Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:8]=[CH:7]2)([O-])=O.C(O)C.[H][H].I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34]>[Pd].CCOCC>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH:1][C:33]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[NH:34])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCCN2CCOCC2)c1
Reactant: [H][H]
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: N=C(Nc1ccc2c(ccn2CCCN2CCOCC2)c1)c1cccs1
Reaction time: 17.5 h
Yield: 62.6 %

Procedure:
To an argon purged round bottom flask containing compound 39 (153 mg, 0.529 mmol) was added 10% by weight palladium on carbon (56 mg, 0.053 mmol) and a magnetic stirbar, followed by the addition of absolute ethanol (10 mL). The system was fitted with a hydrogen filled balloon. The argon atmosphere was removed using a water aspirator and replaced with hydrogen. The atmosphere was removed twice more and replaced with hydrogen a total of 3 times and was stirred for 17.5 hours. TLC (2M NH3 in methanol:CH2Cl2, 5:95) revealed the reaction was complete. The reaction was filtered through a 5 um PTFE frit. The frit washed with absolute ethanol (5 mL). The filtrate was transferred to a reaction vial fitted with a magnetic stirbar, and was purged with argon. Methyl thiophene-2-carbimidothioate hydroiodide (226 mg, 0.793 mmol) was added as a solid and the reaction was stirred at room temperature for 18 hours. The reaction was complete by TLC and was diluted with ether (40 mL) and the reaction was filtered to collect the precipitate. The precipitate washed with ether. The precipitate was dissolved in ethanol and stirred at room temperature with DOWES-66 resin (3.00 g). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate concentrated. The material was purified by silica gel column chromatography (2M NH3 in methanol:CH2Cl2, 2.5:97.5 to 5:95) to obtain compound 40 (122 mg) as a brown oil. 1H NMR (DMSO-d6) δ 7.72 (d, J=3.6 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 7.09 (t, J=4.5 Hz, 1H), 6.97 (s, 1H), 6.69 (d, J=9.0 Hz, 1H), 6.32 (d, J=3.0 Hz, 1H), 6.22 (brs, 2H), 4.17 (t, J=6.6 Hz, 2H), 3.58 (t, J=4.5 Hz, 4H), 2.31 (m, 4H), 2.21 (t, J=6.9 Hz, 2H), 1.90 (m, 2H); ESI-MS (m/z, %): 369 (M+1); ESI-HRMS calculated for C20H25N4OS (MH+): 369.1743, Observed: 369.1754.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][C:3]=1[Br:29].[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37](O)=[O:38])[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37]([NH:1][C:2]2[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:4][C:3]=2[Br:29])=[O:38])[N:35]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(NC(=O)Cc3csc(N)n3)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 115 mg (0.25 mmol) of tert-butyl (2S,5R)-2-(4-amino-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (i-80a) and (2-amino-1,3-thiazol-4-yl)acetic acid (77 mg, 0.30 mmol) in 3.0 mL anhydrous DMF was added HOBt (44 mg, 0.32 mmol) followed by EDC (66 mg) and DIEA (0.22 mL, 1.25 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×2 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by Gilson reverse phase HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA buffer to afforded the product (105 mg, 81%). m/z (ES) 601(M)+ and 603 (M+2)+, also 623 (MNa)+and 625 (MNa+2)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:12][C:11]=2[CH:28]=1)[C:4]#N.C(O)C.[OH-:32].[Na+].Cl.[OH2:35]>>[CH3:1][O:2][CH:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:12][C:11]=2[CH:28]=1)[C:4]([OH:35])=[O:32]
Reactant: [OH-]
Reactant: O
Reactant: COC(C#N)Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)O

Procedure:
A mixture of 2-methoxy-3-[2-((5-methyl-2-phenyl-4-oxazolyl)methyl)benzofuran-5-yl]propanenitrile (0.64 g, 1.7 mmol), ethanol (30 ml) and 6N sodium hydroxide (10 ml) was heated to reflux for 3 hours. Water (30 ml) was added and the solution was acidified with concentrated hydrochloric acid (6 ml), then extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The product was recrystallized from ethyl acetate/hexanes and obtained as a white solid (0.47 g, mp 159°-160.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Br:30])[C:27]=1[O:28]C)[C:5]([N:7]1[CH2:12][CH2:11][O:10][C:9]2[N:13]=[CH:14][C:15]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[CH:16][C:8]1=2)=[O:6].[Br-].[Li+].N1CCNCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Br:30])[C:27]=1[OH:28])[C:5]([N:7]1[CH2:12][CH2:11][O:10][C:9]2[N:13]=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)=[CH:16][C:8]1=2)=[O:6]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C#N)cc4)cc32)cc1Br
Agent: C1CNCCN1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cnc3c(c2)N(C(=O)c2cc(Br)c(O)c(Br)c2)CCO3)cc1

Procedure:
By the same method as in the step d) of Example 45, 4-[1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-benzonitrile (116 mg, 0.22 mmol), lithium bromide (76 mg, 0.88 mmol) and piperazine (29 mg, 0.33 mmol) were dissolved in N,N-dimethyl formamide (3 ml) and reacted at 1000 to obtain the target compound 65, i.e., 4-[1-(3,5-dibromo-4-hydroxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-benzonitrile, as white solid (49 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](O)=[O:9])[CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:21][O:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[N:17]=1)=[O:19]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: COC(=O)c1cccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 93 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (16.3 g, 103 mmol), methyl 6-aminopicolinate (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 41.1 g, 108 mmol), and N-methyl morpholine (12.5 mL, 108 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL) and dried under reduced pressure to afford 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester as a white powder (25.6, 93% yield).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30])=[C:20]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:19]=[CH:18][C:12]=1[CH:13]=[CH:14][C:15]([OH:17])=[O:16])(=[O:4])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[C:46]1([CH3:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30])=[C:20]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:19]=[CH:18][C:12]=1[CH:13]=[CH:14][C:15]([O:17][C:49]1[CH:50]=[CH:51][C:46]([C:52]2[CH:20]=[CH:21][C:11]([O:16][C:15](=[O:17])[CH:14]=[CH:13][C:12]3[CH:18]=[CH:19][C:20]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40])=[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30])[C:11]=3[O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:12][CH:13]=2)=[CH:47][CH:48]=1)=[O:16])(=[O:4])[CH:2]=[CH2:3]
Reactant: Cc1ccccc1
Reactant: C=CC(=O)OCCCCOc1ccc(C=CC(=O)O)c(OCCCCOC(=O)C=C)c1OCCCCOC(=O)C=C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)OCCCCOc1ccc(C=CC(=O)Oc2ccc(-c3ccc(OC(=O)C=Cc4ccc(OCCCCOC(=O)C=C)c(OCCCCOC(=O)C=C)c4OCCCCOC(=O)C=C)cc3)cc2)c(OCCCCOC(=O)C=C)c1OCCCCOC(=O)C=C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Into a three-neck flask, 2,3,4-tri(4-acryloyloxy-butyloxy)cinnamic acid (10.0 g), thionyl chloride (6.1 g), dimethylformamide (0.01 g) and 30 mL of toluene were added and stirred at 40° C. for 30 minutes. After cooling, toluene and excess thionyl chloride were removed by distillation and then 100 ml of tetrahydrofuran was added. To this reaction solution, 4,4′-dihydroxybiphenyl (1.6 g) was added and after cooling to 5° C., triethylamine (2.8 mL) was added dropwise. Subsequently, 4-dimethylaminopyridine (0.1 g) was added and after heating to 25° C., the solution was stirred for 5 hours. The resulting reaction solution was added to water (500 mL) and crystals precipitated were collected by filtration. The obtained crystals were dissolved in dimethylacetamide (20 mL), triethylamine (2.8 mL) was added thereto and the resulting solution was stirred at 60° C. for 1 hour. After cooling, the reaction solution was extracted with ethyl and washed with water. The extract was concentrated and then purified by column chromatography to obtain the titled compound (9.5 g). Yield: 85%. The NMR spectrum of m-40 obtained is shown below.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1C(O)=O.Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)C(C)C)(C)C.CCOC(OC([O:34][CH2:35][CH3:36])=O)=O>O1CCCC1.O>[Cl:1][C:2]1[C:3]([CH2:36][C:35]([N:14]([O:15][CH3:16])[CH3:13])=[O:34])=[CH:7][CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CNOC
Reactant: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)Cc1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-6-methylnicotinic acid (1.00 g, 5.83 mmol) in tetrahydrofuran (10 mL) was successively added with N,O-dimethylhydroxyamine hydrochloride (910 mg, 9.33 mmol), N,N-diisopropylethylamine (3.00 g, 23.2 mmol) and DEPC (1.43 g, 8.77 mmol) on an ice bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 2-chloro-N-methoxy-N,6-dimethylpyridine-3-carboxyamide as colorless solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]3[O:18][CH2:17][CH2:16][C:15]4[CH:14]=[C:13]([C:19]5[N:20]([C:24]6[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=6[F:31])[N:21]=[CH:22][N:23]=5)[S:12][C:11]=4[C:10]=3[N:32]=2)[CH2:2]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C.O>C1COCC1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:20]1[C:19]([C:13]2[S:12][C:11]3[C:10]4[N:32]=[C:6]([NH:5][CH:3]5[CH2:4][N:1]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:2]5)[CH:7]=[CH:8][C:9]=4[O:18][CH2:17][CH2:16][C:15]=3[CH:14]=2)=[N:23][CH:22]=[N:21]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(NC4CNC4)ccc2OCC3)c(F)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC(Nc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.8 %

Procedure:
Azetidin-3-yl-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-amine (452 mg, 1.0 mmol), Methanesulfonyl chloride (136 mg, 1.2 mmol), DIPEA (260 mg, 2.0 mmol) was dissolved in THF (10 mL). The reaction mixture was stirred at room temperature (r.t.) for 1 hour. LC-MS indicated the reaction was completed. To the reaction mixture was added 20 mL of water, the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness. The crude was purified by pre-HPLC to afford 363 (57.2 mg, yield: 11%). 1HNMR (DMSO-d6, 400 MHz): δ 9.50 (s, 1H), 8.72 (s, 1H), 8.31 (s, 1H), 7.97-7.91 (m, 2H), 7.77-7.72 (m, 2H), 7.48-7.43 (m, 2H), 7.15 (s, 1H), 6.99 (s, 1H), 6.72 (d, J=4.4 Hz, 1H), 4.31 (s, 2H), 3.86 (s, 2H), 3.33 (s, 2H), 3.15 (s, 2H), 2.75 (s, 6H). ESI-MS: m/z=531 [M+H+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
20 mg of the target compound (0.06 mmol, 7.32%) was obtained using 1-(2-fluorophenyl)piperazine (296 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1B(O)O>>[CH:33]1[C:34]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:32]=1[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Reactant: OB(O)c1ccc2ccccc2c1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc5ccccc5c4)nc23)CC1
Yield: 91.8 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (164 mg, 0.450 mmol) and 2-naphthylboronic acid (124 mg, 0.720 mmol) were converted to 141 mg of the title compound by the procedure of Example 3. (91%). MS(FD) m/e 341.8 (M+). EA calculated for C23H23N3: C, 80.94; H, 6.74; N, 12.32. Found: C, 88.11; H, 6.87; N, 12.27.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16](Br)[CH:17]=3)=[N:9][CH:10]=2)[CH2:2]1.[C:21]([O:24][CH2:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[CH2:53][CH2:52][N:44]2[C:45]3[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=3[CH:51]=[C:43]2[C:42]1=[O:54])(=[O:23])[CH3:22].O1CCOCC1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:53][CH2:52][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[CH:51]=[C:43]3[C:42]2=[O:54])=[CH:28][CH:29]=[CH:30][C:31]=1[C:16]1[CH:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH:3]3[CH2:4][NH:1][CH2:2]3)=[CH:10][N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1)(=[O:23])[CH3:22]
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CNC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 37.5 %

Procedure:
In a 44-mL sealed tube equipped with a magnetic stirring bar were placed 3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 155n (60 mg, 0.18 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (110 mg, 0.23 mmol), Pd(PPh3)4 (21 mg, 0.0.18 mmol) in 2 N Na2CO3 (3 mL), DME (2 mL), and dioxane (3 mL). After the reaction mixture was stirred at 100° C. for 14 h., it was partitioned between dichloromethane (5 mL) and water (5 mL), and the organic phase was extracted with dichloromethane (5 mL×3). The combined organic phases were washed with water (5 mL×2) and brine (5 mL×1), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (dichloromethane:MeOH, 85:15) to give 40% (40 mg) of 2-(5-(5-(azetidin-3-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 151a as a solid.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH2:21])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=[S:23].[NH4+].[OH-].O>C1COCC1>[CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH:21][C:22]([NH2:24])=[S:23])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Reaction time: 22 h
Yield: 70 %

Procedure:
3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-ylamine (0.97 mmol) is dissolved in THF (10 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 22 hours. 32% NH4OH (20 eq.) is added and stirred 2 hours at room temperature. Water (250 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiourea is obtained as yellow solid in a yield of 70%. HPLC (method C): 2.24 min; LC-MS (method A): 2.372 min, 344.15 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:4].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCCN(C)C1=O>C(Cl)Cl>[CH:27]1[CH:26]=[CH:25][N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:7][CH:8]=3)=[O:13])[CH2:15][C:16]=12
Reactant: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: C1COCCN1
Solvent: CN1CCCN(C)C1=O
Solvent: ClCCl
Product: O=C(CN1CCOCC1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 20 h
Yield: 106.8 %

Procedure:
A stirred suspension of 0.19 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]acetamide in 1 ml of methylene chloride is added 0.44 g of morpholine followed by 1 ml of 1,3-di- methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirring continued for 20 hours. The methylene chloride is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The brown solid is dissolved in 15 ml of ethyl acetate and washed with saturated NaHCO3, brine and dried with Na2SO4. The mixture is filtered and the filtrate evaporated in vacuo to give 0.23 g of a colorless gum which is stirred with ethyl acetate-hexanes to give 0.21 g of white solid. MS(CI): 431(M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([CH3:15])(O)[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].NC(N)CS(F)(F)[F:29].[OH-].[K+].C(OCC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([F:29])([CH3:15])[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: NC(N)CS(F)(F)F
Reactant: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A solution of 1-(6-Bromo-5-(2,4-difluorophenoxy)-1H-indazol-1-yl)-2-methylpropan-2-ol (19.8 g, 49.8 mmol) in DCM (150 mL) was cooled with a dry-ice acetone bath to −73° C. (Diaminoethyl)sulfur trifluoride (6.9 mL, 52.3 mmol) was added dropwise over 2 min; the temperature rose to −62° C. The resulting solution was stirred in the bath for a further 1 hr, then at ambient temperature for 1 hour. The reaction mixture was poured into a separatory funnel containing cold 10% KOH (250 mL), and then diethyl ether (500 mL) was added. After shaking, the organic layer was washed with brine (150 mL), dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using 85/15 hexanes/EtOAc as eluent. Fractions containing product were pooled and the solvent removed under reduced pressure to afford the title compound as an orange oil (13.4 g, 78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:15]=[C:14]2[NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:20][C:19]1[CH:18]=[C:17]2[C:13]([C:14]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])=[N:15][N:16]2[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])=[CH:12][C:11]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccncc3)cc12
Yield: 77.3 %

Procedure:
415 mg of 4-pyridylboronic acid are added to 1 g of N-[[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]]butanamide, described previously, in Example 58, in 90 cm3 of dioxane, followed by addition of a solution of 570 mg of sodium carbonate in 18 cm3 of water and finally 173 mg of tetrakis-(triphenylphosphine)palladium, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and 50 cm3 of water. The organic phase is separated out after settling of the phases has taken place, washed with 50 cm3 of water and 50 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 770 mg of N-[6-chloro-5-(4-pyridyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of white crystals.