Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.[ClH:41].[CH2:42]([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48])[CH3:43]>>[ClH:41].[O:1]=[C:2]1[N:11]([CH2:12][C:13]([NH:48][CH2:47][CH2:46][C:45]([O:44][CH2:42][CH3:43])=[O:49])=[O:15])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: Cl
Product: CCOC(=O)CCNC(=O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Yield: 70.5 %

Procedure:
Using the method similar to that in Example 109 and starting from 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol) obtained in Example 50, and also using b-alanine ethyl ester hydrochloride (408 mg, 2.66 mmol) instead of glycine methyl ester hydrochloride, the ethyl ester of the title compound (1.06 g 65%) was obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[C:21]([CH3:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:16]=[CH:15][O:14][C:13]=1[C:17]([NH:19][NH2:20])=[O:18].C([O:31][CH2:32][CH3:33])(=O)C>>[C:17]([C:13]1[CH:12]=[C:7]([CH:8]=[CH:33][C:32]=1[OH:31])[C:6]([NH:20][NH:19][C:17]([C:13]1[O:14][CH:15]=[CH:16][C:12]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[C:21]([CH3:27])=[C:22]([CH3:26])[CH:23]=[C:24]([CH3:25])[C:2]=1[CH3:1])=[O:18])=[O:5])#[N:19]
Reactant: Cc1cc(C)c(C)c(COc2ccccc2-c2ccoc2C(=O)NN)c1C
Reactant: CCOC(C)=O
Product: Cc1cc(C)c(C)c(COc2ccccc2-c2ccoc2C(=O)NNC(=O)c2ccc(O)c(C#N)c2)c1C

Procedure:
In ethyl acetate (10 ml), a mixture composed of 3-[2-(2,3,5,6-tetramethylbenzyloxy)phenyl]-2-furancarboxylic acid hydrazide (compound of Reference Example 6, 0.36 g) and the compound of Reference Example 63 (0.33 g) was heated at reflux overnight while stirring. The thus-precipitated crystals were filtered and recrystallized from ethyl acetate, thereby giving 0.18 g of the desired compound. Melting point: 215-217° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:12]1([CH2:11][C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:41]#[C:40][C:39]([OH:38])([CH3:43])[CH3:42])=[CH:7][N:6]=2)=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CC(C)(C)O
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)ccc1S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC(C)(C)O)cn2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
A mixture of N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (120 mg, 0.257 mmol), N,N-diisopropylethylamine (0.5 mL, 2.87 mmol), and 3-hydroxy-3-methylbutyne (90 mg, 1.07 mmol) in toluene (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.0157 mmol) and copper(I) iodide (5.5 mg, 0.0288 mmol). The mixture was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned with methylene chloride (25 mL) and a 0.2M aqueous hydrochloric acid solution (20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL), and each aqueous phase was back-extracted with a small volume of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with increasing concentrations of ethyl acetate/hexanes) afforded the 3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-but-1-ynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 77%) as a yellow foam: (ES)+-HRMS m/e calcd for C25H31N3O4S (M+H)+ 470.2108, found 470.2113.
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].I([C:29]1C=CC=C[C:30]=1C(O)=O)(=O)=O>CS(C)=O.O>[CH2:29]([SH:23]1[C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]([CH:24]=[O:25])=[C:2]1[Br:1])[CH3:30]
Reactant: O=C(O)c1ccccc1I(=O)=O
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Solvent: O
Solvent: CS(C)=O
Product: CC[SH]1C(Br)=C(C=O)c2c1n(C)c(=O)n(CCCOC1CCCCO1)c2=O
Temperature: 50 °C
Yield: 53.8 %

Procedure:
To a solution of 6-bromo-5-(bromomethyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 2, Step 3, 800 mg, 1.61 mmol) in DMSO (10 mL) was added 2-iodoxybenzoic acid (541.7 mg, 1.93 mmol). The reaction was heated at 50° C. for 1.5 h, cooled to RT, diluted with water (20 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with aq. NH4Cl (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give ethyl 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2,3,4-tetrahydro thieno[2,3-d]pyrimidine-5-carbaldehyde (400 mg, 57.5% yield) as a white solid. LCMS: [MH+-THP] 347 and TR=1.665 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([F:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([F:43])[CH:37]=2)=[O:34])=[C:4]([F:44])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(C)cc(F)c3)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(C)cc(F)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Yield: 71.1 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea (197 mg, 0.319 mmol) and anisole (172 mg, 1.594 mmol) was stirred in TFA (4 mL) at RT for 3 h. The mixture was concentrated to near-dryness, treated with EtOAc and satd. NaHCO3 and the resulting solid collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea (113 mg, 71% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.18 (br s, 1H), 8.80 (br s, 1H), 8.41 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.73 (s, 1H), 7.52 (d, J=10.8 Hz, 1H), 7.22 (d, J=11.5 Hz, 1H), 7.03 (br s, 1H), 6.92 (s, 1H), 6.67-6.59 (m, 1H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.86 (s, 3H), 2.25 (s, 3H), 1.21 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 498.1 [M+H]+.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: O=Cc1ccc(CC(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(O)Cc1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (120 mg, 0.368 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added 2-(4-formylphenyl)acetic acid (72.4 mg, 0.441 mmol) and sodium triacetoxyborohydride (125 mg, 0.588 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved in methanol (2.000 mL) and sodium hydroxide (1M, 2 mL, 2.000 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions. The fractions containing product were combined, treated and concentrated. The residue was further dried under vacuum to give 54 mg of product (HCl salt) as off-white solid. MS: (M+H)+=379.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.34 (m, 1H), 1.51-1.70 (m, 3H), 1.87-2.13 (m, 3H), 2.56-2.66 (m, 1H), 2.83-3.15 (m, 5H), 3.32 (br. s., 2H), 4.16-4.44 (m, 2H), 7.12-7.43 (m, 7H), 7.45-7.61 (m, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:27]([C:29]([OH:31])=O)[N:28]=1.[C@H:39]12[CH2:45][C@H:42]([CH2:43][CH2:44]1)[C@@H:41]([CH2:46][NH:47][C:48](=[O:53])[C:49]([F:52])([F:51])[F:50])[NH:40]2.CCN(C(C)C)C(C)C>CN(C=O)C.CC(OC)(C)C>[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:27]([C:29]([N:40]2[C@H:41]([CH2:46][NH:47][C:48](=[O:53])[C:49]([F:51])([F:52])[F:50])[C@@H:42]3[CH2:45][C@H:39]2[CH2:44][CH2:43]3)=[O:31])[N:28]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@H]1N[C@@H]2CC[C@H]1C2)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Nc1nc(C(=O)N2[C@@H]3CC[C@@H](C3)[C@H]2CNC(=O)C(F)(F)F)c(-c2cccc(F)c2)s1

Procedure:
TBTU (1.70 mmol, 1.10 eq) is added to a solution of 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid (1.62 mmol, 1.05 eq), N-[(1R,3S,4S)-1-(2-Aza-bicyclo[2.2.1]hept-3-yl)methyl]-2,2,2-trifluoro-acetamide (1.55 mmol, 1.0 eq) and DIPEA (5.41 mmol, 3.5 eq) in DMF (10 mL). After 90 min the mixture is diluted with TBME (50 mL) and washed three times with an aq. NaOH solution (0.5 M, 50 mL each). The combined aq. layers are extracted twice with TBME (30 mL each). The organic layers are combined, washed with water (3×30 mL) and brine (30 mL), dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.82 min; [M+H]+=442.9.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[N:15]=2)[CH:8]=1)[CH3:2].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C1COCC1.CN1C(=O)CCC1>[CH3:2][O:1][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[N:15]=[C:16]([NH:20][C:24](=[O:27])[CH:25]=[CH2:26])[CH:17]=[CH:18][CH:19]=2)[CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cccc(Oc2cc(Nc3cccc(N)n3)ncn2)c1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(Nc2cc(Oc3cccc(OC)c3)ncn2)n1
Reaction time: 2 h

Procedure:
To a stirred solution of N2-(6-(3-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (100 mg, 0.323 mmol) in THF/NMP (1 mL/0.5 mL) was added acryloyl chloride (0.029 g, 0.3 mmol) under N2 atmosphere at −10° C. The stifling was continued at the same temperature for 2 h and the reaction mixture was concentrated under reduced pressure to give a residue that was further purified by column chromatography (SiO2, 60-120, chloroform/methanol) to give N-(6-(6-(3-methoxyphenoxy)pyrimidin-4-ylamino)pyridine-2-yl)acrylamide (I-90) as a pale yellow solid. 1H NMR (DMSO-d6) δ ppm: 3.75 (s, 3H), 5.79 (dd, J=1.8 & 10.08 Hz, 1H), 6.30 (dd, J=1.8 & 16.96 Hz, 1H), 6.65 (dd, J=10.12 & 16.96 Hz, 1H), 6.74-6.76 (m, 2H), 6.82 (td, J=1.52 & 9.24 Hz, 1H), 7.04 (d, J=7.92 Hz, 1H), 7.33 (t, J=8.28 Hz, 1H), 7.70 (t, J=7.96 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.90 (s, 1H), 8.34 (s, 1H), 10.20 (s, 1H), 10.48 (s, 1H); LCMS: m/e 364 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27](C)[C:28](=O)OC(C)(C)C)[CH2:23]2)[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[CH:15][C:8]=3[C:6]=2[N:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH3:28][NH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:4]2[C:5]3[CH2:12][CH2:11][CH2:10][C:9]4[N:13]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:14]=[CH:15][C:8]=4[C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:23]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2nc(N)nc3c2CCCc2c-3cnn2-c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CCN(c2nc(N)nc3c2CCCc2c-3cnn2-c2ccccc2)C1

Procedure:
The product from Example 11E (5 mg) was dissolved in dichloromethane (0.5 ml) and treated with trifluoroacetic acid (0.5 mL) for 1 hour at ambient temperature. The reaction mixture was concentrated and triturated with ether to yield the title compound: 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1 H), 8.16 (s, 1 H), 7.59 (m, 5 H), 3.84 (m, 2 H), 2.91 (t, J=6.78 Hz, 2 H), 2.67 (m, 4H), 2.45 (s, 3H), 2.27 (m, 2 H), 2.14 (m, 3 H); MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11][N:10]([CH3:16])[C:9]1=[O:17])([CH3:4])([CH3:3])[CH3:2].[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]OS(C(F)(F)F)(=O)=O)=[N+:20]=[N-:21].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:19]=[N+:20]=[N-:21])[CH2:11][N:10]([CH3:16])[C:9]1=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=NCCCCCCOS(=O)(=O)C(F)(F)F
Reactant: CN1C[C@H](O)CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C[C@H](OCCCCCCN=[N+]=[N-])CC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a stirred solution of ((3S,6R)-6-hydroxy-1-methyl-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester (0.70 g, 2.6 mmol) in THF (5 mL) cooled to −78° C. is added NaN(Si(CH3)3)2 (2.8 mL 1M THF, 2.8 mmol). After 10 min trifluoro-methanesulfonic acid 6-azido-hexyl ester (0.76 g, 3.1 mmol) is added neat and stirred for 10 min at −78° C. then warmed and stirred at room temperature for 1 h. NaHCO3 (5 mL 1M H2O) is added and the solution is partitioned with H2O/EtOAc, the EtOAc extract is dried with Na2SO4 and evaporated to an oil. The oil is adsorbed on silica and chromatographed (20% EtOAc/CH2Cl2) to give 0.32 g (32%) of [(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester as an oil. 1H NMR (CDCl3) δ 1.34 (s, 9H), 1.24-2.1 (m, 12H), 2.95 (s, 3H), 3.1-3.35 (m, 6H), 3.44 (m, 1H), 3.55 (d, 1H), 4.2 (m, 1H).
Reaction SMILES: C[C:2]1[N:6]2[C:7]([NH2:15])=[C:8]([Cl:14])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]2=[N:4][C:3]=1[CH3:16].[CH3:17][O:18][C:19]([CH3:30])([CH3:29])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1>>[NH2:15][C:7]1[N:6]2[CH:2]=[C:3]([CH3:16])[N:4]=[C:5]2[C:10]([C:11]([NH:28][CH2:27][CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([O:18][CH3:17])([CH3:29])[CH3:30])[CH2:26][CH2:25]2)=[O:13])=[CH:9][C:8]=1[Cl:14]
Reactant: COC(C)(C)CN1CCC(CN)CC1
Reactant: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Product: COC(C)(C)CN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(C)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 2 in EXAMPLE 28 from 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 26, Step 5) and [1-(2-methoxy-2-methylpropyl)piperidin-4-yl]methylamine (EXAMPLE 29, Step 6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH:28]=O>>[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH2:28][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: COc1ccc(Br)c(C=O)c1
Product: COc1ccc(Br)c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-bromo-5-methoxybenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 530.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39](O)=[O:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39]([C:31]4[NH:30][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=4)=[O:40])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nc3ccccc3[nH]2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1H-benzo[d]imidazole-2-carboxylic acid (24 mg, 0.15 mmol).
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH3:23])\[CH2:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([O:17]C)[C:13]([CH3:19])=[C:12]([CH3:20])[C:11]=1[O:21]C)(=[O:3])[CH3:2]>C(#N)C.O>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH3:23])\[CH2:8][CH2:9][C:10]1[C:11](=[O:21])[C:12]([CH3:20])=[C:13]([CH3:19])[C:14](=[O:17])[C:15]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C\COC(C)=O)c1C
Solvent: CC#N
Solvent: O
Product: CC(=O)OC/C=C(/C)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A solution of (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate (0.98 g) in acetonitrile (15 ml) was treated dropwise at -20° C. with a solution of ceric ammonium nitrate (4.1 g) in water (15 ml). After 15 minutes the mixture was warmed to -10° C and left at this temperature for 1 hour. The mixture was diluted with ice-water and extracted twice with methylene chloride. The extracts were washed with water, dried and chromatographed on silica gel with hexane/ethyl acetate 95:5, yielding 0.67 g of (Z)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadienyl)-2-pentenyl acetate as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1Cl.[CH3:32][N:33]([CH3:43])[CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].N>O.ClCCl.CO.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[N:40]1[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][CH2:34][N:33]([CH3:32])[CH3:43])[CH2:38][CH2:39]1
Reactant: O=C(CCC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCCN1CCNCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)CCCN1CCN(c2ccc(C(=O)CCC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)cc2Cl)CC1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
A mixture of 921 mg (2.00 mmol) of 3-{1-[4-(3,4-dichloro-phenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone, 377 mg (2.2 mmol) of 1-(3-dimethylaminopropyl)-piperazine, 10 ml of DMSO and 0.276 g (2.00 mmol) of potassium carbonate was stirred for 24 hours at a reaction temperature of 85° C. The mixture was diluted with 200 ml of water, then extracted exhaustively with EE. The combined extracts were dried over sodium sulphate and concentrated by evaporation in vacuo. The residue remaining was purified twice by column chromatography on silica gel (Amicon, 35–70 μm) (dichloromethane/methanol/conc. ammonia 70/30/1 v/v/v as eluant). The appropriate eluates were combined and after working up in the usual way yielded 30.0 mg (2.5% of theoretical) of the desired substance as a colourless, amorphous substance. Rf 0.68 (El D) or 0.35 (eluant: dichloromethane/methanol/conc. ammonia 50/50/1 v/v/v). MS: M+594/596 (Cl); ESI: (M+H)+=595/597 (Cl)
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][C:69]([O:72][C:73]([N:75]1[CH2:80][CH2:79][CH:78]([C:81](O)=[O:82])[CH2:77][CH2:76]1)=[O:74])([CH3:71])[CH3:70].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:81]([CH:78]2[CH2:79][CH2:80][N:75]([C:73]([O:72][C:69]([CH3:71])([CH3:70])[CH3:68])=[O:74])[CH2:76][CH2:77]2)=[O:82])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3[nH]c(C(=O)NCc4ccc(Cl)c(Oc5cc(Cl)cc(C#N)c5)c4F)cc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (0.0236 g, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography with hexane:ethyl acetate to give the title compound (0.029 g, 41%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (br. s., 1H), 9.72 (br. s., 1H), 8.95 (br. s., 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.41-7.52 (m, 2H), 7.36 (t, 1H), 7.25-7.32 (m, 1H), 7.21 (d, 1H), 7.06 (br. s., 1H), 4.52 (d, 2H), 3.85-4.17 (m, 2H), 2.58-2.94 (m, 2 H), 1.63-1.85 (m, 2H), 1.41-1.53 (m, 2H), 1.36 (s, 9H). ES MS: m/z 680 (M+1).