Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CB(O)O
Reactant: Clc1ccn2c(CC3CC3)nnc2c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)ccn2c(CC3CC3)nnc12
Temperature: 100 °C

Procedure:
To a mixture of D70 (0.6 g, 1.8 mmol) in toluene (15 ml) under a nitrogen atmosphere were added methylboronic acid (0.538 g, 9 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine; S-Phos (0.171 g, 0.36 mmol), palladium(II)acetate (0.04 g, 0.18 mmol) and K2CO3 (0.745 g, 5.396 mmol). The reaction mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with water. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/EtOAc from 100/0 to 20/80 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D71 (0.312 g, 78%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][C:14]=2OC)[N:3]=1.NC1C=CC([CH2:35][CH2:36][PH:37](=[O:41])[O:38][CH2:39][CH3:40])=CC=1>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:35][CH2:36][PH:37](=[O:41])[O:38][CH2:39][CH3:40])=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCO[PH](=O)CCc1ccc(N)cc1
Product: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Yield: 61 %

Procedure:
Prepared as described above for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate using ethyl (4-aminobenzyl)methylphosphinate in place of diethyl (4-amino-3-methoxybenzyl)phosphonate. Following chromatography, the semi-pure product was crystallized from ethyl acetate to afford 1.1 g (61% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1H), 8.79 (d, J=0.51 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.25 (dd, J=2.27, 8.59 Hz, 2H), 3.86-4.01 (m, 2H), 3.15 (d, J=17.68 Hz, 2H), 1.31 (d, J=13.64 Hz, 3H), 1.19 (t, J=6.95 Hz, 3H); MS (ES+): m/z: 396.0708 [MH+]. HPLC: tR=1.41 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([CH3:18])=[N:9][C:10]([N:13]=CN(C)C)=[N:11][CH:12]=1)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]2[N:31]=[C:5]([C:7]3[C:8]([CH3:18])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=3)[CH:4]=[CH:3][N:30]=2)=[CH:26][CH:27]=1
Reactant: N=C(N)Nc1ccc(F)cc1
Reactant: Cc1nc(N=CN(C)C)ncc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)ncc1-c1ccnc(Nc2ccc(F)cc2)n1
Yield: 80 %

Procedure:
A solution of N′-{5-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-methylpyrimidin-2-yl}-N,N-dimethylimidoformamide (27) (50 mg, 0.191 mmol), 1-(4-fluorophenyl)guanidine hydrochloride (102 mg, 0.383 mmol), and K2CO3 (106 mg, 0.765 mmol) in DMF (1018 μl) was heated at 120° C. for 2 d. The crude product was filtered through a syringe filter, then the crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] to obtain ˜80% pure desired product. The product was taken up in 10% MeOH/DCM, then was purified by Biotage™ silica gel chromatography [10 g SNAP column, 2-10% MeOH/DCM] and further purified by trituration with acetone and acetonitrile to obtain the desired product as a pale yellow solid (10.23 mg, 18% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3 H) 6.93 (s, 2 H) 7.02 (d, J=5.05 Hz, 1 H) 7.12 (t, J=8.84 Hz, 2 H) 7.77 (dd, J=9.35, 4.80 Hz, 2 H) 8.44 (s, 1 H) 8.46 (d, J=5.05 Hz, 1 H) 9.61 (s, 1 H). HRMS (ES+) for C15H13FN6.H+ [MH+]: calcd, 297.1264. found, 297.1274. UV-LC: 98.95/100% UV purity at 214/254 nm; tR=4.30 minutes over 7.75 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22]O)[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32]C)=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S1C=CC=C1S(N)(=O)=O.[Cl:43][C:44]1[S:48][C:47]([S:49]([NH2:52])(=[O:51])=[O:50])=[CH:46][CH:45]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH:24]3[CH2:26][CH2:25]3)[CH2:22][NH:52][S:49]([C:47]3[S:48][C:44]([Cl:43])=[CH:45][CH:46]=3)(=[O:51])=[O:50])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([OH:32])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Agent: NS(=O)(=O)c1cccs1
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)c2ccc(Cl)s2)C2CC2)C1=O

Procedure:
The title compound was prepared from methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 263, Step C) by procedures similar to those described in Example 263, Step D and E, substituting thiophene-2-sulfonamide in Step D with the appropriate amount of 5-chlorothiophene-2-sulfonamide.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.[C:62](Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64]>C(Cl)Cl>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([N:45]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:42][CH2:43]1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCc3ccccc3)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(Cc3ccccc3)C(=O)C(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (3S,5R)-3-Benzylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (68.5 mg, 0.098 mmol) in CH2Cl2 is treated with i-Pr2NEt (40.2 μL, 0.235 mmol) and pivaloylchloride (23.9 μL, 0.196 mmol). The solution is stirred at room temperature for 18 h. Additional i-Pr2NEt (20 μL, 0.12 mmol) and pivaloylchloride (12 μL, 0.095 mmol) are added and stirring is continued for 9 h. The reaction mixture is partitioned between EtOAc and 1 M NaHCO3, the organic layer is washed with 1 M NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in THF/piperidine (5:1) (6 mL), the solution is stirred at room temperature for 2.5 h and then concentrated in vacuo. The crude product is purified by RP-HPLC to afford the title compound. MS: 559 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.40 min.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCCCC
Reactant: CCOC(=O)C(F)(F)F
Product: CCCCN(CCCC)C(=O)C(F)(F)F

Procedure:
Under a blanket of nitrogen, 2020.9 g (14.22 moles) of ethyl trifluoroacetate was charged to a 12-liter flask equipped with an overhead stirrer, an addition funnel, thermometer, and a condenser. To the stirred ethyl trifluoroacetate, 2015.0 g (15.59 moles) of dibutyl amine was added over a two hour period, during which the temperature of the stirred reaction mixture rose from 20° to 40° C. At the end of the addition period, the reaction flask was equipped with an 8 inch packed column and distillation head. The ethanol by-product was then removed by distillation with a maximum pot temperature of 135° C. The reaction mixture was then cooled and the product was isolated by distillation, boiling range 79°-87° C. at 2.2-3.2 mmHg. Yield 2850 g (89.0%).
Reaction SMILES: [CH2:1]([C:9]1([O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:20]O.[OH-].[Na+].[Cl-].[NH4+]>CO>[O:14]1[CH:13]2[CH:12]1[C:11](=[O:20])[CH2:10][C:9]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:15][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCCCCCCC1(O[Si](C)(C)C)C=CC(=O)C1
Reactant: OO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC1(O[Si](C)(C)C)CC(=O)C2OC21

Procedure:
To a solution of 3.3 g of 4-octyl-4-trimethylsilyloxy-2-cyclopentenone dissolved in 50 ml of methanol was added, under ice-cooling and stirring, 5.0 ml of an aqueous 30% hydrogen peroxide, and 500 μl of an aqueous 1N sodium hydroxide was added. After the mixture was stirred for 3.5 hours, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The product was filtered and concentrated to give a crude oil of 2,3-epoxy-4-octyl-4-trimethylsilyloxycyclopentanone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[N:13]=[C:14]([N:17]4[CH2:21][CH:20]5[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH:19]5[CH2:18]4)[CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:5]=[CH:4][N:3]=1.Cl>ClCCl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][CH:20]5[CH:19]([CH2:24][NH:23][CH2:22]5)[CH2:18]4)=[N:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccc4nc(-c5ccc(Cl)cc5)c(-c5ccnc(N)c5)n4n3)CC2C1
Agent: Cl
Solvent: ClCCl
Product: Nc1cc(-c2c(-c3ccc(Cl)cc3)nc3ccc(N4CC5CNCC5C4)nn23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of 0.16 g (0.29 mmol) of tert-butyl 5-[3-(2-aminopyrid-4-yl)-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 3 mL of dichloromethane are added 1.5 mL (18 mmol) of concentrated hydrochloric acid. After stirring for 1 hour at room temperature, the solvent is evaporated off under reduced pressure, the oily residue is taken up with aqueous ammonia and the product is extracted with dichloromethane. The organic phase is filtered on a hydrophobic cartridge and concentrated under reduced pressure. The solid obtained is triturated with diisopropyl ether to give 0.091 g of solid after filtering off and drying under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([NH:32]N)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Reactant: NNc1cccc2ccccc12
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 1-(3-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-23) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=399.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23]
Reactant: C=CC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Agent: [Pd]
Solvent: CO
Product: CCC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
To a solution of 66.60D (0.453 g, 1.26 mmol) in MeOH (10 mL) (degassed by N2), was added palladium on carbon (0.135 g, 1.26 mmol). The resulting mixture was stirred at room temperature under H2 for 18 hrs. The reaction mixture was then filtered through silica gel. After removing solvent, 66.62A (394 mg) was obtained as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[N:9]=[C:10]([O:22][CH3:23])[C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:13]=1>CO.[Pd]>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:12]2[CH:13]=[CH:8][N:9]=[C:10]([O:22][CH3:23])[C:11]2=[O:21])=[CH:19][CH:18]=1
Reactant: COc1nc(Cl)cn(-c2ccc(F)cc2)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1nccn(-c2ccc(F)cc2)c1=O
Reaction time: 6 h
Yield: 89.7 %

Procedure:
K2CO3 (1.09 g, 7.85 mmol) and 10% Pd/C (0.42 g, 0.39 mmol) were added to 5-chloro-1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one (2.0 g, 7.85 mmol) in MeOH (100 mL) at room temperature under a H2 atmosphere and the reaction was stirred for 6 hours. The reaction mixture was filtered with MeOH and concentrated under reduced pressure. The crude was treated with CH2Cl2, washed with water, dried over MgSO4, and concentrated to give the desired product (1.55 g, 90%). LRMS (ESI pos) m/e 221.0 (M+1).
Reaction SMILES: O[C:2](C1C=CC=CC=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]1[CH:8]=[C:7]([OH:9])[C:6]([C:10](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[OH:24].[N+]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([O-])=O>>[C:40]1([C:2]2[C:25]3[C:26]([O:24][C:4]4[C:3]=2[CH:8]=[C:7]2[C:6](=[C:10]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[O:9]2)[CH:5]=4)=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Oc1cc(C(O)(c2ccccc2)c2ccccc2)c(O)cc1C(O)(c1ccccc1)c1ccccc1
Product: c1ccc(C2=c3cc4c(cc3Oc3ccccc32)=C(c2ccccc2)c2ccccc2O4)cc1
Yield: 51.2 %

Procedure:
A flask is charged with 2,5-bis-(hydroxy-diphenyl-methyl)-benzene-1,4-diol (Example 1) (9.5 g) and nitrobenzene (50 g). The obtained suspension is heated at reflux for ca. 45 minutes, and then allowed to cool over night. The formed crystals are filtered off, washed several times with ethanol and dried at 10−3 mbar/190° C. for two hours (some sublimation takes place) to give 4.47 g of greenish red crystals, mp.=419° C. (DSC). Elementary analysis: Ccalcd. 88.05%, Cfound 87.62% and 87.78%; Hcalcd. 4.62%, Hfound 4.29% and 4.65%. The proposed structure is confirmed by an X-ray crystal structure, monoclinic, space group C2/c, a=18.961(5), b=6.058(2), c=20.229 (5); alpha=90.00, beta=116.351(9), gamma=90.00; Z=4.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:26][S:27]([CH2:30][CH2:31][NH2:32])(=[O:29])=[O:28]>>[CH3:26][S:27]([CH2:30][CH2:31][NH:32][C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:24])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)CCN
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)NCCS(C)(=O)=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-methanesulfonylethylamine.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][CH:9]=2)[N:4](COC)[CH:3]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:19][CH2:20]3)[N:13]=2)=[N:4][CH:3]=1
Reactant: COCn1cc(Br)sc1=Nc1cccc(CN2CCN(C(=O)c3ccccc3)CC2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)N1CCN(Cc2cccc(Nc3ncc(Br)s3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
81 mg (0.161 mmol) of 1-(6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridin-2-ylmethyl)4-benzoyl-piperazine was dissolved in 10 ml of chloroform, a hydrochloric acid-1,4-dioxane solution (4 M, 4 ml) was added thereto and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, the residue was recrystallized from methanol-ether and filtered and the resulting white solid was dissolved in water (10 ml) and neutralized with sodium bicarbonate. The resulting precipitate was filtered to give 32 mg (0.070 mmol) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][N:10]=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:19]1([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[CH:3][CH:4]=3)[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][N:10]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1ccc(-n2c(-c3ccccc3)nnc2-c2ccccc2)cc1
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
Product: c1ccc(-c2nnc(-c3ccccc3)n2-c2ccc(-c3cccnc3)cc2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
Into a 100 mL three-neck flask were put 2.0 g (5.3 mmol) of 4-(4-bromophenyl)-3,5-diphenyl-4H-1,2,4-triazole, 0.98 g (8.0 mmol) of 3-pyridineboronic acid, and 0.28 g (1.1 mmol) of tetrakis(triphenylphosphine)palladium(0), and 10 mL of 1,2-dimethoxyethane (DME) and 10 mL of a 2M sodium carbonate aqueous solution were added to the mixture. This mixture was degassed under reduced pressure. After that, the air in the flask was replaced with nitrogen. This mixture was stirred at 95° C. for 3 hours. After the stir, dichloromethane was added to the reacted mixture, and the suspension was washed with 1M diluted hydrochloric acid, a saturated sodium hydrogen carbonate solution, and saturated saline. The organic layer and the aqueous layer were separated. Magnesium sulfate was added to the organic layer to dry the organic layer. After the drying, this mixture was subjected to suction filtration through Celite (Catalog No. 531-16855, manufactured by Wako Pure Chemical Industries, Ltd.) to obtain the filtrate. The obtained filtrate was concentrated and purified by silica gel column chromatography. For the column chromatography, first toluene and then a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=1:3) were used as developing solvents. The obtained fraction was concentrated to give a solid. The obtained solid was recrystallized with a mixed solvent of ethanol and hexane to give 1.5 g of a powdery white solid, which was the object of the synthesis, at a yield of 76%.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:31][O:32][CH2:33][CH2:34][NH2:35].CN1CCCC1>O1CCOCC1.CC#N.O>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:24](=[O:29])[NH:23][C:19]1[CH:18]=[C:17]([O:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[O:30])=[N:15][CH:14]=2)[CH:22]=[CH:21][N:20]=1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reactant: COCCN
Agent: CN1CCCC1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: COCCNC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A mixture of Example C2 (0.120 g, 0.290 mmol), 2-methoxyethylamine (0.1 mL, 1.15 mmol) and N-methylpyrrolidine (0.012 g, 0.145 mmol) in dioxane (5 mL) was heated at 80° C. overnight, cooled to RT, and concentrated to dryness. The residue was dissolved in DCM and stirred with sat'd NaHCO3. The aqueous layer was back-extracted with DCM (3×) and the organic phases combined, dried (Na2SO4) and concentrated to afford a light brown oil. The crude residue was purified via silica gel chromatography (MeOH/DCM) to afford a white solid, which was dissolved in MeCN/H2O, frozen and lypholized overnight to afford N-((5-((2-(3-(2-methoxyethyl)ureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide as a white solid (54 mg, 43%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.14 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.07-8.06 (m, 2H), 7.96 (s, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.57 (dd, J=5.9, 2.4 Hz, 1H), 3.35-3.34 (m, 2H), 3.28-3.22 (m, 2H), 3.24 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 431.2 (M+H+).