Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)=O.Cl.[CH3:5][C:6]1([CH3:15])[CH2:11][CH:10]([OH:12])[CH2:9][C:8]([CH3:14])([CH3:13])[NH:7]1.[C:16]([Cl:19])([Cl:18])=[O:17].N1C=CC=CC=1.[Cl-].CC1(C)CCCC[N+]1(C)C.Cl.[NH+]1C=CC=CC=1>CC(=O)CC>[Cl-:18].[CH3:5][C:6]1([CH3:15])[CH2:11][CH:10]([O:12][C:16]([Cl:19])=[O:17])[CH2:9][C:8]([CH3:14])([CH3:13])[NH2+:7]1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: O=C(Cl)Cl
Agent: CC1(C)CCCC[N+]1(C)C
Agent: Cl
Agent: O=C=O
Solvent: CCC(C)=O
Solvent: c1ccncc1
Product: CC1(C)CC(OC(=O)Cl)CC(C)(C)[NH2+]1
Temperature: 80 °C

Procedure:
Into a 500 ml flask equipped with a magnetic stirbar, thermometer, gas inlet adapter, dual condensers (i.e., Dry Ice condenser atop a water cooled condenser), and oil bath were placed 28.2 (0.145 mole) of 2,2,6,6-tetramethyl-4-piperidinol hydrochloride and 250 ml of 2-butanone. The mixture was heated to reflux and 8.0 ml (0.11 mole) of condensed phosgene was allowed to evaporate into the reaction mixture cooling the mass to 73°-75° C. This was followed by pipet addition of 11.5 g (0.145 mole) of pyridine which caused an exothermic reaction raising the temperature to 80° C. An additional 10 ml (0.14 mole) of phosgene were evaporated into the system. During this time the reaction mixture cleared of initially suspended solid and then formed a precipitate. After the addition of phosgene was completed, nitrogen was bubbled into the system for 40 minutes under continued reflux. The mixture was then allowed to cool gradually overnight and then was cooled further in an ice water bath. The very hygroscopic solid was collected by filtration. The liquid was reduced to 50 ml volume by distillation at atmospheric pressure, cooled to ambient, and diluted with 100 ml of tetrahydrofuran. In this manner, more solids were obtained and isolated by filtration. The combined solids were then freed from residual solvent under high vacuum. The product was a mixture of the tetramethylpiperidinium chloride compound and pyridinium hydrochloride. This mixture was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13].CO>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:15][CH:12]([CH3:14])[CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred, cold (0° C.) solution of 4-bromo-1-fluoro-2-nitrobenzene (7 g, 32 mmol) in dichloromethane (100 mL) was added isopropylamine (5 mL, 64 mmol). The mixture was allowed to stir at 0° C. for 3 h and room temperature overnight. It was diluted with water and extracted with CH2Cl2. The organic layer was washed with water and brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo to give a crude red solid. Trituration with MeOH afforded the title compound as an orange-red solid. MS (ESI, pos. ion) m/z: 260.7 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](O)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=S(Cl)Cl.O>N1C=CC=CC=1>[F:16][C:13]([F:14])([F:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)C1
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C(F)(F)F)C1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
To a solution of tert-butyl3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (468 mg, 1.83 mmol) in pyridine (10 mL) was added SOCl2 (1.71 mL) and the reaction mixture was stirred at reflux temperature under nitrogen for 25 min, cooled to room temperature, H2O (20 mL) was added, extracted with ethyl acetate. The combined organic layer was washed with dilute aqueous HCl, saturated aqueous NaHCO3 and H2O successively. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in ethanol (10 mL), Pd/C (10%) (300 mg) was added and it was hydrogenated at room temperature over the weekend. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to give the subtitled compound (100 mg).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]([F:27])([F:26])[C:10]([N:12]([CH2:19][P:20]([O:24]Cl)([O:22]Cl)=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11]>CCOCC>[F:8][C:9]([F:27])([F:26])[C:10]([N:12]([CH2:19][P:20]([O:24][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O:22][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(ONC1CCCCC1)ONC1CCCCC1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of cyclohexylamine (14.6 g, 0.147 mole) in 100 ml. of ether was added dropwise with stirring ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (11.55 g, 0.035 mole) in 200 ml. of ether. The reaction was stirred overnight at room temperature, then filtered and the filtrate concentrated in vacuo to yield a gum-solid. Upon trituration with petroleum ether, ethyl N-trifluoroacetyl-N-(bis(cyclohexylamino)phosphonomethyl)glycinate (6.65 g) was obtained as a white solid, m.p. 118.5°-123° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=2)[NH2:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([N:17]=[C:1]=[O:2])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(CCCc2ccccc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc(CCCc2ccccc2)c1
Reaction time: 6 h
Yield: 95.8 %

Procedure:
170 g of phosgene are dissolved in 200 ml of toluene at -10° C. 145 g of 3-(3-phenylpropyl)-aniline, dissolved in 300 ml of toluene, are slowly added dropwise at -10° C. The mixture is warmed slowly, phosgene is introduced at 60° C., and the mixture is brought to the boil. After 6 hours, excess phosgene is flushed out with nitrogen and the mixture is distilled. 156 g of 3-(3-phenylpropyl)-phenyl isocyanate, of boiling point 107°-110° C./0.1 mbar, are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3[C:32](=O)[C:33]([F:36])([F:35])[F:34])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B.[ClH:39]>O1CCCC1>[ClH:39].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3[CH2:32][C:33]([F:35])([F:34])[F:36])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(C(=O)C(F)(F)F)CC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(CC(F)(F)F)CC2
Temperature: 0 °C

Procedure:
N-[2-({1-[1-(4-Fluorophenyl)cyclobutyl]-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (49 mg, 0.09 mmol) was dissolved in dry tetrahydrofuran (0.6 mL) under an atmosphere of nitrogen. The solution was cooled to 0° C. and a 1M solution of borane in tetrahydrofuran (0.181 mL, 0.181 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then heated under reflux for 2 h. The solvent was evaporated in vacuo, the residue was dissolved in dichloromethane (20 mL) and washed with water (10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The product was dissolved in dichloromethane (2 mL) and treated with 5N isopropanolic hydrochloric acid (27 μL, 0.135 mmol). The solvents were evaporated and the product was dried in vacuo. Yield: 45 mg (0.08 mmol, 88%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(CC)=O>[CH2:3]([N:15]([C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[Br:5])[S:16]([CH3:19])(=[O:17])=[O:18])[CH:2]=[CH2:1]
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Br
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: C=CCN(c1cc([N+](=O)[O-])ccc1Br)S(C)(=O)=O
Yield: 99.8 %

Procedure:
Allyl bromide (1.36 g, 11.25 mmol) was added to a mixture of N-(2-bromo-5-nitrophenyl)methanesulfonamide (1.66 g, 5.62 mmol) and cesium carbonate (5.49 g, 16.86 mmol) in methylethylketone (20 ml). The mixture was heated to reflux for 2 hr. The mixture was cooled and poured onto water. The product was extracted into ethyl acetate (2×75 ml) and the extracts were dried (anhydrous MgSO4) and concentrated to provide 1.88 g of N-allyl-N-(2-bromo-5-nitrophenyl)methanesulfonamide which required no purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:38][C@@:39]1([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:44][C@@H:43]([S:45][C:46]2[NH:50][CH:49]=[N:48][N:47]=2)[C@@H:42]2[C@H:40]1[C@H:41]2[C:51]([O:53][CH2:54][CH3:55])=[O:52].C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:38][C@@:39]1([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:44][C@@H:43]([S:45][C:46]2[NH:50][CH:49]=[N:48][N:47]=2)[C@@H:42]2[C@H:40]1[C@H:41]2[C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Reaction time: 0.33 h

Procedure:
Add thionyl chloride (2.5 mL, 34.32 mmol) to a stirred solution of ditert-butyl (1R,2S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.1 g, 4.23 mmol) in ethanol (40 mL) at 0-5° C. dropwise over 5 minutes with caution (exothermic reaction). Remove the cooling bath and heat the reaction mixture at reflux temperature for 16 hours. Evaporate the volatiles and dry the residue under high vacuum for 7 hours to obtain a colorless foam of diethyl (1R,2S,4R,5R,6R)-2-amino-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride. Add then 2-(tert-butoxycarbonylamino)acetic acid (0.89 g, 5.07 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.93 g, 5.07 mmol) to a solution of diethyl (1R,2S,4R,5R,6R)-2-amino-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate hydrochloride in anhydrous N,N-dimethylformamide (20 mL) at room temperature then add diisopropylethylamine (2 mL, 11.47 mmol) and stir the resulting yellow solution under nitrogen for 18 hours. Concentrate the solvent and partition the residue between ethyl acetate (40 mL) and a saturated solution of sodium hydrogen carbonate in water (40 mL). Stir the mixture for 20 minutes, separate the layers and extract the aqueous layer with more ethyl acetate (40 mL). Combine the organics layers, dry on sodium sulfate and concentrate to dryness. Purify the residue by flash chromatography eluting with ethyl acetate: iso-hexane (80:20 to 100:0) to give the title compound as a colorless solid (2.42 g, 4.86 mmol). MS (m/z): 498 (M+1), 520 (M+23).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12]I>[OH-].[Na+]>[F:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Fc1cccc2nc(S)sc12
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc2cccc(F)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a well-stirred solution of 7-fluoro-2-mercaptobenzothiazole (1.0 g, 5.4 mmol) in 10% aq. NaOH (10 mL) was added methyl iodide (2.14 g, 2.8 eq) dropwise, and the reaction mixture was stirred at rt for 30 min. A yellowish solid was collected by filtration, washed with cold water, and dissolved in ethyl acetate (50 mL). The EtOAc solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. 1H-NMR (CDCl3, 300 MHz): δ=7.66 (d, J=8.1 Hz, 1H), 7.40-7.33 (m, 1H), 7.04-6.97 (m, 1H), 2.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH:18]=[CH:19][C:20]#[N:21])[CH2:17][CH2:16]1.C1CCN2C(=NCCC2)CC1>CC#N>[CH:15]1([CH:18]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:19][C:20]#[N:21])[CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC=CC1CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Temperature: 40 °C
Reaction time: 72 h
Yield: 68.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.44 g, 12.6 mmol), 3-cyclopropylacrylonitrile (Preparation B; 2.34 g, 25.1 mmol) (as a mixture of isomers) and DBU (1.88 mL, 12.6 mmol) were suspended in MeCN (10 mL) and stirred at 40° C. for 3 days. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 25-35% EtOAc/Hexanes) to furnish 3-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (2.48 g, 8.64 mmol, 68.8% yield). MS (apci) m/z=288.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](OC)=[O:10])[CH:5]=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:10][CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)Cc1ccnc(C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCO)ccn1
Reaction time: 1 h
Yield: 60.7 %

Procedure:
Methyl 2-methylpyridin-4-ylacetate (1.78 g, 10.8 mmol) obtained in Step 1 was dissolved in THF (70 mL), then Lithium aluminum hydride (451 mg, 11.9 mmol) was added thereto at 0° C., followed by stirring at the same temperature for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, sodium sulfate decahydrate (3.22 g, 10.0 mmol) was added thereto, and the resulting mixture was further stirred at room temperature for 1 hour. The resulting precipitate was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:ammonia-methanol solution (2.00 mol/L)=40:1] to give 4-(2-hydroxyethyl)-2-methylpyridine (900 mg, yield 61%). Subsequently, 4-(2-aminoethyl)-2-methylpyridine dihydrochloride was obtained in a similar manner to Step 5 of Reference Example 9.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:29])=[C:4]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:5]([O:21][CH3:22])=[C:6]([CH:8]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[C:12]([CH3:20])=[N:11]2)[CH3:9])[CH:7]=1.[CH3:30][N:31](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N>[NH2:19][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:10]([CH:8]([C:6]3[C:5]([O:21][CH3:22])=[C:4]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[C:3]([CH3:29])=[C:2]([CH:7]=3)[C:30]#[N:31])[CH3:9])[N:11]=[C:12]([CH3:20])[C:13]=12
Reactant: CC(=O)N(C)C
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(C)c1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C#N)c(C)c1-c1cnn(C)c1
Temperature: 120 °C
Yield: 27 %

Procedure:
Pre-formed catalyst (0.05 mL, from Example 40) was added to a mixture 1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7.7 mg, 0.019 mmol), zinc (0.54 mg, 0.0082 mmol) and zinc cyanide (2.2 mg, 0.019 mmol) in N,N-dimethylacetamide (0.3 mL). The mixture was degassed with nitrogen 3 times. The reaction was heated at 120° C. for 1.5 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.1 mg, 27%). The product was isolated as a single enantiomer. LCMS calculated for C21H23N8O (M+H)+: m/z=403.2; Found: 403.2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([O:28][C:29]1[C:30]([CH3:46])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C@@:34]([CH3:45])([CH2:41][C:42]([OH:44])=[O:43])[CH2:33][CH2:32]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>O1CCCC1>[CH2:21]([O:28][C:29]1[C:30]([CH3:46])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH3:45])([CH2:41][C:42]([OH:44])=[O:43])[CH2:33][CH2:32]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@](C)(CC(=O)O)O2
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(=O)O)O2

Procedure:
To a solution of 11.0 g. of diisopropylamine in 50 ml. of anhydrous tetrahydrofuran at 0° was added 50 ml. of 2N butyllithium solution. To the resultant solution of lithium diisopropylamide was added a solution of 3.54 g. of (R)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetic acid in 25 ml. of tetrahydrofuran. The resulting mixture was heated at 50° for 4 hours, acidified with 2N HCl and extracted with ether. The ether solutions were washed with brine, dried (Na2SO4) and stripped of solvent to give (±)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetic acid, [α]D25 =±0°, m.p. 130°-133° .
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:5]([F:23])=[CH:4][N:3]=1.[CH2:24]1[CH2:34][O:33][C:32]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[O:25]1>>[CH2:21]([O:20][C:18]([C:15]([CH3:17])([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:23])=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:32]4[O:33][CH2:34][CH2:24][O:25][C:26]=4[CH:27]=3)[N:7]=2)=[CH:10][CH:11]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(C)(C)c1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)C(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to produce N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.31 (s, 1H), 8.97 (s, 1H), 8.03 (d, 1H, J=3.5 Hz), 7.70 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=2.3 Hz), 7.23 (d, 2H, J=8.8 Hz), 6.98 (dd, 1H, J=2.1 and 8.8 Hz), 6.66 (d, 1H, J=8.2 Hz), 4.19-4.15 (m, 4H), 4.07 (qt, 2H, J=7.0 Hz), 1.48 (s, 6H), 1.10 (t, 3H, J=7.0 Hz). LCMS: ret. time: 24.51 min.; purity: 100%; MS (m/e): 453 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)[CH:2]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C>[N+:16]([CH2:19][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:13][CH:12]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(Oc2cccnc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Oc2cccnc2)nc1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 25.5 %

Procedure:
A mixture of 6-(pyridin-3-yloxy)-pyridine-3-carbaldehyde (505.1 mg, 2.52 mmol) described in Manufacturing Example 100-1-1, nitromethane (680 μL, 12.6 mmol), ammonium acetate (388 mg, 5.04 mmol), and acetic acid (20 mL) was stirred for 2.5 hours at 140° C. This reaction mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. To a mixture of this residue in dimethyl sulfoxide (20 mL) and acetic acid (2 mL) was added sodium borohydride (114.0 mg, 3.02 mmol) at room temperature, which was stirred for 15 minutes. Water was added to this reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (157.3 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14](I)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:14]3[CH:13]=[CH:12][C:3]([O:4][CH2:5][CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[C:2]([F:1])[CH:15]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Fc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Fc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(2-fluoro-4-iodo-phenoxy)-ethyl]-pyrrolidine (300 mg, 0.90 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (201 mg, 0.94 mmol).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[N:20]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:19]3[C:18]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:37][C:33]1[CH:32]=[C:31]([NH:30][C:18]2[C:19]3[N:20]([CH:21]=[CH:22][C:23]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:15]([C:13]3[CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=[N:11][CH:12]=3)=[N:16][N:17]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Nc3cccc(F)c3)c3c(-c4ccccc4)ccn23)c1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cncc(-c2nnc(Nc3cccc(F)c3)c3c(-c4ccccc4)ccn23)c1
Temperature: 65 °C
Yield: 55.7 %

Procedure:
N-(tert-Butyl)-5-(1-((3-fluorophenyl)amino)-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.020 g, 0.039 mmol) was dissolved in TFA (0.500 mL, 6.48 mmol) and heated at 65° C. for 4 h. TFA was removed under reduced pressure and the resulting residue was diluted with saturated NaHCO3 (10 mL). The reaction mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (Condition B-9 described in general methods) to afford 5-(1-((3-fluorophenyl)amino)-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (0.010 g, 56%) as a pale yellow solid. LCMS Method B-7: retention time 1.79 min, [M+1]=461.0, Purity 99.6%. LCMS Method B-8: retention time 1.30 min, [M+1]=461.0, Purity 100%. 1H NMR (400 MHz, DMSO-d6) δ ppm: 6.82 (td, J=2.0 Hz, J=8.4 Hz, 1H), 6.95 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 7.12 (d, J=2.8 Hz, 1H), 7.27-7.33 (m, 1H), 7.50-7.65 (m, 6H), 7.71 (dt, J=2.4 Hz, J=12.0 Hz, 1H), 7.77 (br s, 2H), 7.81 (d, J=2.8 Hz, 1H), 8.70 (t, J=2.0 Hz, 1H), 9.20 (d, J=2.0 Hz, 1H), 9.31 (d, J=2.0 Hz, 1H).