Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[Sn:26](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.CCCCCC>[CH2:35]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
Into the solution of tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate 7.13 (1.65 g, 4.8 mmol) in THF (30 mL) was added 1M solution of n-BuLi in hexane (5 mL) and n-Bu3SnCl (1.66 g, 5.1 mmol) at −70° C. After 30 min., the reaction was warmed up to rt. After stirring for 1 h., the reaction mixture was extracted with ethyl acetate and washed with brine. After drying with MgSO4, the organic solvent was removed under vaco., the residue was purified by silica gel chromatography to obtain 0.58 g of tert-butyl 4-(6-(tributylstannyl)pyridin-3-yl)piperazine-1-carboxylate 7.14. LCMS [M+H]+: 554.07.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O.N1C2C=CC=CC=2N=N1>ClCCl>[Cl:22][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(Cl)Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.37 g 1H-Benzotriazole were dissolved in 10.9 ml thionyl chloride. The solution was diluted with dichloromethane to a total volume of 100 ml to obtain a 1.5 M solution of thionylchloride and 1H-Benzotriazole. 600 mg [4-(4-Trifluoromethyl-phenoxy)-phenyl]-methanol were dissolved in 50 ml dichloromethane. 1.86 ml of the above 1.5 M solution of thionylchloride and 1H-Benzotriazole were added. The reaction mixture was stirred at room temperature for three hours. The precipitate was filtered off through a pad of Na2SO4. The filtrate was evaporated in vacuo and the residue purified by flash chromatography on silica gel with the eluents n-heptane:ethyl acetate=1:2=>1:1 to obtain 613 mg 1-Chloromethyl-4-(4-Trifluoromethyl-phenoxy)-benzene.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:25]=[CH:24][C:12]([O:13][CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)O1.Br[C:28]1[C:36]2[O:35][CH:34]=[CH:33][C:32]=2[C:31]([F:37])=[C:30]([F:38])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:37][C:31]1[C:32]2[CH:33]=[CH:34][O:35][C:36]=2[C:28]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])=[CH:24][CH:25]=2)=[CH:29][C:30]=1[F:38]
Reactant: CC1(C)OB(c2ccc(OCc3cccc(C(=O)O)c3)cc2)OC1(C)C
Reactant: Fc1cc(Br)c2occc2c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To the compound (1.67 g, 4.72 mmol) obtained in Step 1, 7-bromo-4,5-difluoro-1-benzofuran (1.1 g, 4.72 mmol), sodium carbonate (1.0 g, 9.44 mmol), and Pd(dppf)Cl2 (catalytic amount), 1,4-dioxane (24 mL) and water (8 mL) were added, and stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and 1 N hydrochloric acid were added and stirred. After that, the insoluble material was filtered off, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the solid was collected by filtration.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH2:13][CH2:12][CH2:11]1)=[O:9].C([Sn](CCCC)=O)CCC.[Si]([N:41]=[N+:42]=[N-:43])(C)(C)C>COCCOC>[NH:41]1[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH2:13][CH2:12][CH2:11][N:10]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:2]=2[CH3:1])=[N:21][N:43]=[N:42]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(C#N)cccc32)c1C
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn[nH]4)cccc32)c1C
Yield: 83.8 %

Procedure:
A solution of 1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinoline-5-carbonitrile (0.020 g, 0.057 mmol), dibutylstannanone (2.86 mg, 0.011 mmol) and TMS-N3 (0.030 mL, 0.230 mmol) in DME (0.3 mL) was stirred at 100° C. for 3 days, and then concentrated in vacuo. The resulting residue was purified by preparative HPLC (PHENOMENEX® Axia Luna column, 5μ, C18, 30×75 mm; 10 min gradient from 75% A:25% B to 0% A:100% B (A=90% H2O/10% MeCN+0.1% TFA); (B=90% MeCN/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (18.7 mg, 82% yield) as an off-white solid. LCMS, [M+H]+=392.1.
Reaction SMILES: [Si](C([O:17][CH:18]([Si](C(C)(C)C)(C)C)[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)C1C=C(Cl)C=C(Cl)C=1)(C(C)(C)C)(C)C.C([Li])CCC.[Cl:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1.Cl>CCCCCC.O1CCCC1>[Cl:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([Cl:26])[C:22]=1[C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([Cl:39])=[CH:41][CH:42]=1)[CH2:18][OH:17]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)C(OC(c1cc(Cl)cc(Cl)c1)[Si](C)(C)C(C)(C)C)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CO)cc1Cl

Procedure:
React t-Butyldimethylsilyl-3,5-dichlorobenzyl ether (858.A1) (1 mole) with n-Butyllithium 1.6M solution in hexane followed by 4-Chlorobenzoyl chloride, (1.01 mole), in Tetrahydrofuran, while cold and treat the intermediate with aqueous Hydrochloric acid to give 3,5-dichloro-4-(4-chlorobenzoyl)benzyl alcohol (858.B).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:6]1=2.[ClH:25]>CO.O1CCOCC1>[ClH:25].[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[CH2:14][NH:15][CH2:16][CH2:17][C:6]1=2
Reactant: COCCn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCn1c2c(c3ccccc31)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-(2-methoxy)ethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (430 mg) was dissolved in methanol (15 mL). 4N HCl in 1,4-dioxan (1.5 mL) was added and the mixture stirred at room temperature overnight. The solution was concentrated in vacuo, azeotroped once with toluene and dried under vacuum. This gave 5-(2-methoxy)ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride as a grey foam (350 mg, 100% assuming HCl salt).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:31])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C>[NH:32]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:31])[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:23]=2)=[N:2][N:34]=[N:33]1
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
In 20 ml of DMF was dissolved 1.20 g of N-[2-(2-cyanophenylthio)phenyl]-4-hexyloxybenzamide followed by addition of 0.36 g of sodium azide and 0.30 g of ammonium chloride, and the mixture was stirred at 120° C. for 3 hours. Then, the same amounts of sodium azide and ammonium chloride as above were added twice at an interval of 3 hours. The reaction mixture was then acidified with diluted hydrochloric acid and the resulting crystals were collected by filtration and washed with water. The crystals were dissolved in chloroform and dried over magnesium sulfate and the solvent was distilled off. The crystals thus obtained were recrystallized from ethyl acetate-n-hexane to give 1.1 g of the title compound as white crystals, m.p. 154°-156° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[N:21]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][CH2:29][CH2:30][O:31][C:26]=2[CH:25]=1)=[C:22]=[O:23].C(N(CC)CC)C.Cl>C(#N)C>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([NH:21][C:22]([NH:1][CH2:2][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[CH2:6]4)=[O:23])=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc5c(c4)OCCO5)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1.00 mmol) and 6-isocyanato-2,3-dihydro-benzo[1,4]dioxine (0.18 g, 1.00 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.00 mmol) at room temperature under nitrogen. After 2 h, dil. aq. HCl (25 mL) was added. The solids were collected by filtration and washed with water (3×30 mL). The product was slurried in EtOAc for 24 h, then filtered and dried in vacuo to give 1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.41 g, 91% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 min; 10/90 to 90/10 CH3CN/0.1% aq H3PO4, Gradient over 15 min, 1.0 mL/min, 7.26 min (99.20%); mp: 230-232° C.; 1H NMR (DMSO-d6) δ 1.86-2.10 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.59 (d, J=17.6 Hz, 1H, CHH), 2.79-3.04 (m, 1H, CHH), 4.17 (q, J=4.8 Hz, 4H, CH2, CH2), 4.30 (d, J=17.4 Hz, 1H, CHH), 4.36-4.53 (m, 3H, CHH, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 6.62 (t, J=5.9 Hz, 1H, NH), 6.66-6.83 (m, 2H, Ar), 7.05 (d, J=2.1 Hz, 1H, Ar), 7.43 (d, J=7.7 Hz, 1H, Ar), 7.50 (s, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.41 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.18, 42.76, 47.10, 51.56, 63.81, 64.19, 107.05, 111.15, 116.66, 121.85, 122.91, 126.86, 130.26, 134.08, 137.90, 142.36, 142.99, 144.94, 155.28, 167.95, 170.99, 172.85; LCMS: MH=451; Anal Calcd for C23H22N4O6: C, 61.33; H, 4.92; N, 12.44. Found: C, 61.14; H, 4.82; N, 12.40.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([OH:9])[CH:7]=[CH:6][CH2:5][O:4]1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:19]([O:1][CH2:2][C@H:3]1[C@@H:8]([OH:9])[CH:7]=[CH:6][CH2:5][O:4]1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: OC[C@@H]1OCC=C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1OCC=C[C@@H]1O
Temperature: 0 °C

Procedure:
To a 0° C., stirred solution of cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol (0.4 g, 2.84 mmol) in CH2Cl2 (40 ml) under an Argon atmosphere was added imidazole (0.231 g, 3.4 mmol) followed by TBSCl (0.428 g, 3.4 mmol). The resulting mixture was stirred for 1H at 0° C. The reaction mixture was washed with water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product purified by flash chromatography (25-40% EtOAc in hexane).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17]>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([C:1](=[O:3])[CH3:2])[CH:13]=[CH:12][C:11]=1[O:16][CH3:17]
Reactant: COc1ccccc1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5–10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition of 2-fluoroanisole (62.6 g, 0.5 mol). The mixture was stirred at 0–10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with water (2×150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford material suitable for use in the next step (77.2 g, 92%): mp 92–94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH:17]=3)[C:12](=[O:27])[N:11]([O:28]CC3C=CC=CC=3)[C:10]2=[O:36])[CH:5]=[CH:6][C:7]=1[F:8]>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH:17]=3)[C:12](=[O:27])[N:11]([OH:28])[C:10]2=[O:36])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)c(Cl)c2)CC1
Agent: [Pd]
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccc(F)c(Cl)c2)CC1
Yield: 87.4 %

Procedure:
Using the General Method 6A. the reaction of 10% Pd/C (0.06 g) with 1-(3-chloro-4-fluorophenyl)-6-fluoro-3-benzyloxy-7-(4-methylpiperazin-1-yl)-1H-quinazoline-2,4-dione (Example R-1, 0.12 g, 0.23 mmol) afforded 0.085 g of the title compound as a solid, mp 197-199° C.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Br:15][CH2:16][CH2:17]C(O)=O>C1(C)C=CC=CC=1>[C:11]([O:10][C:6](=[O:5])[CH2:17][CH2:16][Br:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)CCBr
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCBr
Yield: 80.4 %

Procedure:
28 g (138 mmol) N,N-dimethylformamide di-tert-butyl acetal was slowly added during 50 min to a solution of 5.3 g (34.5 mmol) 3-bromo-propionic acid in 50 ml toluene. The reaction was heated for further 30 min, cooled and extracted with H2O/toluene (2×), aqueous saturated NaHCO3 and aqueous saturated NaCl. The organic phase was dried over Na2SO4 and carefully (low boiling point of the product) evaporated to give 5.8 g (80%) of 3-bromo-propionic acid tert butylester [U. Widmer, A convenient preparation of tert-butyl esters. Synthesis (1983), Issue 2, 135-6].
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][C@H:6]1[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=O.[BH4-].[Na+].[Cl-].[NH4+]>CO>[C:14]([O:13][C:11](=[O:12])[NH:10][CH2:9][C@@H:6]1[CH2:7][CH2:8][C@H:5]1[CH2:3][OH:2])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@@H]1CC[C@H]1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@H]1CC[C@H]1CO
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of Trans-2-(tert-Butoxycarbonylamino-methyl)-cyclobutanecarboxylic acid methyl ester (4.1 g, 16.8 mmol) in methanol (20 mL) at 0° C., sodium Borohydride (1.3 g, 33.6 mmol) was added portionwise. The mixture was stirred 4 h until TLC after TLC indicated completion of the reaction. A saturated solution of ammonium chloride was added, the methanol was removed under vacuum and the water was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, evaporated and purified with column chromatography on silica gel using n-Heptane-EtOAc (1:1). The product fractions were concentrated to give 2.8 g (16.8 mmol, 80% yield) of the title compound as a white solid. MS (m/e): 216.3 (M+H+)
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[C:4]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:3]=1.C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:6][C:23](=[O:24])[C:14]3[N:13]2[CH:17]=[CH:16][N:15]=3)=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Temperature: 25 °C
Yield: 69.3 %

Procedure:
4-Bromo-2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (12.65 g, 0.0413 mol) is stirred under nitrogen with N,N-carbonyldiimidazole (13.8 g, 0.0825 mol) at 135° C. for 7 hours. After being cooled down to room temperature, the mixture is filtered to yield a grey solid, which is suspended in ethyl acetate (500 mL) and stirred at reflux for 10 minutes. After filtration at room temperature, the solid is washed with ethyl acetated (200 mL) and dried under vacuum to afford the title compound as a grey powder (9.5 g, 69.2%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](OCC)=[O:22])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[O:7]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)CCCCc1ccc2c(c1)OCCO2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCCCc1ccc2c(c1)OCCO2
Yield: 88.7 %

Procedure:
To a suspension of lithium aluminum hydride (418 mg) in anhydrous THF (25 mL) was added dropwise under ice-cooling a solution of ethyl 5-(2,3-dihydro-1,4-benzodioxin-6-yl)pentanoate (2.91 g) in anhydrous THF (10 mL) under nitrogen atmosphere. The mixture was stirred under ice-cooling for 30 minutes, and then a saturated aqueous sodium sulfate solution was added dropwise thereto, followed by stirring at room temperature for 1 hour. Ethyl acetate was added thereto, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=65/35) to obtain 5-(2,3-dihydro-1,4-benzodioxin-6-yl)pentan-1-ol (2.17 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1OCC[O:14]1.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[O:14]
Reactant: COc1cccc(Oc2ccccc2C2OCCO2)c1
Agent: Cl
Solvent: O
Product: COc1cccc(Oc2ccccc2C=O)c1
Yield: 95.5 %

Procedure:
2-[2-(3-Methoxyphenoxy)phenyl]-1,3-dioxolane (32.7 g; 0.12 mol) was stirred in a mixture of water (95 ml) and concentrated hydrochloric acid (5 ml) at ambient temperature for 19 hours. The mixture was extracted with ether (2×60 ml) and the combined ether extracts were washed with saturated aqueous sodium bicarbonate solution (30 ml), water (3×30 ml) and saturated brine (30 ml). The resulting solution was dried, filtered and concentrated to give almost pure 2-(3-methoxyphenoxy)-benzaldehyde (A) (26.17 g, 95.4% yield) as an oil. This material was used without purification for the following step. However, an analytical sample was prepared by chromatography using a mixture of ether and hexane as eluant to give an amber oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:19])[F:20])=[CH:18][CH:17]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1ccc(COc2cncc(Cl)n2)cc1
Yield: 93.5 %

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol) and 4-trifluoromethylbenzyl alcohol (581 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). Recrystallization from hexane gave 0.81 g (93%) of the title compound: mp 67-69° C. MS m/z 289 (M+H)+. Anal. (C12H8ClF3N2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:31])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH:19]([F:31])[F:18])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(OCC(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid (CAS 1097730-45-4; WO2009091016) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=427.2 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)O1.[NH2:28][C:29]1[C:30]([C:38]#[N:39])=[N:31][C:32](Cl)=[CH:33][C:34]=1[NH:35][CH3:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:28][C:29]1[C:30]([C:38]#[N:39])=[N:31][C:32]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[C:11]([C:23]([F:24])([F:25])[F:26])[CH:10]=2)=[CH:33][C:34]=1[NH:35][CH3:36]
Reactant: CC1(C)OB(c2ccc(OCc3ccncc3)c(C(F)(F)F)c2)OC1(C)C
Reactant: CNc1cc(Cl)nc(C#N)c1N
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc(-c2ccc(OCc3ccncc3)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A suspension of 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)methyl)pyridine (1.39 g), 3-amino-6-chloro-4-(methylamino)-picolinonitrile (0.669 g), tris(dibenzylideneacetone)dipalladium (0) (173 mg), tricyclohexylphosphine (127 mg) and potassium phosphate (1.621 g) in 1,4-dioxane (15 ml) and water (7.5 ml) was stirred at 100° C. for 2 h. The reaction mixture was cooled, filtered to remove insoluble precipitate. The precipitate was dried in vacuum oven to give 430 mg light brown solid as 3-amino-4-(methylamino)-6-(4-(pyridin-4-ylmethoxy)-3-(trifluoromethyl)phenyl)picolinonitrile (29%). Filtrate was partitioned between water and ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated. Purified by Biotage SNAP cartridge KP-Sil column (25 g, heptane:ethyl acetate=1:0, 1:1, 1:3 to 0:1 then ethyl acetate:methanol=25:1, 20:1 then dichloromethane:methanol=20:1) to give 568 mg of the title compound as a light brown solid (39%).