Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:32][CH2:31]C[NH:29][CH2:28][CH2:27]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([N:26]6[CH2:27][CH2:28][NH:29][CH2:31][CH2:32]6)[N:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCNC1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5CC5)c4)cc32)n1
Product: c1cc(N2CCNCC2)nc(-n2ncc3cnc(-c4cncc(C5CC5)c4)cc32)c1
Yield: 22 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-cyclopropylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepane, 112 was obtained as an off-white solid (30.9 mg, 22%). 1H NMR (400 MHz, DMSO) δ 9.37-9.25 (s, 1H), 9.04-8.98 (s, 2H), 8.67-8.59 (s, 1H), 8.51-8.45 (d, J=2.1 Hz, 1H), 8.05-7.99 (t, J=2.1 Hz, 1H), 7.74-7.66 (dd, J=14.5, 6.5 Hz, 1H), 7.24-7.15 (t, J=7.4 Hz, 1H), 6.65-6.58 (d, J=8.5 Hz, 1H), 3.90-3.73 (dt, J=10.0, 5.5 Hz, 4H), 3.00-2.91 (m, 2H), 2.75-2.65 (dd, J=13.3, 7.3 Hz, 2H), 2.12-2.04 (m, 1H), 1.91-1.81 (m, 2H), 1.12-1.03 (m, 2H), 0.88-0.81 (m, 2H).; MS (ESI) m/z: 412.2 [M+H]+
Reaction SMILES: [C:1]([P:5](=O)([C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[O:15][CH3:16])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[I:31]I.OS([O-])=O.[Na+]>C1COCC1.ClCCl>[C:1]([P:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[O:15][CH3:16])[CH2:6][I:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(OC)c1P(C)(=O)C(C)(C)C
Reactant: II
Agent: CN(C)CCN(C)C
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(OC)c1P(CI)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of 1 (7.4 g, 28.9 mmol, 1 equiv.) and TMEDA (6.50 mL, 43 mmol, 1.5 equiv.) in THF (40 mL) at −78° C. was added 2.5 M BuLi in hexanes (13.9 mL, 35 mmol, 1.2 equiv.) over 10 min. The resulting mixture was stirred at −78° C. for 1 h. To the mixture at −78° C. was added iodine (11.0 g, 43 mmol, 1.5 equiv.) in THF (20 mL) while controlling the temperature <−70° C. After the addition, the mixture was further stirred at −78° C. for 0.5 h and then warmed to 25° C. over 1 h. To the mixture was added 10% NaHSO3 solution (100 mL) and dichloromethane (100 mL). The dichloromethane layer was washed with brine (100 mL), dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluents: EtOAc to EtOAc/MeOH 10/1; monitored at 290 nm) to provide 2 as a thick oil (8.8 g, 23.0 mmol, 80%). 1HNMR (400 MHz, CDCl3): δ=7.40 (t, J=8.4 Hz, 1H), 6.56 (dd, J=8.4, 4.0 Hz, 2H), 3.80 (s, 6H), 3.79 (m, 1H), 3.34 (dd, J=11.2, 8.3 Hz, 1H), 1.18 (d, J=15.6 Hz, 9H); 31PNMR (162 MHz, CDCl3): δ=50.4; 13CNMR (100 MHz, CDCl3): δ=163.2, 134.2, 104.9 (d, J=63 Hz), 104.3 (d, J=6 Hz), 55.9, 35.3 (d, J=71 Hz), 25.0, −1.8 (d, J=59 Hz); ESI-MS: m/z 383 [M+H]+.
Reaction SMILES: BrC1C=CC([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=CC=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.[Br:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)CBr>>[Br:39][C:40]1[CH:47]=[C:46]([CH:45]=[CH:42][CH:41]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([CH3:18])[C:9]=1[C:19](=[O:21])[CH3:20]
Reactant: BrCc1cccc(Br)c1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1cccc(Br)c1

Procedure:
1-(4-(3-Bromobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromo-benzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 3-bromobenzyl bromide. Melting point: 109° C.; MS(ES+): 369/371.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[C:16](Br)[S:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(NCCN(C)C)c1nc2sc(Br)nc2c(=O)n1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2scnc2c(=O)n1Cc1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 6-benzyl-2-bromo-5-(1-{[2-(dimethylamino)-ethyl]amino}propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-3, 1 equiv) and 10% Pd/C in ethanol is hydrogenated at 1 atm. for 3 h. The mixture is filtered and the filtrate is concentrated to provide 6-benzyl-5-(1-{[2-(dimethylamino)ethyl]amino}propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-4).
Reaction SMILES: [CH3:1][C:2]([S:23]([CH3:26])(=[O:25])=[O:24])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+].O>O1CCCC1.CO.Cl>[CH3:1][C:2]([S:23]([CH3:26])(=[O:24])=[O:25])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCc1ccc(Sc2ccccc2)cc1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]butanoate (348.6 mg, 0.887 mmol) in tetrahydrofuran/methanol (4:1, 10 mL) was added a solution of lithium hydroxide monohydrate in water (1.78 M, 3.55 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCl (1N in water) and extracted with diethyl ether 2×. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]butanoic acid as a solid. 323 mg. LCMS: (M−1) 363.3.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(C)=O)C(=O)OCC

Procedure:
Alternatively, diethyl 2-aminomalonate hydrochloride (21.4 g, 100 mmol) and triethylamine (56 mL, 400 mmol, 4.0 eq.) were dissolved in dichloromethane (500 mL) and stirred with acetic anhydride (9.5 mL, 100 mmol, 1.0 eq.) at 0° C. and overnight at r.t. The mixture was washed with brine (2×200 mL) and dried over MgSO4. The organic phase was filtered through a short silica gel column I (6×6 cm, dichloromethane). The product 1 was isolated as a white crystalline solid. Yield: 22.08 g (100%); 99% purity (GC).
Reaction SMILES: Br[C:2]1[C:3](=[O:8])[CH2:4][CH2:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCO.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:7][C:6]1[CH2:5][CH2:4][C:3](=[O:8])[C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=1
Reactant: CC1=C(Br)C(=O)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1=C(c2ccc(C#N)cc2)C(=O)CC1
Temperature: 80 °C

Procedure:
2-Bromo-3-methyl-cyclopent-2-enone (Intermediate TEN1) (commercially available from Aldrich) (2.04 g, 11.4 mmol) and K2CO3 (3.16 g in 11 mL H2O) in toluene (45 mL) was treated with a solution 4-cyanophenylboronic acid (commercially available from Aldrich) (2.2 g, 15 mmol) in EtOH (27 mL). Tetrakis(triphenylphosphine) palladium(0) Pd(PPh3)4 (0.4 g), bis(dibenzylideneacetone) palladium(0), Pd2(dba)3 (0.055 g, ˜5 mol %) and triphenylphosphine (0.4 g) were added and the mixture was purged with N2 for 15 m. The mixture was heated to 80° C. for 15 h. The mixture was diluted with water and EtOAc:hexane. After extracting with EtOAc:hexane, the combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The crude oil was purified by column chromatography on silica gel with CH2Cl2 to give 4-(2-methyl-5-oxo-cyclopent-1-enyl)-benzonitrile (Intermediate TEN2) 1.74 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccncc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-chloro-3-nitro-pyridine (2 g, 12.61 mmol) in dioxane (15 mL) was treated with 1-methylpiperazine (1.515 g, 1.678 mL, 15.13 mmol) and DIPEA (2.445 g, 3.295 mL, 18.92 mmol). The mixture was stirred at 80° C. for 1 hour, cooled to RT. The mixture was partioned between EtOAc and an aqueous saturated solution of NaHCO3 (40 ml). Combined organic extract was dried over MgSO4 and concentrated under reduced pressure to give an orange oil which was purified by chromatography on silica eluting with 5-10% MeOH/EtOAc/0.5-1% NH4OH to give 1-methyl-4-(3-nitro-4-pyridyl)piperazine 14 as a deep yellow oil which crystallised on standing. (2.56 g, 11.52 mmol, 91.36%). MS (ES+) 223.4.
Reaction SMILES: [Cl-].C([Al+]CC)C.CO[C:9]([C:11]1[CH:15]=[C:14]([C:16]2[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=2)[N:13]([CH:26]([CH3:28])[CH3:27])[C:12]=1[CH:29]([NH:39][C:40]1[CH:45]=[C:44]([Cl:46])[C:43](=[O:47])[N:42]([CH3:48])[CH:41]=1)[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([F:38])[CH:31]=1)=[O:10]>>[Cl:46][C:44]1[C:43](=[O:47])[N:42]([CH3:48])[CH:41]=[C:40]([N:39]2[C:9](=[O:10])[C:11]3[CH:15]=[C:14]([C:16]4[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=4)[N:13]([CH:26]([CH3:27])[CH3:28])[C:12]=3[CH:29]2[C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([F:38])[CH:31]=2)[CH:45]=1
Reactant: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(C#N)c(F)c1
Agent: CC[Al+]CC
Agent: [Cl-]
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)c(F)c2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Step H1 but diethylaluminium chloride (1.8M in toluene) [96-10-6] was used instead of trimethylaluminium chloride, and 2-[(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-cyano-3-fluoro-phenyl)-methyl]-5-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step 195.1) was used instead of 2-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester. The title compound was obtained as a white solid. tR: 1.07 min (HPLC 3); ESI-MS: tR=0.93 min, [M+H]+ 563/565 (LC-MS 1); TLC: Rf=0.06 (EtOAc).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][S:2]1.[F:12][B-:13]([F:16])([F:15])[F:14].[CH2:17]([O+](CC)CC)[CH3:18]>>[F:12][B-:13]([F:16])([F:15])[F:14].[CH2:17]([S+:2]1[CH2:3][C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH3:18]
Reactant: CC[O+](CC)CC
Reactant: O=C1CSCc2ccccc21
Agent: F[B-](F)(F)F
Product: CC[S+]1CC(=O)c2ccccc2C1
Yield: 45 %

Procedure:
1.642 g (10 mmol) isothiochroman-4-one (J. Am. Chem. Soc. 1973, 95, 2923) was alkylated with triethyloxonium tetrafluoroborate (10 mmol, 1M in methylene chloride) according to the method described for compound B2. Recrystallization in ethanol gave 1.26 g (50%) of D1 as white crystals; mp=89.6° C. 1H-NMR (acetone-d6) δ 7.65-8.14 (4 H, m, Ar--H), 5.23 (1 H, d, J=16.1 Hz, --CHH--C(O)--), 5.03 (1 H, d, J=16.1 Hz, --CHH--C(O)--), 4.80 (1 H, d, J=17.2 Hz, --CHH--Ar), 4.55 (1 H, dd, J=2.0 and 17.2 Hz, --CHH--Ar), 3.45-3.85 (2 H, m, >S+ --CH2 --CH3), 1.55 (3 H, t, J=7.5 Hz, >S+ --CH2 -- CH3); 13C-NMR (acetone-d6) δ 183.64, 136.04, 131.78, 130.97, 130.75, 130.51, 128.93, 40.06, 34.45, 34.40, 8.85; UV-absorption max. (ethanol): 254, 293 nm; Anal. Calcd for C11H13BF4OS: C, 47.2%; H, 4.7%; S, 11.5%. Found: C, 47.3%; H, 4.6%; S, 11.5%.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:32]2C(=O)C3=CC=CC=C3C2=O)=[C:13]([CH:31]=1)[NH:14][C:15]([O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>NN.CO.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:31]=[C:13]([NH:14][C:15]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:16])[C:12]([NH2:32])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c(NC(=O)OCC2CCN(c3ccncc3)CC2)c1
Agent: NN
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(NC(=O)OCC2CCN(c3ccncc3)CC2)c1
Yield: 85.5 %

Procedure:
A solution of 5-(tert-butyldimethylsilyloxy)-2-phthalimido-N-[[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl]aniline (1.34 g, 2.28 mmol) in 1 M hydrazine in methanol (6 mL) was stirred at ambient temperature for 40 h during which time a white precipitate formed. The mixture was further diluted with methylene chloride and cooled with an ice bath then filtered. The filtrate was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 890 mg (86%) of the title compound as a tan powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][CH:14]=[CH2:15])[CH:3]=1.[N:16]12[CH2:23][C:20]([CH2:24][NH2:25])([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:25][CH2:24][C:20]23[CH2:23][N:16]([CH2:22][CH2:21]2)[CH2:17][CH2:18][CH2:19]3)=[O:8])=[C:4]([O:12][CH2:13][CH:14]=[CH2:15])[CH:3]=1
Reactant: NCC12CCCN(CC1)C2
Reactant: C=CCOc1cc(N)c(Cl)cc1C(=O)O
Product: C=CCOc1cc(N)c(Cl)cc1C(=O)NCC12CCCN(CC1)C2

Procedure:
Following the procedure of Example 1, the title compound is prepared from 4-amino-5-chloro-2-(2-propenyloxy)benzoic acid and 1-azabicyclo[3.2.1]octan-5-methanamine.
Reaction SMILES: Br[CH2:2][C:3]([CH2:14][CH2:15][O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:5]([NH:11][CH:12]=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[P:23]([O:32]C(C)C)([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26]>>[CH2:21]([O:20][C:18]([CH2:17][O:16][CH2:15][CH2:14][C:3]([CH2:2][P:23]([O:28][CH:29]([CH3:31])[CH3:30])([O:24][CH:25]([CH3:27])[CH3:26])=[O:32])=[CH:4][CH:5]([NH:11][CH:12]=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:19])[CH3:22]
Reactant: CCOC(=O)COCCC(=CC(NC=O)C(=O)OCC)CBr
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)COCCC(=CC(NC=O)C(=O)OCC)CP(=O)(OC(C)C)OC(C)C
Reaction time: 18 h

Procedure:
9 g (23.7 mmol) of ethyl 4-bromomethyl-6-ethoxycarbonylmethoxy-2-formylamino-hex-3-enoate and 23.3 ml (94.8 mmol) of triisopropyl phosphite (90%) are heated to 80° C. and stirred for 18 hours under a pressure of 100 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is chromatographed on silica gel with hexane/ethyl acetate 1:3 and then with hexane/ethyl acetate/ethanol (1:3:5%) giving ethyl 6-ethoxycarbonylmethoxy-2-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([O:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC(O)C.Cl>[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=5[F:30])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:53][CH2:54][CH:55]([CH3:57])[CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CC(C)COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: CC(C)COc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 170 °C
Yield: 37.5 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.12 g, 0.25 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-[(2-methylpropyl)oxy]aniline (0.081 g, 0.24 mmol) in anhydrous iPrOH (3 mL) was added HCl (2 drops, 37% weight in H2O). The reaction was heated at 170° C. for 33 min in the microwave. The reaction mixture was poured into half saturated NaCO3, extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography followed by prep-HPLC provided the title compound (0.07 g, 0.09 mmol, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 (d, J=6.6 Hz, 6H), 1.33-1.42 (m, 2H), 1.47 (s, 3H), 1.54 (d, J=11.7 Hz, 3H), 1.72-1.82 (m, 2H), 1.82-1.93 (m, 2H), 2.31 (s, 2H), 2.45 (s, 3H), 2.58-2.69 (m, 2H), 3.75 (d, J=6.2 Hz, 3H), 6.41-6.50 (m, 2H), 6.66 (s, 1H), 6.87-6.98 (m, 1H), 7.20 (t, J=8.2 Hz, 2H), 7.29 (d, J=10.6 Hz, 1H), 7.35-7.47 (m, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 8.20 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 8.43 (s, 1H), 9.31 (d, J=9.9 Hz, 1H), 10.23 (s, 1H). MS (M+H, ES+) 757.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]([NH2:8])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][NH2:8]
Reactant: COc1cc(C(N)=O)ccc1CN1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CN)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
3-Methoxy-4-[(1-pyrrolidinyl)methyl]benzamide (11.2 g, 47.8 mmol) was combined with lithium aluminum hydride (3.8 g 100 mmol, 2.10 eq.) in dry THF (320 mL). The reaction was heated at reflux until all of the starting amide had been consumed by tlc (9:1 CHCl3:MeOH, 1% TEA). The reaction mixture was allowed to cool to room temperature then water (5 mL) slowly was added. After 15 min, aqueous sodium hydroxide (5 mL of 15% w/v) was added followed by more water (15 mL). After 10 min, the reaction mixture was filtered through a pad of diatomaceous earth. The solvent was removed under reduced pressure to give the amine as an amber oil (7.95 g, 76%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.N.C(=O)=O.O>C(Cl)Cl>[O:17]1[CH2:16][CH:15]1[CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][NH:4]2
Reactant: CC(=O)n1ncc2c(OCC3CO3)cccc21
Agent: N
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Product: c1cc(OCC2CO2)c2cn[nH]c2c1

Procedure:
1-Acetyl-4-(2,3-epoxypropoxy)-indazole is stirred for 4 hours in a mixture of methylene chloride and liquid ammonia, using a solid carbon dioxide cooler. The reaction mixture is then evaporated in a vacuum to give a brownish oil which is pure enough for further reactions. By stirring with water, there is obtained a beige product which melts at about 60° C. (after melting, it again solidifies and then melts again at <260° C.).
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[C:13](C(OC)=O)([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].FC(F)(F)C(O)=O.[N+](=C)([O-])[O-]>CO.C1COCC1.[Na+].[Cl-]>[C:4]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)C1(C(=O)OC)CN(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])ccc21
Agent: C=[N+]([O-])[O-]
Agent: C[O-]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])ccc21

Procedure:
NaOMe (4.8 mL of a 1.28 M solution in MeOH, 6.1 mmol) was added dropwise to a solution of 1-(t-butyloxycarbonyl)-3,3-di(methoxycarbonyl)-6-nitroindoline (2.11 g, 5.55 mmol) in THF (100 mL) under nitrogen at 20° C., immediately giving an intense purple colour. After 5 min trifluoroacetic acid (0.51 mL, 6.7 mmol) was added in one portion, causing the nitronate colour to disperse. The pale yellow solution was diluted with aq. NaCl, extracted with EtOAc, and the extracts dried (Na2SO4) and evaporated to give crude title compound as a pale yellow oil. This compound showed signs of air oxidation on standing at room temperature, so was not further purified but used directly in the next step. 1H NMR (CDCl3) δ8.67, 8.34 (2 x br s, 1H, H-7), 7.85 (dd, J=8.2, 2.1 Hz, 1H, H-5), 7.49 (d, J=8.2 Hz, 1H, H-4), 4.48 (dd, J=10.5, 5.4 Hz, 1H, NCH2CH), 4.28 (dd, J=10.5, 5.3 Hz, 1H, NCH2CH), 4.22 (t, J=10.6 Hz, 1H, NCH2CH), 3.82 (s, 3H, CO2Me), 1.60 (s, 9H, t-Bu): 13C NMR δ170.5 (CO2Me), 151.6, 149.1 (C-6,8,9, NCO2, two peaks not observed), 125.5, 117.7, 109.9 (C-4,5,7), (OCMe3 peak not observed), 53.1 (OMe), 50.3 (C-2), 44.4 (C-3), 28.3 (C(CH3)3). HRMS calculated for C15H18N2O6 : 322.11649. Found: 322.11627.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N+:19]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.C(OCC)(=O)C.[Pd]>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reaction time: 3.5 h
Yield: 100.1 %

Procedure:
Part 1. To a solution of methyl 4-[(tert-butoxy)carbonylamino]-3-nitrobenzoate (0.44 g, 1.5 mmol) in methanol (2 mL), ethyl acetate (3 mL) and triethylamine (0.21 mL, 1.5 mmol) was added 10% Pd on carbon (159 mg, 0.15 mmol). The reaction mixture was hydrogenated under 1 atm H2 for 3.5 hours, filtered, and concentrated in vacuo to yield methyl 3-amino-4-[(tert-butoxycarbonyl)amino]benzoate (0.40 g, 99%) as a white solid. ES-MS (M+H—C4H8)+=211.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[CH:26]=[N:25][CH:24]=[N:23][C:22]=3[N:21](C(OC(C)(C)C)=O)[CH:20]=2)[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[CH:26]=[N:25][CH:24]=[N:23][C:22]=3[NH:21][CH:20]=2)[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(Cc3ccccc3)nn2)c2cncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(Cn2cc(-c3c[nH]c4ncncc34)nn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
17 mg (0.13 mmol) of potassium carbonate were added to a solution of 13 mg (0.035 mmol) of tert-butyl 5-(1-benzyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,3-d]pyrimidine-7-carboxylate in 10 ml of methanol, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated, and the residue was purified by preparative HPLC, giving 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine as colourless solid; HPLC/MS: 1.48 min, [M+H] 277;