Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)=[CH:15][CH:14]=3)[CH:12]=1)=[N:8][N:7]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)[CH:6]=2)([O-])=O>C(OCC)(=O)C.[Pd]>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)=[CH:15][CH:14]=3)[CH:12]=[C:4]2[NH2:1])=[N:8]1
Reactant: O=[N+]([O-])c1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12

Procedure:
4-Nitro-2-(tetrahydro-2H-pyran-2-yl)-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazole (2.31 g, 5.45 mmol) was dissolved in ethyl acetate (109 ml) and the compound was reduced using the H-cube (available from ThalesNano) with a 10% Pd/C catalyst cartridge at 30° C. and 30 bar. The solvent was removed in vacuo and the residue was purified using silica gel chromatography eluting with 0-50% ethyl acetate in cyclohexane. Appropriate fractions were combined and the solvent was removed in vacuo to give the title compound, 963 mg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:36])[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27]2)=[CH:22][CH:21]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:36])[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27]3)=[CH:22][CH:21]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 7-hydroxyflavone and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)=[N:7][N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[N:9]2)=[O:4].[OH-].[Na+].Cl>C(O)C>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:13]3[N:8]([N:9]=[CH:10][CH:11]=[CH:12]3)[N:7]=2)=[CH:15][CH:16]=1)[CH3:22]
Reactant: CCOc1ccc(-c2nn3ncccc3c2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2nn3ncccc3c2C(=O)O)cc1

Procedure:
A mixture of 2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylic acid methyl ester (1.2 g), ethanol (10 ml) and 2N sodium hydroxide (10 ml) was heated to 80° for 1.5 h. The mixture was allowed to cool and acidified to pH 1 with 2N hydrochloric acid. The title compound was isolated by filtration as a brown solid (716 mg, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=4[C:21]=3[O:22][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:31][C:32]1[CH:45]=[CH:44][C:35]([O:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:34][CH:33]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13]3[N:14]([CH2:31][C:32]4[CH:45]=[CH:44][C:35]([O:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:34][CH:33]=4)[C:15]4[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=4[C:21]=3[O:22][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCOc1ccc(CCl)cc1
Reactant: COc1ccc2[nH]c3c4ccc(OCc5ccccc5)cc4oc3c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Cn2c3ccc(OC)cc3c3oc4cc(OCc5ccccc5)ccc4c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 7-benzyloxy-3-methoxy-10H-benzo[4,5]furo[3,2-b]indole (102 mg, 0.297 mmol) in DMF (5 mL) was added NaH (37 mg, 60% in mineral oil, 3.0 eq.) followed by [2-(4-chloromethyl-phenoxy)-ethyl]-diethyl-amine hydrochloride salt (99 mg, 0.356 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, warmed to 25° C., and quenched by NH4Cl (solid). EtOAc and water were then added to the mixture. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield crude material. The crude material was purified by silica gel (EtOAc to CH2Cl2:MeOH 5:1) to yield the title compound as a brown solid.
Reaction SMILES: [NH:1]([C@@H:5]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)[C:2]([NH2:4])=[O:3]>Cl>[NH:7]1[CH2:8][CH2:9][C@@H:5]([NH:1][C:2]([NH2:4])=[O:3])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(N)=O)C1
Agent: Cl
Product: NC(=O)N[C@@H]1CCNC1

Procedure:
(R)-tert-butyl 3-ureidopyrrolidine-1-carboxylate from step A was treated with HCl solution (in EtOAc, 30 mL) for 2 hours. The mixture was concentrated in vacuo to give the crude title compound. MS (m/z): 130 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:22]([O:24]CC)=O)=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].C(O)(=O)C>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:24])[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[NH:16][C:14]2=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Reaction time: 1 h

Procedure:
A solution of 118.0 g of ethyl 2-chloro-5-[3-(2-ethoxycarbonyl-1-cyclopenten-1-yl)ureido]-benzoate in 800 ml of absolute 1,2-dimethoxyethane is added dropwise while stirring at 20° C. during 10 minutes to a suspension of 7.7 g of sodium hydride in 800 ml of absolute 1,2-dimethoxyethane. The reaction mixture is subsequently stirred for 1 hour. treated with 20 ml of acetic acid and evaporated to dryness under reduced pressure. The residue is dissolved in 2 l of methylene chloride and washed twice with 1 l of water. The organic phase is dried over anhydrous sodium sulphate and evaporated until crystallization occurs. The residue is treated with 1 l of n-hexane and the crystals are filtered off under suction and rinsed with n-hexane. There is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 178°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH2:11].[Br:12]Br.C([O-])(O)=O.[Na+]>CC(O)=O>[Br:12][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[NH2:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(F)cc([N+](=O)[O-])cc1Br
Temperature: 20 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 2-fluoro-4-nitro-phenylamine (12 g, 77 mmol) in AcOH (50 mL) was added Br2 (3.9 mL, 77 mmol) dropwise at 0° C. The mixture was stirred at 20° C. for 3 h. The reaction mixture was basified with sat. aq. NaHCO3, and extracted with EtOAc (100 mL×3). The combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-6-fluoro-4-nitro-phenylamine (18 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.22 (m, 1 H), 7.90 (dd, J=2.4, 10.8 Hz, 1 H), 4.88 (brs, 2 H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([C:14]([OH:16])=O)=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3C2CCCCO2)[CH3:18])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([C:14]([N:59]4[CH2:64][CH2:63][O:62][CH2:61][CH2:60]4)=[O:16])=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:18])[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1C1CC1
Reactant: C1COCCN1
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: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of 3-cyclopropyl-5-fluoro-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid (64 mg, 0.14 mmol), HATU (63 mg, 0.17 mmol), morpholine (18 μL, 0.216 mmol) and DIPEA (47 μL, 0.28 mmol) in DCM (2 mL) was stirred at RT for 1 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 389 (46 mg, 75%) as a white solid. LCMS (Method K): RT 2.49 and 2.53 min [M+H]+ 451.05. 1H NMR (DMSO-d6, 400 MHz): δ 8.24-7.83 (3H, m), 7.69-7.60 (1H, m), 7.10 (1H, t, J=9.53 Hz), 6.07-5.84 (1H, m), 3.90-3.83 (1H, m), 3.80-3.72 (1H, m), 3.69-3.59 (2H, m), 3.59-3.50 (2H, m), 3.41-3.35 (2H, m), 3.28-3.20 (1H, m), 1.72-1.63 (3H, m), 1.26-0.85 (4H, m)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:36][C:37]#[N:38]>C1COCC1>[C:37]([CH2:36][N:10]1[C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[S:29]([CH3:32])(=[O:31])=[O:30])[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:11]1=[O:28])#[N:38]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC#N)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 68.1 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (115 mg, 250 μmol) was initially charged in THF (1 ml) at 0° C., sodium hydride (14 mg, 350 μmol; 1.4 eq.) was added and the mixture was stirred for 20 min. After addition of bromoacetonitrile (50 mg, 376 μmol; 1.5 eq.), the mixture was stirred at RT for 120 min. The reaction mixture was then purified directly by preparative HPLC (column: Gromsil, C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→75:25). This gave the title compound as a colorless solid (85 mg, 68% of theory).
Reaction SMILES: C[Si](Cl)(C)C.[CH2:6]([O:13][C:14]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:19]=[C:18]([B:29]2[O:33]C(C)(C)[C:31]([CH3:37])(C)[O:30]2)[C:15]=1C=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.[Zn]>[CH2:20]([O:22][C:23](=[O:24])[CH2:37][CH:31]1[O:30][B:29]([OH:33])[C:18]2[CH:19]=[C:20]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:21]=[C:14]([O:13][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:15]1=2)[CH3:19]
Reactant: CC1(C)OB(c2cc(OC3CCCCO3)cc(OCc3ccccc3)c2C=O)OC1(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OCc3ccccc3)c21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 145.4 %

Procedure:
A suspension of Zn (2.91 g, 44.5 mmol) in THF (10 mL) was added TMSCl (0.833 ml, 6.57 mmol) at 40° C. The temperature was increased to 55° C. over 30 min. Then, the temperature was lowered to 37° C. and bromo ethyl acetate (4.55 mL, 41.1 mmol) was added slowly. The resulting solution was stirred for 30 min from 45° C. to room temperature and stood by for 1 h. The top clear layer (3 mL) was added to a solution of 2-benzyloxy-4-(tetrahydro-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.50 g, 3.42 mmol) in THF (5 ml) at −78° C. After the addition, the reaction was warmed to 0° C. using an ice bath and stirred at 0° C. 30 min. The reaction mixture was quenched with NH4Cl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=3:2) to afford the title compound (1.06 g, 73%). MS calcd for (C23H27BO7+H)+: 427.2. MS found: (M+H)+=427.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[N:17]1([CH2:2][CH2:3][CH:4]2[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[O:5]2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN1CC(CCn2ccnc2)Oc2ncccc2C1=O
Temperature: 130 °C

Procedure:
To a solution of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-one, 9.12 g (0.038 mole) in dimethylformamide (30 ml) was added imidazole, 5.66 g (0.083 mole). The solution was heated to 130° C. for 18 hr. Dimethylformamide was removed by rotary evaporation (80° C., vacuum pump) and the residue taken up in chloroform (100 ml). The chloroform was washed with dilute aqueous sodium hydroxide (30 ml), dried over sodium sulfate and concentrated by rotary evaporation (70° C., water aspirator) to an oil. Crystallization was induced with ethanol. White crystals, 1.5 g (14.5%) were collected, m.p. 150°-152° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[CH3:13])[CH3:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:26])[CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:26][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=2)[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:6][C:5]=1[CH3:13])[CH3:2]
Reactant: CCCC(N)c1ccc(OC)cc1
Reactant: CCOc1ccc(C(=O)O)cc1C
Product: CCCC(NC(=O)c1ccc(OCC)c(C)c1)c1ccc(OC)cc1

Procedure:
Prepared in a similar manner to example 4 using 4-ethoxy-3-methyl-benzoic acid and 1-(4-methoxy-phenyl)-butylamine. 1H NMR (500 MHz, CDCl3): δ 0.93-0.96 (t, 3H), 1.31-1.41 (m, 2H), 1.41-1.45 (t, 3H), 1.82-1.92 (m, 2H), 2.28 (s, 3H), 3.79 (s, 3H), 4.04-4.08 (q, 2H), 5.10-5.12 (d, 1H), 6.12-6.14 (d, 1H), 6.78-6.80 (d, 1H), 6.87 (s, 1H), 6.88 (s, 1H), 7.26-7.29 (m, 2H), 7.52-7.53 (d, 1H), 7.57-7.59 (d, 1H). MS (M+H, 342.1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:22][N:21]=2)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 33.9 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.5 g) (from Example 30) and hydrazine hydrate (0.7 g) in ethanol was heated at 80° C. for 24 hours. The precipitate was filtered off and the filtrate was concentrated to give 156 mg of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15](O)=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18].S(Cl)([Cl:26])=O>C1C=CC=CC=1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([Cl:26])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)[CH3:18]
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)Cl)c(Cl)c(Cl)c2C1=O

Procedure:
A solution of (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid (3.57 g., 0.01 mole) and thionyl chloride (2.38 g., 0.02 mole) in benzene (50 ml.) is refluxed for 1 hour. The excess thionyl chloride and benzene are evaporated at reduced pressure as is a subsequent 50 ml. portion of benzene affording (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetyl chloride as a yellow oil which is used in step B without further purification.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:42]1[N:50]=[C:49]2[C:45]([N:46]=[C:47]([CH2:52][N:53]3[CH2:58][CH2:57][CH:56]([C:59]([O:62][CH3:63])([CH3:61])[CH3:60])[CH2:55][CH2:54]3)[N:48]2[CH3:51])=[C:44]([N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)[N:43]=1.[CH3:70][C:71]1[NH:75][C:74]2[CH:76]=[CH:77][CH:78]=[CH:79][C:73]=2[N:72]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:63][O:62][C:59]([CH:56]1[CH2:57][CH2:58][N:53]([CH2:52][C:47]2[N:48]([CH3:51])[C:49]3[C:45]([N:46]=2)=[C:44]([N:64]2[CH2:65][CH2:66][O:67][CH2:68][CH2:69]2)[N:43]=[C:42]([N:72]2[C:73]4[CH:79]=[CH:78][CH:77]=[CH:76][C:74]=4[N:75]=[C:71]2[CH3:70])[N:50]=3)[CH2:54][CH2:55]1)([CH3:60])[CH3:61]
Reactant: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1
Temperature: 140 °C

Procedure:
Alternatively, following General Procedure I, one-step Buchwald coupling, a microwave tube was charged with Xphos (0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.05 equiv.), cesium carbonate (2 equiv.), 4-(2-chloro-8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine (80 mg, 1 equiv.) and 2-methyl-1H-benzo[d]imidazole (1.2 equiv.). The vessel is evacuated and refilled with nitrogen prior to the addition of DMF or 1,4-dioxane. The mixture is heated in a microwave device, such as Biotage at about 140° C. for about 25-35 minutes. The reaction mixture is cooled to room temperature, filtered and concentrated, and purified by RP-HPLC to give 17.1 mg of 179. MS (Q1) 519.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH3:38])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[N:22][C:21]([C:24]([NH:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)=[O:25])=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:7]=1.Cl.[OH-].[Na+]>O>[NH2:29][CH2:28][CH2:27][NH:26][C:24]([C:21]1[N:22]=[CH:23][C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:37][CH3:38])[CH2:9][CH2:10]2)=[N:19][CH:20]=1)=[O:25]
Reactant: COc1ccc(Cl)cc1N1CCN(CCCNc2cnc(C(=O)NCCNC(=O)OC(C)(C)C)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cl)cc1N1CCN(CCCNc2cnc(C(=O)NCCN)cn2)CC1
Temperature: 0 °C

Procedure:
2 g (0.00365 mol) of 1,1-dimethylethyl 2-[[[2-[[3-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]propyl]amino]pyrazin-5-yl]carbonyl]amino]ethylcarbamate are introduced into 10 ml of water in a 0.25 l round-bottomed flask and then 10 ml of concentrated hydrochloric acid are introduced dropwise. The mixture is cooled to 0° C. with an ice/salt/water mixture and 30% sodium hydroxide solution is added portionwise until the pH is basic. Extraction is carried out with dichloromethane, the organic phase is dried over sodium sulphate, filtered and the solvents are evaporated under reduced pressure and 1.32 g (0.00295 mol) of amorphous solid are obtained.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]3)[CH:14]=[C:13]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C1(Cc2cc(OS(=O)(=O)C(F)(F)F)cc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(Cc2cc(-c3ccccc3)cc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 300 mg of 1-tert-butyl 4-ethyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)methyl)piperidine-1,4-dicarboxylate, 87 mg of phenylboronic acid, 69.3 mg of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), 201 mg of potassium phosphate, 3 ml of 1,4-dioxane and 0.3 ml of water was stirred at 100° C. overnight, followed by cooling to room temperature. The reaction mixture was diluted with ethyl acetate. An insoluble matter was filtered off using Celite, and washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=9/1) to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][NH:14]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:30])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+].CCOC(C)=O>C(Cl)(Cl)(Cl)Cl>[Br:30][C:13]1[NH:14][C:15]2[C:11]([C:12]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:10][CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution (0.14 M) of tert-butyl-3-cyclohexyl-1H-indole-6-carboxylate in CCl4 was added NBS (1.1 eq.) portionwise over a period of 1 h at RT. The resulting mixture was stirred 2 h at RT, then a saturated aqueous solution of sodium thiosulfate was added and the reaction mixture vigorously stirred for 1 h. EtOAc was then added and the organic layer was separated and washed with a saturated aqueous solution of sodium thiosulfate (3×) then dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (Flashmaster Personal, petroleum ether:EtOAc, 20:1) to give the title compound (68%) as a solid. 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.33-1.39 (m, 3H), 1.54 (s, 9H), 1.65-1.99 (m, 7H), 2.73-2.81 (m, 1H), 7.52 (d, J 7.6, 1H), 7.70 (d, J 77.6, 1H), 7.83 (s, 1H), 11.92 (br s, 1H); MS (ES+) m/z 379 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:25]([F:28])([F:27])[F:26])=[C:21]([CH:24]=1)[CH:22]=O.[BH4-].[Na+]>CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:25]([F:26])([F:27])[F:28])=[C:21]([CH:24]=1)[CH2:22][NH:15][C:13]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:14]=1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1ccc(Cl)cc1CNc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Temperature: -20 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and 5-chloro-2-(trifluoromethyl)benzaldehyde (85 mg, 408 μmol) in MeOH (3 ml) was stirred at 45° C. for two days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (65.1 mg, 1.72 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated. Trituration with hexanes afforded a white solid as desired product (88 mg, 70% yield). MS +m/z: 436 (M+H)+