Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:11][C:7]=1[CH:6]=[CH:5]2.C1C(=O)N([I:34])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[N:11][C:7]=1[CH:6]=[C:5]2[I:34]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(I)c3cc(Br)ccc3c2[nH]1
Temperature: 70 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
(S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.990 g, 2.38 mmol) was suspended in DMF (8 mL) and treated with NIS (1.03 g, 4.59 mmol). The reaction mixture was stirred at 70° C. for 2 d, then cooled to RT. The mixture was then diluted with EtOAc and the organic solution was washed with 3× with brine then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (30% to 55% EtOAc/Hex) to afford (S)-tert-butyl 2-(7-bromo-5-iodo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (753 mg, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.[Fe]>[CH2:1]([O:8][C:9]1[C:10]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11][C:12]([C:18]([F:21])([F:19])[F:20])=[C:13]([CH:14]=1)[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(C2CCCC2)cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(OCc2ccccc2)c(C2CCCC2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 4 h
Yield: 109.1 %

Procedure:
To a mixture of 1-(benzyloxy)-2-cyclopentyl-5-nitro-4-(trifluoromethyl)benzene (3.0 g, 8.2 mmol) and Fe (2.8 g, 49.3 mmol) in 25% aqueous ethanol (40 mL) was added concentrated HCl (2.1 g, 1.8 mL, 58.7 mmol). The mixture was stirred at 50° C. for 4 h. The reaction was filtered hot and washed with ethanol (2×5 mL). The filtrate was concentrated to ˜20 mL volume, resulting in the precipitation of a yellow crystalline solid. The solid was filtered, washed with water and dried to provide 5-(benzyloxy)-4-cyclopentyl-2-(trifluoromethyl)aniline as a yellow-brown crystalline solid (3.0 g, 98% yield). NMR (400.0 MHz, CDCl3) δ 7.40-7.35 (m, 5H), 7.25 (d, J=6.7 Hz, 1H), 6.24 (s, 1H), 5.06 (s, 2H), 4.03 (s, 2H), 3.28-3.20 (m, 1H), 1.99-1.95 (m, 2H), 1.74-1.65 (m, 2H), 1.67-1.62 (m, 2H), 1.58-1.54 (m, 2H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1)(O)=[O:2].[ClH:18].S(Cl)([Cl:21])=O>C(Cl)Cl>[ClH:21].[Cl:18][C:1]([CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CN1CCC(CCC(=O)O)CC1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.46 g of 4-(2-carboxyethyl)-1-[(ethoxycarbonyl)methyl]-piperidine in 10 ml methylene chloride, is added 1 ml of saturated ethereal hydrochloric acid. 1.2 g of thionyl chloride are added and the mixture is stirred for 3 hours at ambient temperature. The reaction mixture is concentrated by evaporation and the residue is mixed twice with toluene and evaporated down again. The crude product is further reacted in Examples 1 and 2 without being purified.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[O:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[O:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(OC(C)C)n3)c3cc(-c4noc(N)n4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1cncc(-c2c[nH]c3ccc(-c4noc(N)n4)cc23)n1
Temperature: 100 °C
Yield: 34.7 %

Procedure:
To a solution of 3-(3-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (150 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL) was added 10% aq NaOH (0.75 mL) and the reaction was heated at 100° C. for 2 h. The mixture was cooled to RT and treated with ice cold water (1.5 mL). The precipitate was collected through filtration and the crude product was purified with preparative HPLC (eluent: 30-70% AcCN in H2O with 0.01% TFA) to give 3-(3-(6-isopropoxypyrazin-2-yl)-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (35 mg, 34%). MS (ESI, pos. ion) m/z: 337.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 9.10 (s, 1H), 8.72 (s, 1H), 8.37 (d, J=2.8 Hz, 1H), 7.94 (s, 1H), 7.77-7.71 (m, 3H), 7.56 (d, J=8.4 Hz, 1H), 5.51-5.48 (m, 1H), 1.49 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.C([Mg]Cl)(C)C.C([Li])CCC.[CH3:42][C:43]([CH3:45])=[O:44].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:25])[CH3:23])[C:13]([C:43]([OH:44])([CH3:45])[CH3:42])=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1
Reactant: CC(C)=O
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1c(C#N)nc(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in Example 11, step (f), 50.0 mg, 0.100 mmol) in 1 mL of THF at −78° C. under Ar was added isopropyl magnesium chloride (55 μL, 0.11 mmol, 2.0 M in THF). The resulting mixture was warmed to RT and stirred for 15 min, cooled back to −78° C. To the mixture was added n-butyllithium (55 μL, 0.11 mmol, 2.0 M in cyclohexane) and the resulting mixture was stirred at −78° C. for 0.5 h under Ar. Acetone (30 μL, 0.40 mmol) was added and the reaction was warmed to RT and stirred for 16 h under Ar. Treated with 5 mL of saturated NH4Cl aqueous solution followed by 30 mL of EtOAc, the mixture was washed with H2O (10 mL), brine (5 mL) and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (5-10% EtOAc/hexane) to afford 40.0 mg (84%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C26H35BrN4O3Si, 559.2 (M+H), found 558.9.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](B(O)O)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[CH:16]2.Br[C:29]1[CH:30]=[C:31]2[C:40](=[CH:41][CH:42]=1)[C:39]([C:43]([OH:45])=[O:44])=[CH:38][C:37]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1(C)C=CC=CC=1.CCO.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.O.CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:29]2[CH:30]=[C:31]3[C:40](=[CH:41][CH:42]=2)[C:39]([C:43]([OH:45])=[O:44])=[CH:38][C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]3=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[CH:16]2
Reactant: O=C(O)c1cc2ccccc2c2cc(Br)ccc12
Reactant: OB(O)c1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2ccccc2c2cc(-c3c4ccccc4c(-c4ccc5ccccc5c4)c4ccccc34)ccc12

Procedure:
51.6 g (148 mmol) of 10-naphth-2-ylanthracen-9-ylboronic acid, 37.2 g (124 mmol) of 6-bromophenanthrene-9-carboxylic acid and 220 ml of 2 M Na2CO3 solution are suspended in 1 l of toluene and 1 l of EtOH, the suspension is saturated with N2, 2.9 g (3 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is heated at the boil for 2 h. The mixture is poured into 3 l of a mixture of water/MeOH/6 M HCl 1:1:1, and the beige precipitate is filtered off with suction, washed with water, EtOH and toluene and dried. The content of product according to 1H-NMR is about 94% with an overall yield of 58 g (90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:35][CH2:34][CH2:33][N:32]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:31][CH2:30]1)(=[O:28])=[O:27]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCCNCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-(2-naphthylsulphonyl)-1,4-diazepane to give 1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-1,4-diazepane in 42% yield, m.p. 178-180° C.;
Reaction SMILES: Br[CH2:2][Cl:3].C[O:5][C:6]([C@H:8]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[O:9]1)=O.[Li]CCCC.CCCCCC>C1COCC1.O.C(O)(=O)C>[Cl:3][CH2:2][C:6]([C@H:8]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[O:9]1)=[O:5]
Reactant: COC(=O)[C@H]1C=Cc2cc(F)ccc2O1
Reactant: ClCBr
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: O=C(CCl)[C@H]1C=Cc2cc(F)ccc2O1
Yield: 101 %

Procedure:
2.5 g of bromochloromethane (18.8 mmol) were added at room temperature to a solution of 2.0 g of (R)-6-Fluoro-1-benzopyran-2-carboxylic acid methyl ester, obtained after separation of the corresponding racemic mixture on a chiral chromatography column (9.4 mmol, 96.6% A, ee>99%), in 40 ml THF. The solution was then cooled to −80/−85° C. and 7.7 ml of 2.5 M n-BuLi in hexane (19 mmol) were slowly added to maintain the internal temperature between −75° C. and −80° C. The reaction progress was monitored by TLC. The solution was then acidified by the addition of 2 ml glacial acetic acid in 2 ml THF between −70° C. and −80° C. 10 ml of water were then added at −20/0° C. and the aqueous layer was then removed after decantation. The organic layer was concentrated under reduced pressure to give the title compound (2.2 g) as a white-off solid (ee: 97.2%, 94.8% A).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:18]([NH:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cc(N)cn1Cc1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)c1cc(NCc2ccccc2)cn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar, addition funnel and an argon inlet was added 1-[4-amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1 (1.00 g, 4.31 mmol), MeOH (20 mL), benzaldehyde (0.875 mL, 8.61 mmol) and sodium cyanoborohydride (0.541 g, 8.61 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.246 mL, 4.31 mmol) in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5 h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3, aqueous sodium potassium tartrate and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30% EtOAc in hexanes as eluant to give 1-[4-Benzylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVIII-1-1 as a crystalline solid. 1H NMR (CDCl3) δ 2.34 (3H, s), 3.35 (1H, br s), 4.16 (2H, s), 5.41 (2H, s), 6.36 (1H, d, j=2.2 Hz), 6.49 (1H, d, j=2.2 Hz), 6.93 (2H, m), 7.06 (2H, m), 7.30 to 7.37 (5H, complex multiplet).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=O)[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][Cl:15])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1CCl

Procedure:
To a solution of 5-chloro-o-anisic acid (50 g) in toluene (100 mL) was added thionyl chloride (50 mL). The reaction mixture was heated under reflux for 2 hrs and distilled using a short path distillation apparatus to give 5-chloro-o-anisyl chloride, which was used in the next step. To a solution of 2-amino-2-methyl-1-propanol (38 mL) in dichloromethane (200 mL) was added a solution of 5-chloro-o-anisyl chloride in dichloromethane (150 mL) dropwise. The reaction mixture was stirred at ambient temperature for 1 hr, dichloromethane was added and the mixture was washed with 2 N hydrochloric acid. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give N-(2-(1-hydroxy-2-methylpropyl)-5-chloro-2-methoxy benzamide, which was used in the next step. To N-(2-(1 -hydroxy-2-methylpropyl)-5-chloro-2-methoxy benzamide was added thionyl chloride (40 mL) at 0° C. The reaction mixture was stirred for 30 min, warmed to ambient temperature, diluted with diethyl ether (200 mL), and the mixture was stirred for 10 mins. The mixture was decanted, 10% sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to afford 41 g (64%) of product, mp 50-51° C.
Reaction SMILES: C1(OC(=O)N[C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([CH2:13][NH:12][C:11]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:30][CH2:31]2)=[O:19])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCc1cc(CNC(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][C:30](=[O:32])[CH3:31])=[CH:28][C:22]=2[S:21](=[O:34])(=[O:33])[N:20]=1.[OH-].[Na+:36]>O>[C:30]([NH:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[O-:1])=[N:20][S:21](=[O:33])(=[O:34])[C:22]=2[CH:28]=1)(=[O:32])[CH3:31].[Na+:36]
Reactant: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C([O-])c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 993 %

Procedure:
A suspension of the product of Example 44A (0.046 g) in water (1 mL) was treated with 0.997N sodium hydroxide solution (0.090 mL, 0.090 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.45 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.45 (m, 1H) 0.69 (m, 6H) 0.80 (m, 1H) 1.27 (m, 1H) 1.37 (m, 3H) 1.72 (m, 1H) 2.06 (m, 3H) 2.15 (m, 1H) 7.23 (m, 1H) 7.32 (m, 1H) 7.46 (m, 2H) 7.65 (m, 1H) 8.03 (m, 2H) 10.13 (m, 1H) 15.44 (m, 1H). MS (ESI−) m/z 480 (M−H)−.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:52]=[CH:51][N:50]=[C:49]([NH2:53])[CH:48]=2)O1.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>[NH2:53][C:49]1[CH:48]=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:52]=[CH:51][N:50]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccnc(N)c2)OC1(C)C
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+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 39.2 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (200 mg, 0.91 mmol), tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol), and aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) in N,N-dimethylformide (5 ml) according to the method described in Preparation 186 heating at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 100 mg (40% yield) of the title compound. Purity 98%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1([CH:23]([CH2:27][CH3:28])[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(=O)(O)[O-].[Na+]>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:24](=[O:25])[CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:27][CH3:28])=[CH:15][CH:16]=1
Reactant: ClCCCCCCCCOc1ccccc1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC(C(=O)c1ccc(OCCCCCCCCCl)cc1)c1ccccc1
Reaction time: 16 h
Yield: 80.7 %

Procedure:
8-Chlorooctoxybenzene (9.1 g, 38 mmol) was added to a stirred solution of 2-phenylbutyric acid (7.48 g, 46 mmol) in trifluoroacetic anhydride (7.5 ml, 52 mmol) and stirring continued for 16 h. The mixture was poured into saturated sodium bicarbonate solution (100 ml), neutralised by addition of sodium bicarbonate, and extracted with ether (2×100 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residues were column-chromatographed (silica; eluant 5-10% dichloromethane in petrol) to give the title compound as a colourless oil (11.86 g, 81%). NMR (CDCl3) δ=0.87 (3H,t,J=7.3 Hz), 1.26-1.50 (8H, m), 1.69-1.90 (5H,m), 2.08-2.26 (1H,m), 3.51 (2H,t,J=6.6 Hz), 3.94 (2H,t,J=6.6 Hz), 4.38 (1H,t,J=7.3 Hz), 6.83 (2H,d,J=8.8 Hz), 7.15-7.20 (1H,m), 7.20-7.28 (4H,m), 7.93 (2H,d,J=8.8 Hz). IR (liq, cm-1) 2933, 2858, 1673, 1600, 1574, 1510 MS(Chemical Ionisation)m/e=387 (M+ +1, 10%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[C:21](B(O)O)=[CH:22][S:23][CH:24]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:21]3[C:20]([CH3:19])=[CH:24][S:23][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Cc1cscc1B(O)O
Product: Cc1cc(Nc2cc3ccccc3c(-c3cscc3C)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-methyl-thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(4-methyl-thiophen-3-yl)-isoquinolin-3-yl]-amine. LC-MS m/e 321(MH+).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[NH2:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][C:9]([NH:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1cnc(Nc2ccncc2)nc1NC1CCCC1
Agent: [Pd]
Product: Nc1cnc(Nc2ccncc2)nc1NC1CCCC1

Procedure:
Hydrogenation of 4-(cyclopentylamino)-2-[(pyridin4-yl)amino]-5-nitropyrimidine (from Example 2(6) above) over Pd/C gave the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20](F)=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1.C(OC1C=C(C=C(OCC)C=1[N:47]1[CH:51]=[CH:50][CH:49]=[CH:48]1)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20]([N:47]4[CH:51]=[CH:50][CH:49]=[CH:48]4)=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=3)[CH2:12][CH2:11]2)=[O:8])[CH:5]=1
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(C(=O)OC)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), 5-methoxy-N-piperidin-4-yl-isophthalamic acid methyl ester (example 143) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 536.5 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:18][CH:17]=1)[CH3:15]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:18][CH:17]=2)[CH3:15])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3ccccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyridyl)piperazine instead of phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound can be obtained.