Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](C)[CH:3]=1.BrCC(C1C=C(C=CC=1F)C(OC)=O)=O.FC1C(I)=CC(C(OC)=O)=C(C)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1C
Agent: COC(=O)c1cc(I)c(F)cc1C
Agent: COC(=O)c1ccc(F)c(C(=O)CBr)c1
Product: COC(=O)c1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 377.1, except methyl 4-fluoro-3-iodobenzoate (compound 132.1) was used instead of methyl 4-fluoro-5-iodo-2-methylbenzoate (compound 101.2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:26][CH2:27][F:28])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FCCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 86.6 %

Procedure:
290 mg (corresponding to 1.0 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 10 mL of N,N-dimethylformamide, and 413 mg (corresponding to 3.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 138 μL (corresponding to 1.5 mmol) of 1-bromo-3-fluoropropane, and then was stirred at room temperature for 20.5 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC(HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 302 mg (corresponding to 0.866 mmol) of 6-bromo-2-[4′-(3″-fluoropropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1-4, Step 3).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:56]2[N:57]=[C:58]([NH:61][C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[S:59][CH:60]=2)\[C:25]([NH:27][CH:28]2[C:54](=[O:55])[N:30]3[C:31]([C:38]([O:40][CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])=[C:32]([CH2:36]Cl)[CH2:33][S:34](=[O:35])[C@H:29]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:81].[Na+].C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[CH:1]([O:14][C:15]([C:17]1([O:22]/[N:23]=[C:24](/[C:56]2[N:57]=[C:58]([NH:61][C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[S:59][CH:60]=2)\[C:25]([NH:27][CH:28]2[C:54](=[O:55])[N:30]3[C:31]([C:38]([O:40][CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])=[C:32]([CH2:36][I:81])[CH2:33][S:34](=[O:35])[C@H:29]23)=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CI)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The residue obtained in (B) was dissolved in 40 ml of acetone, and 990 mg (6.6 mmol) of sodium iodide was added. The mixture was stirred at room temperature for 30 minutes. Then, 120 ml of ethyl acetate and 20 ml of a 5% sodium thiosulfate aqueous solution were added to the reaction solution for liquid separation. The organic layer was washed with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The concentrated residue was subjected to silica gel flush column chromatography (ethyl acetate/n-hexane=1/2). The fraction containing the desired product was collected, and concentrated under reduced pressure, and isopropyl ether was added to the residue to obtain 2.92 g of a powder of the above identified compound (yield from A: 80.3%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:31][C:32]#[N:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCCO3)cc1OC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCCO3)cc1OC
Yield: 86.4 %

Procedure:
(2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,4-dimethoxyphenyl)methanone (3.01 g, 10.02 mmol), cyanomethylphosphonic acid diethyl ester (3.15 ml, 20.05 mmol) in anhydrous THF (20 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 20.05 ml, 20.05 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give an oil, which was lyophilized to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile as an light yellow foam (2.80 g, 86%): 1HNMR (DMSO-d6) δ 7.09-6.69 (m, 6H, Ar), 6.15 (s, 0.49H, double bond proton of one isomer), 6.09 (s, 0.45H, double bond proton of the other isomer), 4.33-4.25 (m, 4H, 2CH2CH2), 3.83-3.74 (multiple singlets, 2OCH3); 13C NMR (DMSO-d6) δ 161.0, 160.9, 150.9, 150.0, 148.6, 148.3, 145.6, 144.7, 143.2, 143.0, 131.3, 130.5, 130.1, 129.2, 122.6, 122.4, 122.3, 122.0, 118.7, 118.7, 118.0, 117.2, 117.1, 117.0, 112.7, 111.4, 111.2, 111.1, 93.1, 93.0, 64.3, 64.2, 64.0, 64.0, 55.6, 55.5. Anal. Calcd. For C19H17NO4 (+0.45H2O): C, 68.85; H, 5.44; N, 4.23. Found: C, 68.69; H, 5.31; N, 4.04.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][C@H:2]1[CH2:7][N:6]([CH3:21])[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](C)CN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](C)CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of phenylmethyl trans-2,5-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) (1.35 g, 5.43 mmol) in dichloromethane (40 mL) at 0° C. was added formaldehyde (0.817 mL, 37% water solution, 10.87 mmol) followed by sodium triacetoxyborohydride (1.726 g, 8.14 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield phenylmethyl trans-2,4,5-trimethyl-1-piperazinecarboxylate (enantiomeric mixture) (1.42 g, 100%). Phenylmethyl trans-2,4,5-trimethyl-1-piperazinecarboxylate (enantiomer 1) (480 mg) and phenylmethyl trans-2,4,5-trimethyl-1-piperazinecarboxylate (enantiomer 2) (400 mg) were separated by chiral chromatography. LCMS: (M+H)+: 263.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][C:20](OC(C)=O)=[O:21].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1)(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(-c2cc(=O)c3cccnc3o2)cc1
Yield: 52.7 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.5 g, 6.27 mmol), Ac2O (700 mg, 6.89 mmol) and a catalytic amount of DMAP (50 mg) in pyridine (10 mL) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer washed with water, dried and concentrated to give a 2-(4-acetoxyphenyl)-pyrano[2,3-b]pyridin-4-one (930 mg, 53%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][OH:12])[CH:7]=[C:8]([F:10])[CH:9]=1.[CH3:13]I>CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][O:12][CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
NaH (60% dispersion in mineral oil, 245 mg, 6.12 mmol) was added to a solution of (3-bromo-5-fluorophenyl)methanol (1.195 g, 5.83 mmol) in 2-Me THF (20 mL). After gas evolution had ceased, MeI (0.455 mL, 7.29 mmol) was added and the resulting mixture was stirred at r.t. for 16 h. Another portion of NaH (50 mg, 2.1 mmol) and MeI (0.10 mL, 1.6 mmol) were added and the mixture was heated to 60° C. for 2 h. The cooled mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (gradient of 0-15% EtOAc in heptane) to give 0.810 g (63% yield) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (s, 3 H), 4.38-4.46 (m, 2 H), 7.18 (m, 1 H), 7.37 (s, 1 H), 7.44-7.50 (m, 1 H); MS (EI) m/z 218 M|.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]3=[C:20]4[C:14](=[C:15]5[N:24]([CH3:25])[CH:23]=[CH:22][C:21]([C:26](O)=[O:27])=[C:16]5[CH:17]=[CH:18]3)[C:13](=[O:29])[NH:12][C:11]4=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:48][CH3:49])=[C:44]([CH2:46][NH2:47])[CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:48][CH3:49])=[C:44]([CH:45]=1)[CH2:46][NH:47][C:26]([C:21]1[CH:22]=[CH:23][N:24]([CH3:25])[C:15]2[C:16]=1[CH:17]=[CH:18][C:19]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH:10]=[C:11]3[NH:12][C:13](=[O:29])[C:14]=2[C:20]=13)=[O:27]
Reactant: COc1ccc(F)cc1CN
Reactant: CN1C=CC(C(=O)O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc(F)cc1CNC(=O)C1=c2ccc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(F)cc1
Yield: 8 %

Procedure:
A stock solution of Example 56d and N,N-diisopropylethylamine (0.15 M and 0.42 M in N,N-dimethylacetamide, respectively, 254 μL) and (5-fluoro-2-methoxyphenyl)-methanamine (0.4 M in N,N-dimethylacetamide, 115 μL), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.22 M in N,N-dimethylacetamide, 254 μL) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to give 0.0016 g (8%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.39 (d, J=2.14 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J=8.24, 2.14 Hz, 1H), 7.37 (d, J=8.24 Hz, 1H), 7.05 (m, 4H), 6.87 (m, 2H), 6.56 (m, 2H), 4.49 (s, 2H), 4.07 (s, 3H), 4.61 (m, 2H), 3.85 (s, 3H). MS (APCI+) m/z 527.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:33][O:34][C:35](=[O:68])[NH:36][CH:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:54]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:56]3[CH:57]=[CH:58][C:53]([C:50]4[NH:49][C:48]([CH:44]5[CH2:45][CH2:46][CH2:47][N:43]5[C:41](=[O:42])[CH:37]([NH:36][C:35]([O:34][CH3:33])=[O:68])[CH:38]([CH3:40])[CH3:39])=[N:52][CH:51]=4)=[CH:54][CH:55]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)c4ccccc34)cc2)[nH]1)C(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
(1-{2-[5-(4-Bromo-naphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.115 g), [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.111 g), and NaHCO3 (0.0623 g) were dissolved in a mixture of 1,2-dimethoxyethane (3 mL) and water (1 mL). The solution was degassed with nitrogen, and Pd(PPh3)4 (0.0114 g) was added. The reaction mixture was stirred at 85° C. for 16 hours and evaporated under vacuum. Solid was dissolved in ethyl acetate (10 mL) and extracted twice with water (10 mL) and once with brine (10 mL). Solution was evaporated, dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-1-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.037 g, 21%) as a white solid: 1H-NMR: 300 MHz, (CHCl3-d1) δ: 8.9 (m, 1H), 7.6 (m, 2H), 7.4 (m, 5H), 7.0 (m, 2H), 6.8 (m, 2H), 5.8 (m, 2H), 5.3 (m, 2H), 4.3 (m, 2H), 4.0 (m, 4H), 3.6 (s, 6H), 2.4 (m, 6H), 2.0 (m, 6H), 0.8 (m, 12H); MS (ESI) m/z 789 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:5](=[CH:6][C:7]3[CH2:11][CH2:10][O:9][C:8]=3[CH:12]=2)[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19].C(Cl)[Cl:22]>CO.C(#N)C>[ClH:22].[CH2:19]([NH:1][CH:2]1[CH2:14][C:13]2[C:5](=[CH:6][C:7]3[CH2:11][CH2:10][O:9][C:8]=3[CH:12]=2)[CH2:4][CH2:3]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: ClCCl
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: C=CCNC1CCc2cc3c(cc2C1)OCC3
Product: Cl
Reaction time: 20 h

Procedure:
5.2 g of 7-amino-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan dissolved in 27.6 ml of methylene chloride are stirred at room temperature in the presence of 8.3 ml of 40% strength sodium hydroxide, 3.3 g of allyl bromide and 1 ml of 40% strength Triton B in methanol. After 20 hours' stirring, 1 ml of Triton B is added again, followed by a further 2 ml after 24 hours' stirring. After 96 hours' stirring, the mixture is separated off after being left to settle and evaporated under vacuum. The residue, taken up in ethyl ether, is washed with water and then dried over anhydrous sodium sulfate. After evaporation, 4.6 g of base are obtained. The corresponding hydrochloride is obtained in acetonitrile by adding a stoichiometric quantity of ethereal hydrogen chloride, and then recrystallized in water.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[O-]S([O-])(=O)=O.[Mg+2].[CH3:15][NH:16][NH2:17]>C(Cl)(Cl)Cl>[CH3:15][NH:16][N:17]=[C:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=O
Reactant: CNN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)=NNC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
To a suspension of ethyl pyruvate (37.8 mL, 338 mmol) and MgSO4 (40.8 g, 339 mmol) in CHCl3 (500 mL) was added a solution of methylhydrazine (18.0 mL, 332 mmol) in CHCl3 (100 mL) at 0° C. The reaction mixture was warmed to room temperature. After stirring for 24 hours at room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 44 g (94%) of the desired product that was used directly without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]3[N:17]=[CH:18][C:19]4[N:25]([CH3:26])[C:24](=[O:27])[C:23]([F:29])([F:28])[CH2:22][N:21]([CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]=4[N:35]=3)=[CH:9][C:8]=2[F:36])[CH2:2]1.[CH3:38][C:39]([CH3:41])=O>>[CH:30]1([N:21]2[CH2:22][C:23]([F:28])([F:29])[C:24](=[O:27])[N:25]([CH3:26])[C:19]3[CH:18]=[N:17][C:16]([NH:15][C:10]4[C:11]([O:13][CH3:14])=[CH:12][C:7]([C:6]([NH:5][CH:3]5[CH2:2][N:1]([CH:39]([CH3:41])[CH3:38])[CH2:4]5)=[O:37])=[C:8]([F:36])[CH:9]=4)=[N:35][C:20]2=3)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)=O
Reactant: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CN(C(C)C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized by following the Reductive Amination Procedure using N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide and acetone. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.06 Hz, 6 H) 1.44-1.80 (m, 6 H) 1.95 (br. s., 2 H) 2.27 (m, 6.09 Hz, 1 H) 2.89 (t, J=7.33 Hz, 2 H) 3.50 (t, J=7.33 Hz, 2 H) 3.92 (s, 3 H) 4.08 (t, J=13.89 Hz, 2 H) 4.29-4.42 (m, 1 H) 4.72-4.89 (m, 1 H) 7.19 (d, J=6.82 Hz, 1 H) 8.05 (s, 1 H) 8.25 (d, J=13.39 Hz, 1 H) 8.29-8.32 (m, 1 H) 8.40 (d, J=7.07 Hz, 1 H). [M+H] calculated for C27H34F3N7O3, 562; found 562.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[C:5](=[O:21])[N:4]([CH3:22])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:59][NH:60][CH2:61][CH2:62][OH:63]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:60]([CH2:61][CH2:62][OH:63])[CH3:59])=[O:15])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[C:5](=[O:21])[N:4]([CH3:22])[CH:3]=1
Reactant: CNCCO
Reactant: Cn1cc(Br)nc(Nc2ccc(C(=O)O)c([N+](=O)[O-])c2)c1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-2-nitro-benzoic acid (3) (1.0 g, 2.72 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [BOP] (120 mg, 2.72 mmol,), diisopropylethylamine (1.42 mL, 8.15 mmol) and 2-methylaminoethanol (0.33 mL, 4.07 mmol) are dissolved in DMF (25 mL) at room temperature and allowed to react for 60 min. The reaction is quenched by the addition of water (120 mL) and the resulting suspension was allowed to stir for 15 min. The suspension is then filtered, washed with water (3×50 mL) and then air-dried to give 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-N-(2-hydroxy-ethyl)-N-methyl-2-nitro-benzamide (4) as a yellow solid (1.05 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:30]2[CH:35]=[C:34]([C:36]3[O:41]C(C)(C)[O:39][C:38](=O)[CH:37]=3)[CH:33]=[CH:32][N:31]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:38](=[O:39])[CH2:37][C:36]([C:34]1[CH:33]=[CH:32][N:31]=[C:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:35]=1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2ccnc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) and 6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J14) according to the general procedure K. Obtained as a brown solid (284 mg).
Reaction SMILES: COC(=O)C(C[C:10]1[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1[O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])C(OC)=O.[OH2:34]>>[CH2:18]([CH:17]([O:16][C:15]1[CH:14]=[C:13]([CH3:22])[N:12]=[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[C:10]=1[CH:10]([CH3:11])[C:15]([OH:16])=[O:34])[CH2:20][CH3:21])[CH3:19]
Reactant: O
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CC(C(=O)OC)C(=O)OC
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C(C)C(=O)O

Procedure:
Hydrolysis of 2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic acid dimethyl ester with phosphoic/water at reflux to give the title compound as a white foam. Anal. For C23H32N2O3. ¾H2O calc.: C, 69.40; H, 8.48; N, 7.04; found: C, 69.17; H, 8.62; N, 6.90.
Reaction SMILES: [C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]([O:10][C:11](=[O:41])[C:12]2[CH:17]=[CH:16][C:15](CC3C4C(=CC=C(NC(=O)CC5CCCC5)C=4)N(CC)C=3)=[C:14]([O:39][CH3:40])[CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:48]1([CH2:53][C:54]([NH:56][C:57]2[CH:65]=[C:64]3[C:60]([CH:61]=[CH:62][N:63]3[CH2:66]C3C=CC(C(O)=O)=CC=3OC)=[CH:59][CH:58]=2)=[O:55])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[C:1]1([N:7]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:8]([O:10][C:11](=[O:41])[C:12]2[CH:17]=[CH:16][C:15]([CH2:66][N:63]3[C:64]4[C:60](=[CH:59][CH:58]=[C:57]([NH:56][C:54](=[O:55])[CH2:53][CH:48]5[CH2:49][CH2:50][CH2:51][CH2:52]5)[CH:65]=4)[CH:61]=[CH:62]3)=[C:14]([O:39][CH3:40])[CH:13]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCn1cc(Cc2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Reactant: COc1cc(C(=O)O)ccc1Cn1ccc2ccc(NC(=O)CC3CCCC3)cc21
Product: COc1cc(C(=O)OC(=O)N(c2ccccc2)c2ccccc2)ccc1Cn1ccc2ccc(NC(=O)CC3CCCC3)cc21
Yield: 92 %

Procedure:
Using a procedure similar to part (f) of Example 4, but using 4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoic acid (Q) instead of acid (J), there was obtained 4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoic N,N-diphenyl carbamic anhydride (O) as an off-white powder (1.4 g, 92%); partial NMR: (80 MHz, DMSO-d6): 3.98(s, 3H, OCH3) 5.30(s, 2H, NCH2Ar), 7.40(s, 10H, NArH), 9.69(s, 1H, CONH).