Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([O:18]C(C)(C)C)=[O:17])[CH2:3]1.OC1CCCN(C2N=C3C=C(/C=C/C4SC=C(C(C)C)N=4)C=CN3C(=O)C=2/C=C/C(O)=O)C1>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH2:3]1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@H](O)C4)nc3c2)n1
Agent: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCCC(O)C4)nc3c2)n1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCC[C@H](O)C4)nc3c2)n1
Yield: 54.7 %

Procedure:
The tert-butyl (E)-3-{2-[(3S)-3-hydroxyhexahydro-1-pyridinyl]-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (72.7 mg, 0.139 mmol) obtained in (B) was treated in the same manner as in Example 102, (I) to obtain the title compound (35.5 mg, 55%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Cl:20][C:21]1[C:22]([CH3:44])=[C:23]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])=[N:37][CH:38]=2)[C:24]([O:30][CH2:31][CH3:32])=[C:25]([CH:27](Cl)[CH3:28])[CH:26]=1>CN(C)C=O.O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:27]([C:25]3[C:24]([O:30][CH2:31][CH3:32])=[C:23]([C:33]4[CH:34]=[CH:35][C:36]([C:39]([N:41]([CH3:42])[CH3:43])=[O:40])=[N:37][CH:38]=4)[C:22]([CH3:44])=[C:21]([Cl:20])[CH:26]=3)[CH3:28])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from CNH Technologies, 120 mg, 0.46 mmol), cesium carbonate (200 mg, 0.62 mmol) and potassium iodide (7.0 mg, 0.042 mmol) in N,N-dimethylformamide (1 mL) was added 5-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (160 mg, 0.42 mmol, from Example 14, step 4) and the mixture was stirred at 140° C. for 1 hour. The reaction mixture was diluted with water, extracted with ether. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give the desired product (0.12 g, 47%). The product was isolated as a racemic mixture. LCMS calculated for C24H26ClIN7O2 (M+H)+: m/z=606.1; Found: 606.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:22][NH2:23]>CO>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:23][CH3:22])=[O:5]
Reactant: CN
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Solvent: CO
Product: CNC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of methyl 2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (500 mg, 1.73 mmol) in methanol (15 mL) was slowly added aqueous 40% methylamine (3 mL) at 0° C. After addition was complete the reaction mixture was kept on stirring at room temperature for 2 days. The volatiles were removed in vacuo to give the subtitled compound (500 mg).
Reaction SMILES: BrCC1CC1(F)F.[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[CH3:20][C:21]1[N:22]=[C:23]([N:31]2[CH2:35][CH2:34][NH:33][C:32]2=[O:36])[S:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH3:20][C:21]1[N:22]=[C:23]([N:31]2[CH2:35][CH2:34][N:33]([CH2:14][C:13]3[CH:16]=[CH:17][C:10]([C:9]([F:19])([F:18])[F:8])=[CH:11][CH:12]=3)[C:32]2=[O:36])[S:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Yield: 92 %

Procedure:
Following the procedure as described in Preparation 13, making variations to replace bromomethyl-2,2-difluorocyclopropane with 4-(trifluoromethyl)benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 92% yield: mp 126-127° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 4.51 (s, 2H), 4.17 (q, J=6.9 Hz, 2H), 4.00 (t, J=8.1 Hz, 2H), 3.47 (t, J=8.1 Hz, 2H), 2.49 (s, 3H), 1.23 (t, J=6.9 Hz, 3H); MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=3[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[OH:57][C:58]1[C:67]2[C:62](=[C:63]([OH:68])[CH:64]=[CH:65][CH:66]=2)[N:61]=[C:60]([C:69]([OH:71])=O)[CH:59]=1>>[OH:57][C:58]1[C:67]2[C:62](=[C:63]([OH:68])[CH:64]=[CH:65][CH:66]=2)[N:61]=[C:60]([C:69]([NH:18][C@H:19]([C:44]([NH:46][C:47]2[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=2[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:71])[CH:59]=1
Reactant: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Reactant: O=C(O)c1cc(O)c2cccc(O)c2n1
Product: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2cc(O)c3cccc(O)c3n2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-2,5-dimethoxyaniline (703 mg, 0.94 mmol, example 82, step A) as described for example 82 (step B) using 4,8-dihydroxyquinoline-2-carboxylic acid (291 mg, 1.42 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using initially 20% then 50% EtOAc/CH2Cl2. The title compound was obtained as white crystals (150 mg, 22%).
Reaction SMILES: [Br-:1].P(Br)(Br)Br.[CH2:6](O)[C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(OCC)C>[Br:1][CH2:6][C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC#CCC#CCC#CCO
Reactant: [Br-]
Agent: BrP(Br)Br
Solvent: CCOCC
Product: CCCCCC#CCC#CCC#CCBr

Procedure:
The alcohol obtained in (a) was directly converted to the corresponding bromide by adding 2 cm3 of phosphorus tribromide (0.0216 mole) to this alcohol diluted in 50 cm3 of ethyl ether. This stirred mixture under an inert atmosphere and protected from light was heated to the boiling temperature of the solvent for 2 hours and then washed at room temperature using a saturated aqueous solution of ammonium chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])([CH:16]([CH3:18])[CH3:17])[O:12][C:11]2=[O:24])[CH3:9])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:29]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:19][CH2:20][C:21]([O:23][CH3:29])=[O:22])([CH:16]([CH3:17])[CH3:18])[O:12][C:11]2=[O:24])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)C1(CCC(=O)O)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC1(C(C)C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoic acid (41 mg, 0.1 mmol) in MeOH (10 mL) was added SOCl2 (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h, concentrated, and purified by preparative TLC to give methyl 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoate (42 mg, 96% yield).
Reaction SMILES: C([O:8][N:9]([CH2:12][C:13]1([C:20]([NH:22][NH:23][C:24]2[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]([CH2:12][C:13]1([C:20]([NH:22][NH:23][C:24]2[N:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][N:25]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11]
Reactant: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=CN(O)CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCCC1
Yield: 74.4 %

Procedure:
To a solution of N-benzyloxy-N-{1-[N′-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazinocarbonyl]-cycloheptylmethyl}-formamide (0.11 g, 0.24 mmol) in methanol (10 mL) was added 10% Pd/C (0.03 g). The reaction mixture was subjected to hydrogenation for, 0.25 h at room temperature. The reaction mixture was then filtered through a pad of Celite@, and washed with methanol (20 mL). Removal of the solvent provided the title compound as a white solid (0.067 g, 75%). MH+376.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH2:3][C:4](=[CH:11][O:12]C)[CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8].Cl(O)(=O)(=O)=O>C(OCC)C>[CH3:1][CH:2]([CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH2:3][CH:4]([CH:11]=[O:12])[CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8]
Reactant: CCCC(C)CC(C)CC(=COC)CC(C)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CCCC(C)CC(C)CC(C=O)CC(C)C(=O)O
Temperature: 25 °C

Procedure:
To an ice-cold solution of 4-(2,4-dimethylheptanyl)-5-methoxy-2-methyl-4-pentenoic acid (11) (1.85 g, 6.85 mmol) in 95 ml diethyl ether in a 250 ml flask fitted with a magnetic stirrer and a dropping funnel, 25 ml of a 70 volume percent aqueous solution of perchloric acid was added slowly under a nitrogen atmosphere. After the addition was completed, the solution was stirred at room temperature for ten hours. The reaction mixture was poured into ice water, the organic layer separated, and the aqueous layer thoroughly extracted with three 100 ml portions of ether. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the aldehyde acid 4-(2,4-dimethylheptanyl)-2-methyl-5-oxo-pentanoic acid (12) as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:13](=[O:14])[CH2:12][C:11](=[O:15])[NH:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([N:34]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>CN(C=O)C.C1COCC1>[C:41]([N:34]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:32](=[O:33])[CH2:31][N:10]1[C:11](=[O:15])[CH2:12][C:13](=[O:14])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]1=2)([CH3:42])([CH3:43])[CH3:44]
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: CC(C)(C)N(C(=O)CBr)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 600 mg (2.38 mmol) 1-Phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2,4-dione in 16 mL DMF is added 2.62 mL (2.62 mmol, 1.1 equiv) of 1M Sodium bis(trimethylsilyl)amide in THF at ambient temperature and stirred 0.5 h. To this solution is added 707 mg (2.62 mmol, 1.1 equiv) 2-Bromo-N-tert-butyl-N-phenyl-acetamide, prepared as in Part A, in 4 mL DMF and stirred 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into 50 mL EtOAc, washed successively with H2O (30 mL), 1N HCl (30 mL), satd. NaHCO3 (30 mL), and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on 40 g silica gel eluted successively with EtOAc/Hexanes (2:3, 500 mL), (1:1, 750 mL). Appropriate fractions were combined and concentrated in vacuo to give 748 mg (1.69 mmol) of N-tert-Butyl-2-(2,4-dioxo-5-phenyl-2,3,4,5,-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-phenyl-acetamide as a white foam: 1H NMR (CDCl3, 300 MHz) δ7.45-7.21 (m, 12H), 7.08 (t, 1H), 6.90 (m, 1H), 4.30 (d, 1H, J=16.4), 3.85 (d, 1H, J=16.6), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.43 (s, 9H); TLC Rf =0.24 (EtOAc/Hexanes, 1:1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][C:13]#[N:14].C1CCCCC1.Br.C(N)C1C=CC=CC=1>C(OCC)C>[CH2:1]([NH:8][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: N#CCCCBr
Agent: Br
Solvent: CCOCC
Solvent: C1CCCCC1
Product: N#CCCCNCc1ccccc1
Yield: 66 %

Procedure:
32.2 g of benzylamine, 14.8 g of 4-bromobutyronitrile and 30 ml of cyclohexane are stirred at room temperature for 12 hours. After the addition of diethyl ether the separated benzylamine hydrobromide is filtered off; the ether phase is washed with water, dried and concentrated by evaporation. The residue is distilled in vacuo to yield 11.5 g (66% of theory) of 4-benzylaminobutyronitrile (B.P. 114° to 120°/0.05 mm Hg).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.C1(C)C=CC=CC=1.[CH3:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1>C(O)(=O)C>[CH3:7][C:6]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH3:16])=[CH:20][CH:21]=2)[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-n2c(C)ccc2C)cc1
Temperature: 25 °C

Procedure:
To a solution of acetonyl acetone (11.7 mL, 100 mmol) and toluene (750 mL) was added p-phenetidine (12.9 mL, 100 mmol) and glacial acetic acid (1 mL). The mixture was heated at reflux overnight. After cooling to rt, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (15% EtOAc/hexanes) to give 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.13-7.10 (m, 2H), 6.97-6.94 (m, 2H), 5.88 (br s, 2H), 4.08 (q, 2H), 2.02 (s, 6H), 1.46 (t, 3H); MS (ESI) 216 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[C:19]([C:23]1[O:24][C:25]([CH3:30])=[C:26]([CH2:28]Cl)[N:27]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:28][C:26]2[N:27]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:24][C:25]=2[CH3:30])=[CH:8][C:7]=1[CH3:14]
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 46 c], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester was reacted with 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (example 1, step b]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2,6-dimethyl-phenyl]-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][N:8]([CH2:12][CH2:13]Cl)[C:7](=[O:15])[C:6]=2[CH:16]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[I-].[Na+].C(N(CC)CC)C.C([O-])(=O)/C=C/C([O-])=O>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][N:8]([CH2:12][CH2:13][N:26]3[CH2:27][CH2:28][N:23]([C:18]4[N:17]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][CH2:25]3)[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: O=C1c2cc(Cl)ccc2OC=CN1CCCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2cc(Cl)ccc2OC=CN1CCN1CCN(c2ncccn2)CC1
Yield: 67 %

Procedure:
14 mg of the compound of Example 1 was dissolved in 5 ml of dimethylformamide, 13 mg (1.5 equivalents) of 1-(2-pyrimidinyl)piperazine, 16 mg (2 equivalents) of sodium iodide, and 11 mg (2 equivalents) of triethylamine were added, and the resultant mixture was agitated at 90° C. for 10 hours. This was allowed to cool, then water was added and extraction was performed twice with ethyl acetate. The entire organic layer was washed with an aqueous solution of sodium hydrogencarbonate, water, and saturated saline, then was dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (methylene chloride:methanol=30:1) to obtain the above-referenced compound in an amount of 14 mg (yield of 67%). Note that the fumarate can be obtained by an ordinary method, then making it into an amorphous powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)(=[O:9])=[O:8].[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH2:29]>>[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH:29][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])=[CH:11][C:12]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccccn2)cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(=O)(=O)c2ccccn2)cc1-c1ccccc1

Procedure:
The resultant product from Example 14B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21]([F:25])[C:22]=3[F:24])[NH:17][C:16]=2[Si](CC)(CC)CC)=[O:11])=[CH:8][CH:7]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:26])=[C:21]([F:25])[C:22]=3[F:24])[NH:17][CH:16]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(F)c(F)c(F)c2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1c[nH]c2cc(F)c(F)c(F)c12)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(4,5,6-trifluoro-2-(triethylsilyl)-1H-indol-3-yl)ethyl)benzamide (0.057 g; 0.105 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.027 g (60%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7](B2OC(C)(C)C(C)(C)O2)=[C:8]([NH:10]C(=O)OC(C)(C)C)[CH:9]=1.Br[C:28]1[C:29]([C:34]#[N:35])=[N:30][CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.C(Cl)Cl.O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2=[C:28]3[C:29](=[C:34]([NH2:35])[N:10]=[C:8]2[CH:9]=1)[N:30]=[CH:31][CH:32]=[CH:33]3
Reactant: COCc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: N#Cc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COCc1ccc2c(c1)nc(N)c1ncccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from the previous step) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction mixture was diluted with 2% MeOH in DCM and water. The two phases were separated, and the aqueous layer was extracted twice with 2% MeOH in DCM. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-100% EtOAc/Hexanes to give 8-(methoxymethyl)benzo[f][1,7]naphthyridin-5-amine as a white solid: 1H NMR (methanol-d4): δ 8.97 (dd, 1H), 8.91 (dd, 1H), 8.41 (dd, 1H), 7.83 (dd, 1H), 7.59 (d, 1H), 7.37 (dd, 1H), 4.62 (s, 2H), 3.45 (s, 3H). LRMS [M+H]=240.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[O:18][CH:17]=[C:16]([C:19](O)=[O:20])[CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[C:4]([CH2:22][CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:36]1([CH2:41][C:42]2[CH:43]=[C:44]([CH2:48][NH2:49])[CH:45]=[CH:46][CH:47]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[O:18][CH:17]=[C:16]([C:19]([NH:49][CH2:48][C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([CH2:41][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:43]=3)=[O:20])[CH:15]=2)[CH3:12])(=[O:9])=[O:10])=[C:4]([CH2:22][CH3:23])[CH:3]=1
Reactant: NCc1cccc(CN2CCCC2)c1
Reactant: CCc1cc(Br)ccc1S(=O)(=O)N(C)Cc1cc(C(=O)O)co1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CCc1cc(Br)ccc1S(=O)(=O)N(C)Cc1cc(C(=O)NCc2cccc(CN3CCCC3)c2)co1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-bromo-2-ethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.10 mmol), CDI (32 mg, 0.2 mmol) and 1-[3-(pyrrolidin-1-ylmethyl)phenyl]methanamine (57 mg, 0.3 mmol) in DCE (2 mL). The crude product was purified using prep method A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]3[CH2:19][CH2:18]3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[I:20]Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:17]3[CH2:19][CH2:18]3)[C:11]3[N:12]([C:14]([I:20])=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: ClI
Reactant: Clc1ccc(-c2cc(C3CC3)c3nccn3c2)cc1
Product: Clc1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1

Procedure:
Prepared from 6-(4-chloro-phenyl)-8-cyclopropyl-imidazo[1,2-a]pyridine (example C.27 step 4) (3.1 g, 11.5 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as an off-white solid (1.098 g, 24% pure material, crystallized from EtOAc/heptane; 2.001 g, 42% contains dicylopropyl material). MS (ISP) 394.8 [(M+H)+], 396.9 [(M+2+H)+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH3:14])=[O:12]>N1C=CC=CC=1.C(Cl)Cl>[CH3:14][O:13][C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:12]
Reactant: c1ccc2c(c1)CCN2
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CCc2ccccc21
Yield: 56 %

Procedure:
A solution of 10 g of indoline in 10 ml of pyridine is cooled to 0° C. a solution of 7.9 g of methyl chloroformate in 10 ml of DCM is added dropwise and the mixture is stirred for 1 hour at 0C. A further solution of 7.9 g of methyl chloroformate in 10 ml of DCM is then added and the reaction mixture is concentrated under vacuum. The residue is taken up with water and extracted with AcOEt, the organic phase is washed with a 5% solution of potassium hydrogensulfate, with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 8.3 g of the expected product after trituration in a DCM/iso ether mixture and then filtration. M.p.=69°-70° C.