, J=8.2 Hz), 2.03 (m, 4H), 0.94 (t, 6H, J=7.4 Hz); MS (EI) m/z 315(M+, 53%). Anal. Calc. For C18H18ClNO2: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.16; H, 5.81; N, 4.32.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of 2-bromo-1-(4-fluorophenyl)ethanone (5.00 g, 23.0 mmol) and potassium thiocyanate (2.24 g, 23.0 mmol) in ethanol (50 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, water (60 ml) was poured into the reaction solution, and a crystal was separated by filtration, which was washed with 50% aqueous ethanol solution to give the desired product (3.71 g, 82.5%) as a solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][CH:10]=[C:9]([C:16]([OH:18])=[O:17])[CH:8]=2)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][CH:10]=[C:9]([C:16]([O:18][CH2:24][CH3:25])=[O:17])[CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2ccc(C(=O)O)cc2[nH]1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCCCc1nc(=O)c2ccc(C(=O)OCC)cc2[nH]1

Procedure:
A mixture of 5.0 g of 2-butyl-7-carboxy-4(1H)-quinazolinone in 100 ml of absolute ethanol containing 2 ml of sulfuric acid is refluxed for 48 hours. The solvent is evaporated in vacuo and the residue partitioned between water and chloroform. The organic layer is washed with aqueous saturated sodium bicarbonate, dried with anhydrous sodium sulfate, filtered and evaporated to a residue which crystallizes from ethyl acetate-hexane to afford 4.5 g of the desired product, mp 145° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:19][OH:20])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[C:6]([F:17])[CH:7]=2.Br[CH2:22][C:23]#[N:24].CC(C)([O-])C.[Li+]>C1COCC1>[NH2:1][C:2]1([CH2:19][O:20][CH2:22][C:23]#[N:24])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[C:6]([F:17])[CH:7]=2
Reactant: N#CCBr
Reactant: NC1(CO)c2cc(Br)c(F)cc2Oc2ncc(Cl)cc21
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCOCC1(N)c2cc(Br)c(F)cc2Oc2ncc(Cl)cc21
Yield: 43.5 %

Procedure:
A solution of (5-amino-7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)methanol (2.83 g, 7.87 mmol) and bromoacetonitrile (5.48 mL, 79 mmol) in 16 mL THF was heated to 40° C. and treated drop wise with lithium tert-butoxide [1N in THF (79 mL, 79 mmol)] over a time period of 4 hours. After completed addition the reaction mixture was concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-40% (95:5 EtOAc/MeOH)/DCM] gave 2-((5-amino-7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)methoxy)acetonitrile (1.362 g, 3.42 mmol, 43.4% yield).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22]>>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:6]1[C:7](=[O:15])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:22]
Reactant: O=c1[nH]c2ccccc2c2ccccc12
Reactant: O=C(Cl)c1ccco1
Product: O=C(c1ccco1)n1c(=O)c2ccccc2c2ccccc21

Procedure:
5-(Furan-2-carbonyl)-5H-phenanthridin-6-one was prepared from 5H-phenanthridin-6-one and 2-furoyl chloride according to GP 1. Yield, 2%. 1H-NMR (CD3OD): δ=6.77 (dd, J=3.6 Hz, J=1.8 Hz, 1H), 7.44 (ddd, J=J=7.5 Hz, J=1.0 Hz, 1H), 7.41 (ddd, J=J=7.7 Hz, J=1.1 Hz, 1H), 7.48 (ddd, J=J=7.5 Hz, J=1.1 Hz, 1H), 7.54 (ddd, J=J=7.5 Hz, J=1.1 Hz, 1H), 7.57 (dd, J=3.6 Hz, J=0.7 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.95 (dd, J=1.8 Hz, J=0.7 Hz, 1H), 8.47 (d, J=7.7 Hz, 1H); (+)-ESI-MS: m/z=290 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:17]/[S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: C/C(=N\[S@@](=O)C(C)(C)C)c1ccc(Br)cc1

Procedure:
To a solution of 1-(4-bromophenyl)ethanone (2.0 g, 10 mmol) and (S)-2-methylpropane-2-sulfinamide (1.2 g, 10 mmol) in THF (20 mL) was added Ti(OiPr)4 (5 mL). The reaction mixture was refluxed overnight. The mixture was quenched with sat. NH4Cl solution and diluted with EtOAc. The mixture was filtered through a pad of Celite and washed with EtOAc. The layers were separated and the organic layer was washed with brine, dried and concentrated to give the titled compound.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[N+:38]([C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1)([O-:40])=[O:39]>C(Cl)(Cl)Cl>[C:24]([CH2:23][N:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:22][CH2:21][CH2:20][N:19]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=2)[CH2:18][CH2:17]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1CCCNCCN(CC(=O)OC(C)(C)C)CCCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1CCCN(Cc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.9 %

Procedure:
To a solution of compound (5) (1.27 g, 2.96 mmol) in dry CHCl3 (50 ml) were added triethylamine (1.21 ml, 0.90 g, 8.88 mmol) and 4-nitrobenzyl bromide (0.64 g, 2.96 mmol). After stirring at an ambient temperature for 10 hours, the solvent was removed under reduced pressure, and the residue was purified through column chromatography on alumina (basic). Extraction with a mixture of ethyl acetate and methanol (10:2) gave a purified clear oil, which was then solidified to obtain compound (7) (1.30 g, 78% yield). 1H NMR (500 MHz, CDCl3): δ 8.11-8.10 (dd, 2H), 7.55-7.53 (dd, 2H), 3.56 (s, 2H), 3.24 (s, 2H), 3.20-3.06 (m, 6H), 3.01 (brs, 2H), 2.70-2.58 (m, 4H), 2.54-2.42 (m, 4H), 2.39 (brs, 2H), 1.93 (brs, 2H), 1.75 (brs, 2H), 1.39-1.36 (dd, 18H); 13C NMR (125 MHz, CDCl3): δ 171.3, 170.5, 147.0, 146.6, 130.1, 123.3, 81.9, 81.2, 58.1, 56.4, 55.8, 54.9, 53.1, 51.6, 51.5, 51.2, 49.6, 48.5, 46.1, 28.0, 25.1, 22.7; HRMS (FAB) calculated for C29H50N5O6: 564.3761 [(M+H)+], measured value: 564.3757 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[OH:13])=[O:4].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[O:13][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:4]
Reactant: O=C(Nc1ccc(Cl)cc1O)C(F)(F)F
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2NC(=O)C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 62.3 %

Procedure:
To a solution of 2-trifluoroacetylamino-5-chlorophenol (350 mg) and methyl 4-bromomethylbenzoate (435 mg) in DMF (3 ml), potassium carbonate (263 mg) was added at room temperature. The mixture was stirred for 1.5 hours at 60° C. After the termination of reaction, the reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-benzene) to give the title compound (353 mg) having the following physical data.
Reaction SMILES: [C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)([O:3]CC)=[O:2].[OH-].[Na+]>O.C(O)C>[C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)Cc1nnc(S)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1nnc(S)o1

Procedure:
A solution of 3.15 g (0.017 mol) of 2-carbethoxymethyl-1,3,4-oxadiazole-5-thiol in 25 ml of water and 25 ml of ethanol was stirred for 5 hours while maintaining the pH at 10-11 by addition of 10% aqueous sodium hydroxide solution. The mixture was neutralized to pH 7.0 then evaporated to dryness. The residue was dissolved in 15 ml of water, 50 ml of ethyl acetate was added and the solution was acidified to pH 1.5 with 3N hydrochloric acid. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was evaporated to give a residue which was recrystallized from ether-cyclohexane to give 2-carboxymethyl-1,3,4-oxadiazole-5-thiol, m.p. 167° -169° (dec.)
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH:2]=[CH2:3].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:3][CH2:2][CH2:1][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Brc1ccccc1
Product: N#Cc1ccc(N(CCCc2ccccc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized according to Example 84B from 4-[2-propen-1-yl(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and bromobenzene: MS (El) m/z 386 (M+, 6%), 281 (84%), 197 (100%), 170 (76%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li].[Li].C1C2C(=CC=CC=2)C=CC=1.C=CC=C.C(=[O:33])CCCCC>O1CCCC1>[CH3:1][CH2:2][C:3]#[C:4][CH:5]([OH:33])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC=O
Reactant: c1ccc2ccccc2c1
Agent: C=CC=C
Agent: [Li]
Solvent: C1CCOC1
Product: CCC#CC(O)CCCCC
Temperature: 55 °C

Procedure:
Following the procedure of Example 1, but with a pressure equalizing dropping funnel in place of the gas addition tube, 100 g. of naphthalene (0.77 moles) were added to 7.3 g. of lithium metal powder (1.05 moles) in 100 ml. tetrahydrofuran forming a dark green-brown lithium-naphthalene adduct over a period of about 30 minutes. 168 g. of the gaseous hydrocarbon mixture of Example 1 dissolved in 800 ml. tetrahydrofuran were added to the flask over a two hour period while maintaining the slurry at a temperature of about 55°C. Near the end of the addition, the slurry turned to an olive green color and became light brown after stirring for an additional hour. An aliquot of the resultant product was reacted with 1-hexanal producing 3-decyn-5-ol which, by gas chromotograph analysis, establishes a yield of butynyllithium in excess of 90%, based on lithium.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.COC1C=CC(P(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:63][C:64]1[CH:73]=[CH:72][CH:71]=[C:70]2[C:65]=1[C:66](=[O:84])[C:67]([C:77]1[CH:82]=[CH:81][CH:80]=[C:79]([F:83])[CH:78]=1)=[C:68]([CH:74](O)[CH3:75])[O:69]2>C1COCC1.O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@@H:74]([C:68]3[O:69][C:70]4[C:65]([C:66](=[O:84])[C:67]=3[C:77]3[CH:82]=[CH:81][CH:80]=[C:79]([F:83])[CH:78]=3)=[C:64]([F:63])[CH:73]=[CH:72][CH:71]=4)[CH3:75])[N:15]=[C:14]([C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:9][CH2:10][O:11][CH2:12][CH2:13]4)=[C:2]([F:1])[CH:3]=3)[C:22]=12
Reactant: CC(O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(N4CCOCC4)c(F)c3)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: COc1ccc(P(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(N3CCOCC3)c(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
This example is also described in Example 59 of WO 2012/151525. To a solution of 3-(3-fluoro-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.080 g, 0.254 mmol) in THF (2 ml), tris(4-methoxyphenyl)phosphine (0.134 g, 0.381 mmol) and diisopropylazodicarboxylate (0.07 ml, 0.381 mmol) is added and stirred at room temperature (RT) for 10 minutes. To this mixture (−)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one (0.077 g, 0.254 mmol) is added and stirred for 12 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid. MP: 242-245° C. Enantiomeric excess: 96.21% Mass: 599.1 (M++1).