Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O)(=O)C.[C-:20]#[N:21].[K+]>C(OCC)C>[OH:15][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:20]#[N:21]
Reactant: [C-]#N
Reactant: CCCCCCCCCCCCCC=O
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCC(O)C#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
To an ice-cooled solution of tetradecanal (18.75 g) in diethyl ether (100 ml) was added acetic acid (5.66 ml) and potassium cyanide (6.64 g). The mixture was warmed to room temperature and stirred for 72 hours. The resulting solution was washed with water, and the aqueous phase was extracted with diethyl ether (50 ml). The combined organic phase was dried, and concentrated to dryness. The residue was purified by silica gel chromatography and triturated in diisopropyl ether (10 ml) to give 2-hydroxypentadecanenitrile (4.66 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH:9]([NH2:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.O=C1CCC(=O)N1[O:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH:34]=[N:35][N:36]2C(OC)=O)=O.[OH-].[Na+]>O.CO.CN(C=O)C>[NH:36]1[C:37]2[C:33](=[C:32]([NH:31][C:29]([NH:11][CH:9]3[CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:10]3)=[O:28])[CH:40]=[CH:39][CH:38]=2)[CH:34]=[N:35]1
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: NC1CC(c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1cccc2[nH]ncc12)NC1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
An orange solution of Example 56B (98 mg, 0.666 mmol), DMF (1 mL), i-Pr2NEt (0.244 mL, 1.40 mmol), and methyl 4-((2,5-dioxopyrrolidin-1-yloxy)carbonylamino)-1H-indazole-1-carboxylate (232 mg, 0.699 mmol) was stirred at ambient temperature 15 minutes, followed by the addition of MeOH (2.00 mL) and sodium hydroxide (50% in water, 0.105 mL, 2.00 mmol). After 10 minutes, water (3 mL) was added dropwise and a sticky gum was observed. The mixture was heated to reflux and a slurry persisted. The mixture was cooled slowly to ambient temperature and filtered, washing with 1:1 MeOH/water (6 mL). The white solid was dried in a vacuum oven at 50° C. to provide (1H-indazol-4-yl)-3-(3-phenylcyclobutyl)urea (144 mg, 0.470 mmol, 70.6% yield). Analytical chiral HPLC (20% IPA/hexanes isochratic method, 0.7 mL/min, AD-H column) showed two peaks (Retention times: major: 10.1 min; minor: 12.1 min) in a 2:1 ratio. The mixture was dissolved in 1:1 IPA/MeOH (20 mL) and separated on a 30×250 mm AD-H semi-prep column (10 mL/min, 2 mL/injection, 15% IPA/hexanes isochratic, 28 min runs, stack injection) to provide the title compound (55 mg, 0.18 mmol, 38% yield) and Example 57 (23 mg, 0.074 mmol, 16% yield). 1H NMR (500 MHz, DMSO-d6) 13.15 (s, 1H), 8.75 (s, 1H), 8.24 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.62-7.25 (m, 6H), 7.21 (d, J=8.3 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.33 (dq, J=16.5, 8.2 Hz, 1H), 3.35-3.24 (m, 1H), 2.84 (ddd, J=15.6, 7.7, 2.8 Hz, 2H), 2.13 (td, J=10.4, 2.6 Hz, 2H). MS (DCI) M/Z 324 [M+NH4]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]([C:25]2[N:30]=[C:29]([O:31][C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[CH:28]=[N:27][CH:26]=2)=[N:8]1.[Cl:45][C:46]1[N:51]=[C:50](Cl)[CH:49]=[CH:48][N:47]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:45][C:46]1[N:51]=[C:50]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[C:9]3[C:25]2[N:30]=[C:29]([O:31][C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:33]3)[CH:28]=[N:27][CH:26]=2)[CH:49]=[CH:48][N:47]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(B5OC(C)(C)C(C)(C)O5)cc34)n2)C1
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: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccnc(Cl)n5)cc34)n2)C1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
A glass microwave reaction vessel was charged with (3R)-tert-butyl 3-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (600 mg, 0.99 mmol), 2,4-dichloropyrimidine (192 mg, 1.29 mmol, Fluka) and Pd(PPh3)4 (57 mg, 0.050 mmol). The tube was sealed and evacuated under vacuum and back-filled with N2 three times. 2 M Na2CO3 (2.48 mL, 4.95 mmol) and dioxane (5 mL) were added. The reaction was stirred and heated in at 100° C. for 3 h. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-60% EtOAc in hexanes, to provide (3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (505 mg, 0.85 mmol, 86% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 592.1 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:9][C:10]([C:12]1[S:16][C:15]([CH3:17])=[N:14][C:13]=1[CH3:18])=O)[CH3:8]>O1CCCC1>[CH3:17][C:15]1[S:16][C:12]([CH2:10][NH:9][CH2:7][CH3:8])=[C:13]([CH3:18])[N:14]=1
Reactant: CCNC(=O)c1sc(C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNCc1sc(C)nc1C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
0.8 g of lithium aluminum hydride and 20 mL of tetrahydrofuran were added in a 150 mL of single-neck flask equipped with a magnetic stirrer. After stirred for 0.5 to 1.0 hour under ice bath cooling, 1.5 g of N-ethyl-2,4-dimethylthiazole-5-carboxamide in 10 mL of tetrahydrofuran solution are added dropwise, and reacted at the same temperature for 0.5 to 10 hours, and then for 1 to 2 hours at room temperature. The reaction mixture was then extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 1.0 g of 2,4-dimethyl-5-ethylaminomethylthiazole which was used in the next step directly without purification.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[C:11]=1[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:21]O>>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:21])=[C:12]([F:19])[C:11]=1[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccc(B(O)O)c(F)c1F
Reactant: OO
Product: CCCCCCCCCc1ccc(O)c(F)c1F

Procedure:
Quantities: compound from Example 32 (13.6 g, 60 mmol) and H2O2, (10%, 61 cm3). The experimental procedure was described in Example 37.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](Cl)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]=[S:23]1(=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25](=[S:32])[NH:24]1.[OH-].[Na+]>CO>[O:33]=[S:23]1(=[O:22])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([S:32][CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:17]([O:19][CH3:20])=[O:18])=[N:24]1
Reactant: O=S1(=O)NC(=S)c2ccccc21
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)SC1=NS(=O)(=O)c2ccccc21

Procedure:
The solution of 0.3 g (0.001 mol) of methyl 3-[4-(benzyloxy)phenyl]-2-chloropropionate in methanol (2 ml) was added dropwise to the solution of 0.2 g (0.001 mol) 1,1-dioxo-1,2-benzoisothiazol-3(2H)-thione (thiosaccharine) and 0.04 g (0.001 mol) NaOH in methanol (3 ml). The solution thus obtained was heated at reflux for 5 h. The crude product obtained after evaporating the solvent was used without purification in the next step of the synthesis.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH3:17][O:18][C:19](=[O:49])[N:20]=[C:21]([S:47][CH3:48])[C:22]([C:36]1[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([OH:46])[CH:37]=1)=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:49])[N:20]=[C:21]([S:47][CH3:48])[CH:22]([C:36]1[CH:37]=[C:38]([O:46][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(O)c(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N=C(SC)C(Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
After adding 300 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran to a solution of 100 mg of {2-(3-hydroxy-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give (2-{3,4-dimethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]-1-methylsulfanylethylidene)carbamic acid methyl ester (80 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].CS(O[CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17]1)(=O)=O>CC(N(C)C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17]1
Reactant: CC(C)N1CCC(OS(C)(=O)=O)C1
Reactant: Oc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCC(Oc2ccccc2Br)C1
Temperature: 150 °C

Procedure:
To a solution of 2-bromophenol (2.6 g) in dimethylacetamide (20 ml) was added sodium hydride (640 mg) portionwise. A solution of 1-isopropylpyrrolidin-3-yl methanesulphonate [Example 134 (c)] in dimethylacetamide (20 ml) was added and the mixture was heated to 150° C. for 18 h. The mixture was allowed to cool and partitioned between water and dichloromethane. The organic phase was extracted with 2N aqueous hydrochloric acid which was then neutralised and extracted with dichloromethane. The extracts were dried (MgSO4), the solvent removed under vacuum and the product purified by silica chromatography using dichloromethane/aqueous ammonia/methanol mixtures to yield the title compound as a brown oil (496 mg).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]N=[C:4]([CH2:8]CCCC)[CH:3]=1.C([Mg]Br)CCCCC.Cl[C:22]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][N:23]=1>>[CH2:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:8])[CH:27]=1)[CH3:29]
Reactant: CCCCCc1cc(C)ccn1
Reactant: CCc1ccnc(Cl)c1
Agent: CCCCCC[Mg]Br
Product: CCCCCCc1cc(CC)ccn1

Procedure:
This compound was obtained using the same experimental procedure as per 4-methyl-2-pentyl-pyridine (see above), using hexyl magnesium bromide instead of pentyl magnesium bromide and 2-chloro-4-ethyl pyridine instead of 2-bromo-4-methylpyridine. The product was obtained with similar yield and purified in the same way.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23](C(=O)C(F)(F)F)[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate in 20 mL of methanol, 5 mL of water and 0.53 g of potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour 15 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate as a light yellow oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][N:30]([CH:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)[C:31](=[O:33])[CH3:32]>>[CH3:29][N:30]([CH:34]1[CH2:38][CH2:37][N:36]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:35]1)[C:31](=[O:33])[CH3:32]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(=O)N(C)C1CCNC1
Product: CC(=O)N(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N-methyl-N-(pyrrolidin-3-yl)acetamide via General Procedure E to give 25.5 mg of 298 following reverse phase purification. MS (Q1) 504.2 (M)+
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C(O)[C@@H](O)C=O>>[OH:23][CH2:1][C:2]([C@H:3]([C@@H:4]([C@@H:5]([CH2:6][OH:8])[OH:20])[OH:21])[OH:22])=[O:7]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C[C@H](O)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Operating the system in accordance with the conditions set forth in Table 1 results in a 97% recovery of dextrose in the raffinate stream and 87% recovery of fructose in the extract stream. The higher sugars, which include maltose, triose and higher saccharides, are also concentrated in the raffinate stream as compared to the extract stream. The extract stream is readily concentrated in suitable evaporators to provide a high fructose syrup having a dry solids (ds) of 77 percent, and a fructose content of 90-94% by weight dry solids basis.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.Br[C:27]1[CH:28]=[C:29]2[N:34]([CH:35]=1)[N:33]=[C:32]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:39][CH:38]=1)[N:31]=[CH:30]2.CC1(C)C(C)(C)OB([C:58]2[CH:67]=[CH:66][CH:65]=[CH:64][C:59]=2[O:60][CH2:61][C:62]#[N:63])O1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:49][N:46]1[CH2:47][CH2:48][N:43]([C:40]2[CH:39]=[CH:38][C:37]([NH:36][C:32]3[N:31]=[CH:30][C:29]4=[CH:28][C:27]([C:58]5[CH:67]=[CH:66][CH:65]=[CH:64][C:59]=5[O:60][CH2:61][C:62]#[N:63])=[CH:35][N:34]4[N:33]=3)=[CH:42][CH:41]=2)[CH2:44][CH2:45]1
Reactant: CN1CCN(c2ccc(Nc3ncc4cc(Br)cn4n3)cc2)CC1
Reactant: CC1(C)OB(c2ccccc2OCC#N)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc4cc(-c5ccccc5OCC#N)cn4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1155h. Into a 8-dram vial, Palladium Acetate (0.0059 g, 0.000026 mol) and Triphenylphosphine (0.019 g, 0.000074 mol) were added. The mixture was purged under an atmosphere of Nitrogen for 10 minutes. 1,4-Dioxane (2.00 mL, 0.0256 mol) was added and stirred for 10 minutes at room temperature. (6-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.102 g, 0.000264 mol), [2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-acetonitrile (0.137 g, 0.000527 mol), N,N-Dimethylformamide (4.0 mL, 0.052 mol), and 1.50 M of Sodium carbonate in Water (1.58 mL, 0.00237 mol) were added. The reaction was heated at 90° C. for 3 hours. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions afforded a solid. The solid was triturated with Et2O and filtered to give (2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-6-yl}-phenoxy)-acetonitrile a yellow solid (5 mg, 3%). LCMS (E/I+) 440.18 (M+H). NMR 1H (DMSO-d6)-9.57 (s, 1H), 9.29 (s, 1H), 8.93 (s, 1H), 8.18 (s, 1H), 7.81 (d, 1H, J=7.81 Hz), 7.69 (d, 2H, J=8.19 Hz), 7.34 (t, 1H, J=7.80 Hz), 7.26 (d, 1H, J=7.80 Hz), 7.21 (s, 1H), 7.14 (t, 1H, J=7.02 Hz), 7.00 (d, 2H, J=8.19 Hz), 5.32 (s, 2H), 3.75 (d, 2H, J=12.58 Hz), 3.485-3.59 (m, 2H), 3.09-3.24 (m, 2H), 2.80-2.97 (m, 5H).
Reaction SMILES: [Na].[CH2:2]([N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH3:21][O:22][C:23]1[C:24](=[O:32])[CH2:25][C:26]([CH3:31])([CH3:30])[CH2:27][C:28]=1[CH3:29]>C(O)C>[CH2:2]([N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:29][C:28]2[CH2:27][C:26]([CH3:30])([CH3:31])[CH2:25][C:24](=[O:32])[C:23]=2[O:22][CH3:21])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: COC1=C(C)CC(C)(C)CC1=O
Agent: [Na]
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=O)CC(C)(C)C2)c(OC)c1
Temperature: 60 °C
Yield: 61.2 %

Procedure:
In 10 ml of ethanol, 0.32 g (13.9 mmol) of sodium was dissolved. Next, 2.36 g (8.96 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 1.58 g (9.39 mmol) of 2-methoxy-3,5,5-trimethyl-2-cyclohexenone were dissolved in ethanol and added to the mixture. The mixture was stirred with heating at 60° C. for 17 hours and concentrated. The residual liquid was purified by silica gel column chromatography to give 2.27 g of a dark red oily matter (yield: 61.2%).
Reaction SMILES: O=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:8]=2)[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.O>C1(C)C=CC=CC=1>[S:33]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:8]=2)[NH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=S)N2
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a solution of 5-(2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-pyrrole-2-carbonitrile (0.55 g, 1.8 mmol, 1 eq) in toluene (50 mL) was added Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq) and the reaction was heated to 80° C. for 1 hour. The reaction was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel gave the product as a white solid (0.32 g, 55%). 1H NMR (d6-DMSO, 500 MHz) δ 1.36–1.99 (m, 10 H), 3.7 (s, 3 H), 6.35 (d, 1 H, J=4.2 Hz), 7.05 (d, 1 H, J=4.2 Hz), 7.16 (d, 1 H, J=7.9 Hz), 7.44 (dd, 1 H, J=1.6, 8.1 Hz), 7.83 (d, 1 H, J=1.6 Hz), 12.75 (s, 1 H). MS (ESI) [M−H]−=320. Anal. calcd. for C19H19N3S: C, 70.99; H, 5.96; N, 13.07. Found: C, 68.69; H, 5.36; N, 12.27.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[N+]([NH:19][C:20](N)=[O:21])([O-])=O.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][N:9]([C:20]([NH2:19])=[O:21])[CH2:8]1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.1 %

Procedure:
To a solution of 2.2 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine in 45 ml of methylene chloride and 45 ml of absolute ethyl alcohol was added 7 g (0.066 mole) of nitrourea and the mixture was stirred at room temperature for 48 hr. The mixture was filtered. The filtrate was evaporated to dryness and the residue was partitioned between 75 ml methylene chloride and 75 ml water. The water layer was extracted three times with 50 ml of methylene chloride. The methylene chloride extracts were combined and evaporated to dryness. The residue was treated (washed) with a mixture of 1 ml methylene chloride and 20 ml of toluene and filtered. The precipitate was recrystallized from ethanol-water to give pale yellow crystals. The crystals were mixed with 2 ml of methylene chloride and 20 ml toluene and the mixture was heated on a steam bath for 2 hrs. The mixture was stored in a refrigerator for approximately 72 hrs. and filtered to give 1.2 g of the product as white crystalline needles, m.p. 151°-152° C.