Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:24]([C:27]1[N:31]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:30]=[C:29]([CH:36]=O)[CH:28]=1)[CH2:25][CH3:26]>>[C:32]([N:31]1[C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][C:29]([CH2:36][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)=[N:30]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: CCCc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1C(C)(C)C
Yield: 86 %

Procedure:
Compound 93 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])[CH:34]=[CH:35][CH:36]=1>>[C:25]([C:24]1[CH:23]=[C:22]([N:8]2[C:6]3[N:7]=[C:2]([NH:30][C:31]4[CH:32]=[C:33]([CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])[CH:34]=[CH:35][CH:36]=4)[N:3]=[CH:4][C:5]=3[CH:11]([CH3:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[C:9]2=[O:21])[CH:29]=[CH:28][CH:27]=1)#[N:26]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Cl)ncc3C2C)cc1
Reactant: CC(=O)OCCc1cccc(N)c1
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOC(C)=O)c4)ncc3C2C)cc1
Temperature: 110 °C

Procedure:
A mixture of (±)-3-[7-chloro-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (1.00 g; 2.42 mmol) (from Example 2 supra) and acetic acid 2-(3-amino-phenyl)-ethyl ester (2.03 g; 11.3 mmol) (from Example 3b supra) was heated in an oil bath at 110° C. for 1.5 hours. Upon cooling, the mixture was triturated with hexanes containing a small volume of ethyl acetate. The supernatant was decanted away and the residue was purified, in two runs, by flash chromatography (Biotage 40M; 50:50 to 70:30 ethyl acetate-hexanes gradient). The purified material was crystallized from ethyl acetate-hexanes to give (±)-acetic acid 2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl ester as a white solid. (1.03 g; 77.5%). Melting Point: 170–172° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([NH2:15])=[N:11][NH:12]2)=[CH:8][CH:7]=1>N1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([NH:15][C:1](=[O:3])[CH3:2])=[N:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 3 °C
Reaction time: 48 h

Procedure:
0.32 cm3 of predistilled acetyl chloride is added to 750 mg of 6-chloro-1H-indazole-3-amine in 10 cm3 of pyridine, after the reaction medium has been cooled to about 3° C. The medium is then allowed to return to 19° C. over 48 hours. The reaction medium is evaporated to dryness under reduced pressure (2 kPa; 40° C.). The residue is taken up in 75 cm3 of ethyl acetate and 50 cm3 of distilled water. The organic phase is washed again with 50 cm3 of distilled water and then dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 40° C.). After drying (90 Pa; 45° C.), 700 mg of N-(6-chloro-1H-indazol-3-yl)-acetamide, melting at 240° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12](Cl)=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].[NH3:23]>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12]([NH2:23])=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: O=C(Cl)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reactant: N
Solvent: ClCCl
Product: NC(=O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 0.25 h

Procedure:
Over a period of 15 minutes, 4.86 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid chloride are added dropwise, while stirring, to 15 ml of a 2.5 % solution of ammonia in dichloromethane. Stirring is carried out for 7 hours at room temperature, small amounts of a finely crystalline precipitate are filtered off and the filtrate is concentrated to dryness by evaporation, chromatographed over silica gel using dichloromethane/methanol (15:1) as eluant and recrystallised from ether/hexane. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxamide is obtained having a melting point of 174°.
Reaction SMILES: [CH2:1]([C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)(C(OCC)=O)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[CH2:1]([CH:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 7 h
Yield: 59.1 %

Procedure:
A mixture of diethyl benzyl-4-nitrobenzylmalonate (24 g), KOH (14 g) and water (100 ml)-ethanol (150 ml) was stirred at 90°-100° C. for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1N HCl and extracted with ethylacetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in pyridine (100 ml) and the solution was stirred at 90° C. for 16 hours. The organic solvent was evaporated off and the residue was acidified with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residual oil was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:3, v/v) gave 2-benzyl-3-(p-nitrophenyl)propionic acid (10.5 g, 59%) as crystals.
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:21][N:22]([CH3:29])[CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26]>O>[CH:17]1([C:3]2[C:2]([NH:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][N:22]([CH3:29])[CH3:21])=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: CN(C)CC(C)(C)CN
Solvent: O
Product: CN(C)CC(C)(C)CNc1nn2c(-c3ccccc3)nnc2cc1C1CCC1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine (100 mg) and N,N,2,2-tetramethyl-1,3-propanediamine (2 ml) were heated together in a sealed tube at 70° C. for 16 hours. Cooled and water (5 ml) added. Precipitate filtered, washed (water, ether) and dried. 1H NMR (250 MHz, DMSO) δ 1.20 (6H, s), 2.10 (1H, m), 2.24–2.65 (14H, m), 3.53–3.70 (2H, m), 7.69–7.82 (4H, m), 8.03 (1H,s), 8.70 (2H, m). MS (ES+) MH+=379
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8](B(O)O)=[CH:9]3)=[CH:4][C:3]1=2.[CH2:22]([N:25]1[CH:29]=[C:28](I)[CH:27]=[C:26]1[C:31]([O:33][CH3:34])=[O:32])[CH2:23][CH3:24]>>[CH2:22]([N:25]1[CH:29]=[C:28]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:12]4[C:13]([CH3:17])([CH3:16])[CH2:14][CH2:15][C:2]([CH3:21])([CH3:1])[C:3]=4[CH:4]=3)[CH:9]=2)[CH:27]=[C:26]1[C:31]([O:33][CH3:34])=[O:32])[CH2:23][CH3:24]
Reactant: CC1(C)CCC(C)(C)c2cc3cc(B(O)O)ccc3cc21
Reactant: CCCn1cc(I)cc1C(=O)OC
Product: CCCn1cc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1C(=O)OC
Yield: 22.3 %

Procedure:
Following the basic procedure of Example 7(f), by reacting 1.7 g (6 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthrylboronic acid with 1.47 g (5 mmol) of methyl N-propyl-4-iodo-2-pyrrolecarboxylate, 450 mg (22%) of methyl N-propyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)-2-pyrrolecarboxylate were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[O:17])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(C2(C(=O)O)CCOCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc(C2(C(=O)N3CCN(C)CC3)CCOCC2)cc1
Yield: 77 %

Procedure:
The title compound (515 mg, 77%) was prepared using 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid, N-methyl-piperazine and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) similarly to the procedure used for example 166. HRMS ESI+ m/z 319.2009 [MH]+.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C@H:16]1[NH:38][CH2:37][C:20]2=[C:21]3[C:25](=[CH:26][CH:27]=[C:19]2[O:18][CH2:17]1)[N:24]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:23]=[CH:22]3.C=O>C1COCC1>[CH3:1][N:38]1[CH2:37][C:20]2=[C:21]3[C:25](=[CH:26][CH:27]=[C:19]2[O:18][CH2:17][C@H:16]1[CH3:15])[N:24]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:30])[CH:23]=[CH:22]3
Reactant: C[C@@H]1COc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2CN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1COc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2CN1C
Reaction time: 0.33 h
Yield: 38.7 %

Procedure:
Sodium triacetoxyborohydride (7.5 mg, 0.040 mmol) was added to a solution of (3R)-3-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 73, 0.010 g, 0.029 mmol) and formaldehyde (37 wt. % in H2O, 0.020 mL, 0.25 mmol) in THF (1 mL). The mixture was stirred for 20 minutes, evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (4 mg) in the form of the trifluoroacetate salt. MS m/z 357 [M+H]+.
Reaction SMILES: I[C:2]1[C:3]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.C(OC(OCC)/C=C/B1OC(C)(C)[C:33]([CH3:39])([CH3:38])O1)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH2:5]([N:6]([CH2:7][CH3:2])[CH2:39]/[CH:33]=[CH:38]/[C:2]1[C:3]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:4]
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Reactant: Nc1ncc(I)c2onc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCN(CC)C/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)noc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-Iodo-3-(4-phenoxyphenyl)isoxazolo[4,5-c]pyridin-4-amine (0.100 g, 0.233 mmol) in 1,2-dimethoxyethane (4 mL) and water (2 mL) was reacted with an 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.09 g, 0.35 mmol), sodium carbonate (0.05 g, 0.47 mmol) and tetrakis triphenylphosphine palladium (0) (0.02 g, 0.014 mmol) at 90° C. for 18 hours. The solvent was removed in vacuo and the residue was dissolved in acetone/water 95:5 (10 mL) then p-toluene sulfonic acid was added. The mixture was stirred at ambient temperature for 18 hours then evaporated and the residue dissolved in 1,2-dichloroethane (4 mL). Diethylamine (100 mg) was added followed by sodium triacetoxyborohydride (100 mg). The mixture was stirred for 18 hours then the concentrated and by preparative RP-HPLC (Rainin C18, 8 mm, 100 Å, 25 cm; 20% acetonitrile-0.1M ammonium acetate isocratic for 5 minutes, then 20-80% acetonitrile-0.1M ammonium acetate over 30 min, 21 ml/min) followed by treatment with Silica-carbonate and lyophilization: 1H NMR (DMSO-d6, 400 MHz) δ 8.08 (s, 1H), 7.7 (d, 2H), 7.46 (t, 2H), 7.16-7.25 (m, 5H), 6.6 (d, 1H), 6.49 (m, 1H), 6.33 (bs, 2H), 3.25 (d, 2H), 2.50 (q, 4H), 1.0 (t, 6H); Rt=2.90 min (Conditions a), MS m/e: 413 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([OH:13])(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>C1(C)C=CC=CC=1>[C:2]1([NH:1][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C/C=C/C(=O)O
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)Nc1ccccc1
Yield: 60.7 %

Procedure:
A mixture of aniline (3.0 g, 32 mmol) and crotonic acid (2.0 g, 23 mmol) in toluene (20 mL ) was heated at reflux for 18 h. Removal of solvent and chromatography (silica gel, EtOAc/hexane, 9/1 ) of the crude material afforded 2.5 g (61%) of 3-phenylaminobutanoic acid. The acid was treated with PPA (20 mL ) at 110° C. for 6 h and the reaction mixture was poured into ice water (50 mL) and then was neutralized with Na2 CO3 to pH 7. Extraction with EtOAc (3×60 mL) followed by chromatography (silica gel, EtOAc/hexane, 4/6) afforded 1.0 g (44%) of 1,2,3,4-tetrahydro-2-methyl-4-quinolinone (structure 59A of Scheme XLVIII, where R1 =R3 =H, R2 =methyl) as a yellow solid. The quinolinone was treated with di-tert-butyl dicarbonate (2.2 g, 10 mmol) and DMAP (0.84 g, 6.8 mmol) in THF (15 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) to afford 1.1 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone as a yellow oil. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.99 (d,J=7.5, 1H), 7.78 (d,J=7.5, 1H), 7.50 (t, J=7.5, 1H), 7.12(t,J=7.5, 1H), 5.10(m, 1H), 3.04(dd,J=17.3, 5.8, 1H), 2.57(dd,J=17.3, 1.7, 1 H), 1.56 (s, 9 H), 1.22 (d,J=6.9, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH2:13](N(CC)CC)[CH3:14]>C(O)C>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH:13]=[CH2:14])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc2cccc(Br)c2n1
Solvent: CCO
Product: C=Cc1cccc2ccc(C)nc12
Yield: 73.3 %

Procedure:
A suspension of 4.80 g (21.60 mmol) 8-bromo-2-methylquinoline (commercially available from ACB Block Ltd, Moscow, Russia), 0.89 g (1.10 mmol) PdCl2dppfCH2Cl2, 4.48 g (32.40 mmol) potassium vinyl tetrafluoroborate and 3.10 ml (22.10 mmol) triethylamine in 150 ml ethanol was heated at reflux for 3 h. The resulting yellow suspension was filtered and the filtrate evaporated to dryness. The residue was suspended in ethyl acetate, filtered and the filtrate extracted with water. The organic layer was evaporated to dryness and the isolated crude product purified by silica gel chromatography (CH2Cl2/ethyl acetate 98:2) to yield 2.68 g (73%) of the title compound as a colorless oil. MS: 169.1 (M+). 1H-NMR (300 MHz, CDCl3): 2.74 (s, 1H); 5.47 (dd, J=11.1, 1.6 Hz, 1H); 5.97 (dd, 17.9, 1.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H); 7.43 (t, J=7.7 Hz, 1H); 7.66 (dd, J=8.1, 1.2 Hz, 1H); 7.87 (dd, J=7.3, 1.2 Hz, 1H); 7.97 (d, J=8.4 Hz, 1H); 8.05 (dd, J=17.9, 11.1 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[CH2:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35](/[CH:38]=[CH:39]/[C:19]2[CH:18]=[C:17]3[C:22]([C:14]([CH:11]4[CH2:12][CH2:13][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH2:9][CH2:10]4)=[N:15][NH:16]3)=[CH:21][CH:20]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A mixture of [4-(6-bromo-1H-indazol-3-yl)-piperidin-1-yl]-acetic acid tert butyl ester (1.34 g, 3.40 mmol), 4-vinyl-piperidine-1-carboxylic acid tert-butyl ester (0.75 g, 3.57 mmol), triethylamine (1.4 ml, 10.2 mmol), palladium (ii) acetate (0.050 g, 0.22 mmol) and tri(o-tolyl)phosphine (0.210 g, 0.6 mmol) in DMF (60 ml) was stirred at 120° under nitrogen for 16 h. The mixture was evaporated in vacuo and purified by flash chromatography on silica gel (Merck 9385), eluant ethyl acetate:cyclohexane:triethylamine (50:50:2→100:0:2), to give the title compound as a yellow solid (1.18 g, 66%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:32].[CH:33](I)([CH3:35])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>CC(CC)=O>[CH:33]([N:4]1[C:5]2=[N:11][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:17][CH:18]=3)[C:9]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:32])([CH3:35])[CH3:34]
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccn4)cc3)c(Nc3ccccc3)c2c1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CC(C)n1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc21
Reaction time: 1 h

Procedure:
Methylethylketone (1.2 mL) is added into a 0.5˜5 mL reaction vessel containing 5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (25 mg, 0.0589 mmol), isopropyl iodide (0.0707 mmol) and Cs2CO3 (0.0707 mmol). The sealed vessel is put onto a Biotage Microwave instrument and the microwave reaction is carried out at 140° C. for 1 hour. The obtained crude product is then purified by silica-gel flash chromatography to give pure product MS (ESI) m/z 467.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:14]1([CH2:13][O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[PH](CCCCc1ccccc1)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(CCCCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
(4-Phenylbutyl)phosphinic acid, phenylmethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride according to the procedure of Example 1(c) to yield N-[N-[phenyl-methoxy(4-phenylbutyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CO>[CH3:3][CH:2]([C:4]1[C:12]2[C:7]([NH:8][CH:9]=[N:10][C:11]=2[N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)=[N:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCC(NC(=O)c4ccccc4)CC3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Reaction time: 2 h

Procedure:
To a solution of N-{1-[5-(1-methylethyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D9 (140 mg) in THF (2 mL) and MeOH (1 mL) was added cesium carbonate (272 mg, 0.834 mmol) and the mixture stirred for 2 hours. LCMS showed a small amount of starting material so the reaction was stirred for a further 2 hours. The mixture was then partitioned between EtOAc (20 mL) and water (20 mL) and the organic phase washed with water (20 mL) and brine (20 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by MDAP. The compound-containing fractions were concentrated and dried in a vacuum oven to give E20 (23 mg) as a white solid, 1H NMR (d6-DMSO) δ 11.62 (1H, s), 8.39 (1H, d), 8.26 (1H, s), 7.88 (2H, d), 7.52 (1H, t), 7.46 (2H, t), 7.09 (1H, s), 4.05 (1H, m), 3.90 (2H, d), 3.16 (1H, septet), 3.00 (2H, t), 1.94 (2H, d), 1.77 (2H, ddd), 1.28 (6H, d), MS(ES+) 364 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:6]1=2.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:18][C:16]2[CH:15]=[CH:14][C:7]3[C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]=3[CH:17]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCCC(C)(C)c2ccc(N)cc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)CCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 1-(2-Methoxy-ethyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a light yellow solid (23%). LCMS: m/z=527.49 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.56 (bs, 1H), 8.07 (s, 1H), 7.18 (m, 6H), 6.86 (bs, 1H), 6.74 (d, 1H, J=8.3 Hz), 3.47 (m, 2H), 3.40 (s, 3H), 2.93 (d, 3H, J=4.6 Hz), 2.73 (m, 4H), 1.72 (m, 2H), 1.53 (m, 2H), 1.34 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]CC3C=CC=CC=3)[CH:13]=2)[NH:8][CH:7]=1)[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[NH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]c2ccc(O)cc12
Yield: 128.1 %

Procedure:
5-Benzyloxy-1H-indole-3-acetic acid ethyl ester (8.1 g, 20.3 mmol) was hydrogenated in ethanol using 3 g of Raney Ni in 150 mL of ethanol at approximately 40 psi (2.76×105 Pa) of hydrogen. The catalyst was filtered and the filtrate concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with a gradient, 30% ethyl acetate/hexane→50% ethyl acetate/hexane, to give 5.7 g (90% yield) of 5-hydroxy-1H-indole-3-acetic acid ethyl ester.