Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([C:19]#[N:20])=[CH:9][N:8]=1)(=O)=O.[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O.C1COCC1>C(Cl)Cl>[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]#[N:20])=[CH:9][N:8]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cnc(OS(=O)(=O)C(F)(F)F)c(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc(-c2ccc(C=O)cc2)c(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 5-cyano-3-phenylpyridin-2-yl trifluoromethanesulfonate (1-2; 328 mg, 1.0 mmol), 4-formylphenylboronic acid (225 mg, 1.5 mmol), Pd(dppf)(CH2Cl2) (16 mg, 0.02 mmol), 2 M of Cs2CO3 water solution (2 mL, 4 mmol), and THF (2 mL) was microwaved (Smith-Synthesizer) at 160° C. for 10 min. After cooled to rt, the reaction mixture was treated with DCM (40 mL) and washed with water, brine and dried over anhydrous Na2SO4. Filtration and concentration afforded the crude product which was purified by flash chromatography on silica gel to give pure 6-(4-formylphenyl)-5-phenylnicotinonitrile (1-3). Analytical LCMS: single peak (214 nm), 3.240 min. 1H NMR (500 MHz, CDCl3): δ 10.01(s, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 1H), 7.31-7.39 (m, 3H), 7.13-7.18 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]23)[CH:21]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Product: Fc1cccc(F)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2,6-difluorophenyl boronic acid and following the procedures described in EXAMPLE 9, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 14. 1H NMR (CDCl3, 300 MHz): δ 7.19 (m, 1H), 6.93 (m, 2H), 6.83 (m, 3H), 3.81 (m, 2H), 3.59 (m, 1H), 3.41 (m, 1H), 3.21 (m, 2H), 3.0 (m, 2H), 2.82 (m, 3H), 2.60 (m, 1H), 1.80 (m, 2H). LRMS (ES+): 359 (M+H)+.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[O:19][CH2:20][O:21][CH3:22].CN(C)CCN(C)C.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[C:10]([O:19][CH2:20][O:21][CH3:22])=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:13][C:14]=1[CH3:1]
Reactant: [Li]CCCC
Reactant: COCOc1c(C(OC)OC)cccc1C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COCOc1c(C(F)(F)F)ccc(C)c1C(OC)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A n-butyllithium-1.59M n-hexane solution (40.0 ml, 64.4 mmol) was added dropwise to a solution of 1-(dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzene (12.0 g, 42.9 mmol) obtained in Example (6-4) and N,N,N′,N′-tetramethylethylenediamine (9.70 ml, 64.4 mmol) in tetrahydrofuran (100 ml) at −40° C. over 5 minutes. The reaction mixture was stirred at 0° C. for 15 minutes. After the reaction mixture was cooled to −40° C., methyl iodide (5.3 ml, 85.85 mmol) was added thereto and the mixture was further stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1) to give 2-(dimethoxymethyl)-3-(methoxymethoxy)-1-methyl-4-(trifluoromethyl)benzene as an oil (7.19 g, yield: 57%).
Reaction SMILES: CN(C)CCCN=C=O.[CH2:10]([C:17]1[NH:25][C:24]2[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:21](=[O:33])[N:20]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=3)[C:19]=2[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.NN.[H][H]>[Pd]>[NH2:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][N:20]2[C:19]3[N:18]=[C:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:25][C:24]=3[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[C:21]2=[O:33])=[CH:41][CH:40]=1
Reactant: CN(C)CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: CN(C)CCCN=C=O
Agent: NN
Solvent: O
Product: CN(C)CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By methods well known in the art 3-dimethylaminopropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-dimethylaminopropyl)xanthine, which in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl) xanthine.
Reaction SMILES: ClC1C=CC(C[CH:9]([NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=CC=1.[OH-].[K+].[CH2:35](O)[CH3:36].[ClH:38]>O>[Cl:38][C:11]1[CH:12]=[CH:13][C:35]([C:36]#[C:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=2)=[CH:9][CH:10]=1
Reactant: CCCCCCCCCCCC(Cc1ccc(Cl)cc1)Nc1ccc(C(=O)OCC)cc1
Reactant: CCO
Reactant: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A 4 g. sample of ethyl 4-[13-(4-chlorophenyl)-12-tridecylamino]benzoate is hydrolyzed with 1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected, dried in vacuo and crystallized from acetone to yield the title compound as a white powder.
Reaction SMILES: [F:1][C:2]([F:23])([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]#[N:15])=[CH:8][CH:7]=1)=[O:4].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:23])([C:16]([F:21])([F:22])[C:17]([F:19])([F:20])[F:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[NH:26][N:25]=[N:24][N:15]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: N#CCCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(CCc2nnn[nH]2)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 130 °C
Yield: 43.3 %

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-cyanoethyl)phenyl]butanamide (3.9 g), sodium azide (3.7 g), ammonium chloride (3 g) and dimethylformamide (60 mL) was stirred under a nitrogen atmosphere and heated in a 130° C. oil bath for 48 hours. Water (300 mL) was added to the hot mixture to dissolve all suspended salts and the solution was allowed to cool to room temperature. More water was added and the precipitate was collected by filtration. The tan solid was dried at 65° C. in vacuo overnight and recrystallized from a hexane/tetrahydrofuran mixture to give 1.9 g (43% yield) of the title compound as a tan solid, m.p. 161°-162° C.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[CH3:36])[CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH3:37][N:38]([CH3:45])[CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][NH2:42]>>[CH3:37][N:38]([CH3:45])[CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][NH:42][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[CH3:36])[CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CN(C)CC(C)(C)CN
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cccc(-c4ccc(F)cc4C)c3)c3ccccc23)n1
Product: Cc1cc(F)ccc1-c1cccc(C(=O)Nc2ccc(Oc3ccnc(NCC(C)(C)CN(C)C)n3)c3ccccc23)c1

Procedure:
Compound is prepared from 4′-fluoro-2′-methyl-biphenyl-3-carboxylic acid[4-(2-methylsulfanyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-amide and N,N,2,2-tetramethyl-1,3-propanediamine according to conditions described in general procedure J. (23 mg). 1H NMR (400 MHz, CDCl3) δ 8.01-8.1(m, 4H), 7.88(dd, 1H, J=0.8 and 8 Hz), 7.5-7.65(m, 5H), 7.26-7.33(m, 2H), 6.98-7.08(m, 2H), 6.21(d, 1H, J=6 Hz), 2.3(s, 3H), 2.0-2.2(brm, 10H), 0.6-0.9(brs, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15].N1CCOCC1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:15]#[C:14][CH2:13][OH:16])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCO
Reactant: FC(F)(F)Oc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: OCC#Cc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
To a solution of 1-iodo-3-(trifluoromethoxy)benzene (0.5 g, 1.73 mmol) in toluene (10 mL) was added prop-2-yn-1-ol (0.15 g, 2.62 mmol) and morpholine (0.5 mL). Then cuprous iodide (4 mg, 0.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) were added to the mixture under nitrogen. The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:6 to 1:3) to give 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-ol (0.3 g, 80.2%) as a yellow oil. LCMS retention time 1.552 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:13]2[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([C:13]2[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=2)[C:3]([CH3:22])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethanone (60 mg, 0.2 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodium cyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) and acetonitrile (0.7 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (60 mg, 100%). LCMS calculated for C16H22ClN4O (M+H)+: m/z=321.1. found: 321.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O.O.NN>C1COCC1.CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(C=CCO)cc1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc(C=CCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of 1.5 g (8.37 mmol) of 4-nitrocinnamyl alcohol in THF/methanol (60 mL, 1:1 v/v) was added a catalytic amount of Raney Nickel and hydrazine monohydrate (1.22 mL, 25.1 mmol). The mixture was stirred at room temperature for 3 h, additional hydrazine monohydrate (1.22 mL) being added after 1.5 h. The reaction mixture was filtered over HFLO and concentrated under reduced pressure to 5 mL. Dichloromethane (100 mL) was added and the resultant solution was washed with water, dried over Na2SO4, filtered, and concentrated, which gave 10 (1.24 g, 8.31 mmol, 99%).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH3:24])[CH2:11][N:12]1[C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:23])(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCCC.CCOC(C)=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:12]([CH2:11][C@H:10]([CH3:24])[CH2:9][OH:8])[C:13](=[O:23])[CH2:14][O:15][C:16]=2[CH:21]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2cc(F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: C[C@H](CO)CN1C(=O)COc2cc(F)ccc21
Yield: 100.4 %

Procedure:
The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methy-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (111MF14) (3.79 g, 10.7 mmol) and tetrabutylammonium flouride monohydrate (3.99 g, 14.3 mmol) were mixed according to GP8. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF18) (2.57 g, 100%). 1H NMR (CDCl3) δ 6.99-6.95 (m, 1H), 7.77-7.72 (m, 2H), 4.63 (m, 2H), 4.23-4.16 (m, 1H), 3.58-3.40 (m, 3H), 2.86 (s, 1H), 2.05-1.97 (m, 1H), 1.04 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3) 164.6, 159.2 (d, J=244.5 Hz), 146.4 (d, J=11.6 Hz), 124.9 (d, J=3.1 Hz), 115.9 (d, J=9.6 Hz), 109.4 (d, J=22.7 Hz), 105.3 (d, J=26.1 Hz), 67.5, 63.8, 43.8, 34.0, 15.0.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Cl([O-])(=O)=O.[Na+].[ClH:16].[Cl:17]Cl>O>[Cl:16][C:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[CH:1]=[C:2]([Cl:17])[C:3]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCl
Reactant: Cl
Agent: [Na+]
Agent: [O-][Cl+2]([O-])[O-]
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Yield: 95.6 %

Procedure:
139 part of p-nitrophenol are suspended in 200 parts of water and the suspension is ground. The finely particulate suspension of p-nitrophenol so obtained is then added simultaneously with 260 parts of a 33 % solution of sodium chlorate to 1250 parts of 33 % hydrochloric acid. The simultaneous addition of educt and chlorinating agent is made at a temperature of 25° C. and such that the sodium chlorate is added over 240 minutes and the p-nitrophenol for 20 minutes longer over 260 minutes. The batch is subsequently allowed to react for 30 minutes and residual chlorine is expelled over a further 30 minutes. Any chlorine still remaining is destroyed with sodium bisulfite. The product is then isolated by filtration, washed until neutral and dried, affording 199.5 parts of 2,6-dichloro-4-nitrophenol in 99.7 % purity. The yield is 95.6 %; melting point: 119°-120° C. (lit.: 125° C.). Analysis by gas chromatography shows that the product has the same retention time as authentic material.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=1[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=2[CH3:39])=[CH:16][CH:17]=1
Reactant: Cc1cc(C#N)ccc1Br
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)ccc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 4-bromo-3-methylbenzonitrile (0.20 g), 2M aqueous sodium carbonate solution (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.02 g) in toluene (5 ml) and ethanol (2 ml). The reaction mixture was heated at 100° C. under nitrogen for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer was neutralised with a saturated solution of sodium bicarbonate in water and extracted with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil (0.15 g)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[CH2:30][CH:31]=O>>[C:22]1([CH3:21])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[C:30]1[CH:31]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: Cc1cc(C)c(CC=O)c(C)c1
Product: Cc1cc(C)c(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)c(C)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2,4,6-Trimethyl-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 405.9; HRMS: calcd for C25H20F3NO+H+, 408.15697; found (ESI, [M+H]+), 408.1573.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]2[C:14]3=[C:15]([CH3:19])[C:16]([OH:18])=[CH:17][N:13]3[N:12]=[CH:11][N:10]=2)=[CH:6][N:5]=[C:4]2[NH:20][CH:21]=[CH:22][C:3]=12.[CH3:23][C:24]([OH:27])(C)[CH3:25]>C(N(CC)CC)C>[F:1][C:2]1[C:7]([O:8][C:9]2[C:14]3=[C:15]([CH3:19])[C:16]([O:18][CH2:23][C@H:24]([OH:27])[CH3:25])=[CH:17][N:13]3[N:12]=[CH:11][N:10]=2)=[CH:6][N:5]=[C:4]2[NH:20][CH:21]=[CH:22][C:3]=12
Reactant: CC(C)(C)O
Reactant: Cc1c(O)cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12
Solvent: CCN(CC)CC
Product: Cc1c(OC[C@@H](C)O)cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12
Temperature: 80 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
An oven dried sealed tube was charged with 4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (Example 5) (7.5 mg, 0.025 mmol), t-BuOH (0.25 mL), 0.5M of a solution of triethylamine in t-BuOH (5 μL, 0.0025 mmol) and R-(+)-propylene oxide (21 μL, 0.300 mmol). The tube was sealed and the mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled and concentrated in vacuo. The crude material was purified by preparative HPLC to afford the title compound (5 mg, 56%) as a off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, s), 8.31 (1H, d, J=9.6 Hz), 7.95 (1H, s), 7.93 (1H, s), 7.61 (1H, t, J=3.0 Hz), 6.59 (1H, dd, J=1.9, 3.4 Hz), 4.91 (1H, d, J=4.8 Hz), 4.02-3.94 (1H, m), 3.92-3.83 (2H, m), 2.42 (3H, s), 1.16 (3H, d, J=6.3 Hz). LCMS: (M+H)+=358, (M−H)−=356.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.N1C=CC=CC=1.O>CCOCC>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C(C)COCCc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: CC(COCCc1ccccc1)c1cccc(O)c1
Temperature: 190 °C

Procedure:
A mixture of 2-(3-methoxyphenyl)propyl 2-phenylethyl ether (176 mg., 0.65 mmole), pyridine (0.4 ml., 4.96 mmole) and dry pyridine hydrochloride (4 g., 34.6 mmole) is heated at 190° C. for 6 hours. The reaction mixture is cooled and added to a mixture of water (100 ml.) and ether (150 ml.). The ether extract is washed once with water (50 ml.) and, along with a second ether extract (50 ml.) of aqueous phase, is dried over magnesium sulfate and evaporated to an oil. The oil is purified via preparation layer chromatography on silica gel plates, eluted six times with 30% ether-pentane to yield the title product.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.C(O[CH2:14][N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[CH2:21]([N:15]1[CH2:16][CH:6]2[CH:5]([CH2:4][CH2:3][CH:2]([CH3:1])[C:7]2=[O:8])[CH2:14]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1CCC=CC1=O
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCC2CN(Cc3ccccc3)CC2C1=O
Reaction time: 3 h

Procedure:
To a solution of 1 g of 6-methyl-cyclohex-2-enone in 15 cm3 of dichloromethane are added, at room temperature, 3 drops of trifluoroacetic acid, followed by 3.6 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine. The reaction mixture is brought to reflux, with stirring, for 3 hours. After cooling, potassium carbonate is added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 25 cm3 fractions. Fractions 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.7 g of (3aRS,5RS,7aSR)-2benzyl-5-methyl-4-perhydroisoindolone is obtained in the form of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1(/[CH:28]=[CH:29]/[CH2:30][C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:31](=[O:32])[CH2:30]/[CH:29]=[CH:28]/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)C/C=C/c1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(C/C=C/c1ccccc1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 69.2 %

Procedure:
Preparation of example 120 from the title compound of Example 7 (hydrochloride) (44 mg, 0.141 mmol), (E)-4-phenyl-but-3-enoic acid (27 mg, 0.169 mmol), triethylamine (0.059 mL, 0.423 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (64 mg, 0.169 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. When the reaction was judged complete, the mixture was filtered to collect the solids which were then washed with methanol. After drying under vacuum, the title compound (41 mg, 0.0.095 mmol) was obtained as a yellow powder in 68% yield.