Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:25]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[O:23]C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[N:9][CH:10]=[C:11]([CH:25]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[OH:23]
Reactant: COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Into the reaction flask was added 6-chloro-12-methoxy-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene (1.35 g, 3.82 mmol), methylene chloride (20 mL), and 1.0 M of boron tribromide in methylene chloride (19.1 mL). The reaction mixture was stirred at rt overnight. To the mixture was added 1.0 M of sodium bicarbonate in water (30 mL). The precipitate formed was collected by vacuum filtration. The cake was washed with water and methylene chloride, and air dried to provide the desired product (1.25 g, 96%). LCMS for C17H15ClN5O (M+H)+: m/z=340.1.
Reaction SMILES: CC1C=C([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14]C3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.O1C=CN=C1CN>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:7][CH2:11][C:10]4[O:14][CH:13]=[CH:12][N:9]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1ncco1
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ncco1
Yield: 35 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with oxazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 35% yield: 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.31-7.24 (m, 2H), 7.09-7.00 (m, 3H), 6.34 (t, J=5.0 Hz, 1H), 6.12 (s, 1H), 4.71 (d, J=5.0 Hz, 2H), 4.44 (s, 2H), 3.84-3.76 (m, 2H), 3.47-3.40 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 437.1 (M+23).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[CH3:21][N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2>>[CH3:21][N:22]1[CH2:27][C@@H:26]2[CH2:28][C@:23]1([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=1[CH:4]=[CH:5][N:6]3[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12])[CH2:24][NH:25]2
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Reactant: CN1C[C@@H]2C[C@H]1CN2
Product: Cc1ccccc1S(=O)(=O)n1ccc2c([C@@]34CN[C@H](CN3C)C4)cccc21
Yield: 19 %

Procedure:
The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane according to Method 1 to give 25 mg (19%) of a white solid: 1H NMR (CD3OD) δ 7.91-6.44 (m, 9H), 4.67-4.63 (m, 1H), 4.35-4.33 (m, 1H), 4.09-4.07 (m, 1H), 3.99-3.95 (m, 1H), 3.72-3.70 (m, 1H), 3.21-3.17 (m, 1H), 2.95 (s, 3H), 2.33-2.31 (m, 2H); MS (ESI) 382.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][C:8]([Sn](CCCC)(CCCC)CCCC)=[C:9]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[C:10]=1[P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])CCC.[Cu]C#N.I[C:52]1([C:57]2[S:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][CH:55]=[CH:54][S:53]1.Cl>>[CH2:22]([O:21][P:19]([C:9]1[C:10]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:54]2[S:53][C:52]([C:57]3[S:58][CH:59]=[CH:60][CH:61]=3)=[CH:56][CH:55]=2)[S:7][C:8]=1[C:54]1[S:53][C:52]([C:57]2[S:58][CH:59]=[CH:60][CH:61]=2)=[CH:56][CH:55]=1)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc([Sn](CCCC)(CCCC)CCCC)c(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Reactant: IC1(c2cccs2)CC=CS1
Agent: N#C[Cu]
Agent: Cl
Product: CCOP(=O)(OCC)c1c(-c2ccc(-c3cccs3)s2)sc(-c2ccc(-c3cccs3)s2)c1P(=O)(OCC)OCC
Temperature: 70 °C
Reaction time: 13 h

Procedure:
2,5-bis(tributylstannyl)-3,4-bis(diethoxyphosphoryl)-thiophene and commercially available copper(I) cyanide (2.2 equivalents) were dissolved in solvents indicated in the following Table 11, to which 2-iodobithiophene (2.2 equivalents) was added at room temperature. Thereafter, the reaction mixture was heated to 70° C. and stirred for 4 to 22 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 0.6M hydrochloric acid aqueous solution was added, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance 1.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][OH:6].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([C:21]1[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[C:41]5[C:36](=[N:37][CH:38]=[CH:39][CH:40]=5)[NH:35][C:34]4=[O:42])[CH2:29][CH2:28]3)[C:24](I)=[CH:23][N:22]=1)=[O:20])[CH2:14][CH2:13]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCOCC1.C1COCC1.[Cu]I>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([C:21]1[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[C:41]5[C:36](=[N:37][CH:38]=[CH:39][CH:40]=5)[NH:35][C:34]4=[O:42])[CH2:29][CH2:28]3)[C:24]([C:3]#[C:4][CH2:5][OH:6])=[CH:23][N:22]=1)=[O:20])[CH2:14][CH2:13]2
Reactant: C[Si](C)(C)C#CCO
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c(I)cn1)N1CCc2cc(F)ccc21
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c(C#CCO)cn1)N1CCc2cc(F)ccc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Under an argon atmosphere 44 mg (0.34 mmol) 3-trimethylsilanyl-prop-2-yn-1-ol, 50 μL TEA, 13 mg 1,1′-bis(diphenylphosphine)ferrocene dichloropalladium (II) and 3 mg (20 μmol) copper(I) iodide were added to 0.10 g (0.17 mmol) 1-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-iodo-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in 4.0 mL 1,4-dioxane. Then 0.36 mL (0.36 mmol) of a 1 molar tetrabutylammonium fluoride solution in THF were added dropwise and the mixture was then stirred for 4 h at 80° C. The reaction mixture was mixed with water and the precipitate formed was suction filtered. The precipitate was stirred in 6 mL DMF and suction filtered. The filtrate was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[C:10]([CH3:12])[CH:11]=2)[N:5]=[C:6]([CH3:8])[CH:7]=1.C1(PC2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40]([CH:42]([NH2:45])[CH2:43][CH3:44])[CH3:41]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:9]1[N:4]2[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:45][CH:42]([CH2:43][CH3:44])[CH2:40][CH3:41])[C:3]2=[CH:11][C:10]=1[CH3:12]
Reactant: Cc1cc(Br)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Reactant: CCC(N)CC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCC(CC)Nc1cc(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-bromo-7-(2,4-dichlorophenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazine (0.253 g, 0.683 mmol), 5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl](diphenyl)phosphine (0.043 g, 0.068 mmol), Cs2CO3 (0.311 g, 0.956 mmol) and Pd2(dba)3 (0.031 g, 0.034 mmol) in dioxane (7.0 mL) is stirred at room temperature for 5 min followed by the addition of 1-ethylpropylamine (0.16 mL, 0.119 g, 1.37 mmol). The resulting mixture is refluxed for 10 h. After cooling to room temperature, 5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl](diphenyl)phosphine (0.022 g, 0.034 mmol), Pd2(dba)3 (0.016 g, 0.017 mmol) and 1-ethylpropylamine (0.08 mL, 0.06 g, 0.68 mmol) are added and the mixture is refluxed for an additional 7 h. The mixture is filtered through a pad of celite and washed with EtOAc. The filtrate is concentrated in vacuo to dryness, the residue is subjected to preparative TLC (silica gel, 1/15 EtOAc/heptane) to give 0.167 g (65%) of light yellow oil as the title compound. The product is solidified and recrystalized from pet ether to give a light yellow solid: mp 115–118° C.; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.36 (dd, J=2.1, 8.3 Hz, 1H), 6.32 (s, 1H), 5.58 (s, 1H), 4.21 (d, J=8.7 Hz, 1H), 3.50–3.42 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 1.79–1.69 (m, 2H), 1.63–1.56 (m, 2H), 1.04–0.98 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 153.9, 143.5, 136.7, 134.7, 134.5, 130.2, 130.0, 127.1, 123.1, 120.8, 119.9, 94.9, 88.3, 55.3, 27.5, 22.8, 12.7, 10.7; IR (liq.) 2965, 2929, 2326, 1996, 1748, 1614, 1563, 1487, 1461, 1443, 1374, 1333, 1002, 821, 813 cm−1; MS (EI) m/z 378 (M++H), 376 (M++H); HRMS (FAB) calcd for C20H23Cl2N3+H 376.1347, found 376.1353; Anal. Calcd for C20H23Cl2N3: C, 63.83; H, 6.16; N, 11.17. Found: C, 63.93; H, 6.23; N, 11.12.
Reaction SMILES: CN1CCN=C1C1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Br:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9]C=1.[N:35]1([N:40]=[C:41]2C=CC(N)=C[CH2:42]2)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(Cl)CCl>CN(C=O)C.O>[N:35]1([N:40]=[C:41]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Br:33])[NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:18])=[CH:9][CH2:42]2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Br)cc1
Reactant: NC1=CCC(=NN2CCCC2)C=C1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=CCC(=NN2CCCC2)C=C1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 77, 60 mg, 0.16 mmol) and 4-(pyrrolidin-1-ylimino)phenylamine (60 mg, 0.31 mmol) in DMF (4 mL) and H2O (1 mL), EDC (120 mg, 0.62 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (70 mg). MS 554.2 and 556.2 (M+H, Cl+Br pattern).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:27][C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:39][CH2:40][CH2:41]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:20][C:21]4[N:27]([CH2:41][CH2:40][F:39])[C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCI
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CCN4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (101 mg, 0.21 mmol) in dry DMF (1 ml) was added sodium hydride (12 mg, 0.32 mmol) and 1-fluoro-2-iodoethane (27 μl, 0.32 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 100% EtOAc in cyclohexane) to give the title compound (52 mg, 47%). 1H NMR (500 MHz, CDCl3): 7.62 (1H, s), 7.31-7.22 (7H, m), 7.16-7.14 (2H, m), 5.01 (1H, s), 4.75 (1H, br s), 4.74 (2H, dt), 4.07 (2H, dt), 3.92-3.88 (2H, m), 2.73 (2H, t), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[S:3](OC1C(C)(C)[C@H]2[C@](C)(CC=1)[C@@H]1[C@](C)([C@@]3(C)[C@H](CC1)[C@H]1[C@H](C(C)=C)CC[C@]1(NCCN1CCS(=O)(=O)CC1)CC3)CC2)(=[O:5])=[O:4].[CH3:49][C:50]1[CH:51]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:52][CH2:53][C:54](=[O:56])[CH:55]=1>>[CH3:49][C:50]1[CH:51]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:52][CH:53]=[C:54]([O:56][S:3]([C:2]([F:48])([F:47])[F:1])(=[O:5])=[O:4])[CH:55]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Product: CCOC(=O)C1CC=C(OS(=O)(=O)C(F)(F)F)C=C1C
Yield: 62.7 %

Procedure:
The title compound was prepared following the procedure described in Method 2 for the preparation of Intermediate 1, Step 6, using ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate as the reactant. (62.7% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.93 (t, J=1.3 Hz, 1H), 4.30-4.09 (m, 2H), 2.83-2.68 (m, 2H), 2.62-2.43 (m, 2H), 2.18 (t, J=1.9 Hz, 3H), 1.37-1.20 (m, 3H). 19F NMR (376 MHz, CHLOROFORM-d) δ −73.63 (s, 3F).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[N:13]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[N:17][C:18]([CH3:24])=[CH:19][CH:20]=3)[N:15]=2)[C:12](=[O:25])[C:11]2[S:26][CH2:27][CH:28]([O:31][CH3:32])[CH2:29][S:30][C:10]1=2.Cl.Cl[C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)=[O:36].N1C=CC=CC=1>C(Cl)Cl>[CH3:32][O:31][CH:28]1[CH2:29][S:30][C:10]2[C:9](=[O:8])[N:13]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][C:18]([CH3:24])=[CH:19][CH:20]=4)[N:15]=3)[CH:12]([O:25][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:36])[C:11]=2[S:26][CH2:27]1
Reactant: COC1CSC2=C(SC1)C(O)N(c1ccc3ccc(C)nc3n1)C2=O
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CSC2=C(SC1)C(OC(=O)N1CCN(C)CC1)N(c1ccc3ccc(C)nc3n1)C2=O
Temperature: 45 °C
Yield: 43.1 %

Procedure:
Triethylamine (24.5 cc) is added, at about 15° C., to a suspension of 6-hydroxy-3-methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.3 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (11.7 g) in anhydrous methylene chloride (300 cc), and anhydrous pyridine (130 cc) is then added to the resulting mixture. The mixture is heated at 45° C. for 3 hours. 1-Chlorocarbonyl-4-methylpiperazine hydrochloride (6.0 g) is then added and the mixture is heated for a further 1/2 hour at 45° C. After cooling, the mixture is diluted by adding methylene chloride (300 cc). The organic phase is washed three times with distilled water (total 600 cc), dried over sodium sulphate and evaporated. The resulting residue (25.0 g) is dissolved in boiling acetonitrile (70 cc). After cooling the solution for 48 hours at 2° C., the resulting crystals are filtered off, washed twice with ice-cooled acetonitrile (total 20 cc) and dried under reduced pressure (20 mm Hg) at 20° C. The resulting product (5.25 g; m.p. 220° C.) is dissolved in methylene chloride (100 cc) and the solution is filtered through silica (0.2-0.5 mm; 200 g) contained in a column of diameter 2.1 cm. Elution is carried out with methylene chloride (400 cc); the eluate is discarded. Elution is continued with a mixture of methylene chloride (784 cc) and methanol (16 cc); this eluate is evaporated under reduced pressure (20 mm Hg) at a temperature below 60° C. The residue is dried under reduced pressure (0.2 mm Hg) at 50° C. 3-Methoxy-7-(7-methyl-1,8-naphthyridin-2-yl)-6-(4-methylpiperazin-1-yl)carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (4.2 g), melting at 225° C., is obtained.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:18])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([I:16])[CH:12]=2)[C:7]1=[O:17].[O-][CH2:20][CH2:21][CH2:22]C.[Na+].Cl>C(O)CCC>[CH2:2]([O:3][C:4]([C:5]1[NH:6][C:14](=[O:15])[C:13]2[C:8]([C:7]=1[OH:17])=[CH:9][CH:10]=[C:11]([I:16])[CH:12]=2)=[O:18])[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)CN1C(=O)c2ccc(I)cc2C1=O
Reactant: CCCC[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCCCO
Product: CCCCOC(=O)c1[nH]c(=O)c2cc(I)ccc2c1O
Temperature: 80 °C

Procedure:
Freshly cut sodium metal, 0.40 g, was dissolved in 22 ml of n-butanol at 65° C. under a nitrogen atmosphere. A mixture of 3.0 g of (5-iodo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid methyl ester in 22 ml of n-butanol was added to the sodium butoxide solution and the reaction mixture was heated to 80° C. for 2 h. The cooled reaction mixture was acidified with 100 ml of 1M hydrochloric acid to give a solid precipitate. The solid was collected by filtration and separated by silica gel chromatography (eluant; 19:1 dichloromethane:ethyl acetate) to give 0.219 g of 4-hydroxy-7-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(−)-ion, M−1=386.0 amu, and 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(−) ion, M−1=386.0 amu.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[CH2:10][N:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[O:14][CH2:13][C@H:12]1[C:19]([OH:21])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)CN[C@H](C(O)=O)CO1.[Cl:34][C:35]1[CH:36]=[C:37]2[C:45](=[C:46]([NH2:48])[CH:47]=1)[NH:44][C:43]1[CH:42]=[N:41][CH:40]=[C:39]([CH3:49])[C:38]2=1.CCN=C=NCCCN(C)C>N1C=CC=CC=1.CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH3:22])[CH2:10][N:11]1[C@H:12]([C:19](=[O:21])[NH:48][C:46]2[CH:47]=[C:35]([Cl:34])[CH:36]=[C:37]3[C:45]=2[NH:44][C:43]2[CH:42]=[N:41][CH:40]=[C:39]([CH3:49])[C:38]3=2)[CH2:13][O:14][C:15]([CH3:17])([CH3:18])[CH2:16]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cncc2[nH]c3c(N)cc(Cl)cc3c12
Reactant: C[C@@H](CN1CC(C)(C)OC[C@H]1C(=O)O)NC(=O)OC(C)(C)C
Agent: CC1(C)CN[C@H](C(=O)O)CO1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cncc2[nH]c3c(NC(=O)[C@@H]4COC(C)(C)CN4C[C@H](C)NC(=O)OC(C)(C)C)cc(Cl)cc3c12
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A solution of (S)-4-((S)-2-tert-butoxycarbonylamino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (3.316 g, 10.5 mmol) (prepared by reductively alkylating (S)-6,6-dimethyl-morpholine-3-carboxylic acid with N-(tert-butoxycarbonyl)-L-alanal) in anhydrous pyridine (75 mL) was stirred at room temperature. 6-chloro-4-methyl-9H-β-carbolin-8-ylamine (1.869 g, 8.09 mmol) was added, followed by EDCI (2.894 g, 15.1 mmol). The reaction was stirred at room temperature for 14-18 hours under argon. The reaction was partially concentrated, diluted with H2O (20 mL) and transferred to a separatory funnel. The mixture was diluted with brine (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried, filtered and concentrated to afford a dark residue. Column chromatography (0-8% MeOH/CH2Cl2) yielded {(S)-2-[(S)-5-(6-Chloro-4-methyl-9H-β-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-1-methyl-ethyl}-carbamic acid tert-butyl ester as a light tan solid (2.688 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(CCC(=O)CCc2ccc(N)cc2)cc1

Procedure:
A mixture of 1,5-bis-(4-nitro-phenyl)-pentan-3-one from Example HH (9.00 g, 27.4 mmol), 5% Pd on BaSO4 (0.7 g), and THF (600 mL) was shaken in a hydrogen atmosphere of 52 psi at 26° C. for 17 hours. The catalyst was filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 4% MeOH in CH2Cl2, to give the title compound. 1H NMR (CDCl3) δ 2.60 (m, 4 H), 2.74 (m, 4 H), 3.45 (bs, 4 H), 6.56 (m, 4 H), 6.91 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([NH:11][C:12](=[NH:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:4]([CH:22]([CH3:24])[CH3:23])[CH:3]=1.Cl[CH2:26][CH:27]=O.C(=O)(O)[O-].[Na+].CC(O)C>O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([N:11]2[CH:27]=[CH:26][N:21]=[C:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:4]([CH:22]([CH3:24])[CH3:23])[CH:3]=1
Reactant: COc1cccc(C(=N)Nc2c(C(C)C)cc(Br)cc2C(C)C)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(-c2nccn2-c2c(C(C)C)cc(Br)cc2C(C)C)c1
Yield: 78.6 %

Procedure:
A 500 ml round bottom flask was charged with N-(4-bromo-2,6-diisopropylphenyl)-3-methoxybenzimidamide (19.73 g, 50.7 mmol), 2-chloroacetaldehyde (12.83 ml, 101 mmol), sodium bicarbonate (12.77 g, 152 mmole) and 2-Propanol (300 ml). The reaction was allowed to reflux for 16 hours. The reaction mixture was diluted with deionized water and extracted with ethyl acetate, the organic portion was combined and subjected to a column chromatography (SiO2 gel; 20% THF in heptane) to yield the desired product (16.47 g, 79%).
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([Br:1])=[CH:3][C:4]3[CH2:8][CH2:7][O:6][C:5]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 5-(5-bromo-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (139) (13 mg, 0.044 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (38 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(5-bromo(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)]carboxamide (140) (15.5 mg, yield: 81.6%, purity>90%) as white solid.