Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[O-:7][C:8]#[N:9].[K+].C(CC(O)=O)#N.C(OC(=O)C)(=O)C>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:8]([NH2:9])=[O:7]
Reactant: N#C[O-]
Reactant: COCCCN
Agent: N#CCC(=O)O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: COCCCNC(N)=O

Procedure:
3-Methoxypropyl urea was prepared from methoxypropylamine and potassium cyanate. Seventy-six grams of this product was mixed with 43 g. of cyanoacetic acid and 100 ml. of acetic anhydride. The mixture was stirred and heated on a steam bath. When the temperature of the mixture reached 85°C., heat of reaction evolved and external cooling was applied to keep the temperature under control. After stirring for 1 hour on the steam bath, the mixture was cooled. The cyanoacetyl urea was recovered by filtration, washing with ether and drying. Yield 77.5 g., mp 128.5-130.5°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[H-].[Na+].[CH2:15](I)[CH3:16]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridin-3-yl-acetic acid ethyl ester (22.5 g, 0.136 mol) in tetrahydrofuran (50 mL) was slowly added to a suspension of sodium hydride (60% in mineral oil, 6 g, 0.4 mol) in tetrahydrofuran (50 mL) at 0° C. A solution of ethyl iodide (23.4 g, 0.150 mol) in tetrahydrofuran (50 mL) was added to and the reaction mixture was allowed to stir overnight at room temperature. The mixture was poured into ice and the aqueous layer was extracted three times with ethyl acetate. The organic layer washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude residue was purified by preparative reverse phase liquid chromatography (13.5 g, 0.0699 mol, 51.3%). ESI-MS m/z calc. 193.1. found 194.2 (M+1)+ 1H NMR (CDCl3) δ: 9.42-9.39 (m, 2H), 8.58-8.55 (m, 1H), 8.17-8.13 (m, 1H), 5.09-4.97 (m, 2H), 4.35 (t, 1H, J=7.6 Hz), 3.04-2.95 (m, 1H), 2.74-2.65 (m, 1H), 2.10 (t, 3H, J=7.2 Hz), 1.79 (t, 3H, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)=[C:10]([C:20](OC)=[O:21])[C:9]=2[C:24](OC)=[O:25])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[NH4+].[OH-]>ClCCl.CCOCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=43)=[C:10]([CH2:20][OH:21])[C:9]=2[CH2:24][OH:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: OCc1c(CO)c2sc3ccccc3n2c1-c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
A solution of dimethyl 1-(4-chlorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate (2.1 g, 5.0 mmol) in anhydrous dichloromethane (30 mL) was added dropwise to a stirred mixture of lithium aluminum hydride (0.45 g, 12.5 mmol) in anhydrous ether (20 mL) at −5° C. to 0° C. The reaction mixture was allowed to stir at this temperature for 20 min. The excess hydride was decomposed by adding water (1 mL) followed by NH4OH (1 mL) and water (1 mL) at −5° C. to 0° C. The mixture was filtered through a pad of Celite, washed with several times with dichloromethane. The combined filtrate and washings were washed successively with water and brine solution. The organic layer was dried (Na2SO4) and concentrated to dryness in vacuo. The residue was triturated with ether to give (1-(4-chlorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-diyl)dimethanol (BO-1582), 1.5 g (88%); mp 151-152° C. 1H NMR (DMSO-d6) δ 4.22 (2H, d, J=4.4 Hz, CH2), 4.66 (2H, d, J=4.4 Hz, CH2), 4.76 (1H, t, J=5.2 Hz, exchangeable, OH), 5.14 (1H, t, J=5.2 Hz, exchangeable, OH), 6.91-6.93 (1H, m, ArH), 7.16-7.22 (2H, m, 2×ArH), 7.53 (2H, d, J=8.4 Hz, 2×ArH), 7.61 (2H, d, J=8.4 Hz, 2×ArH), 7.79-7.82 (1H, m, ArH). Anal. Calcd. for (C18H14ClNO2S): C, 62.88; H, 4.10; N, 4.07; S, 9.33. Found: C, 62.73; H, 4.09; N, 4.06; S, 9.19.
Reaction SMILES: C(O[C:4]([O:6][NH:7]/[C:8](=[N:42]/[H])/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[CH:21]=[C:22]([CH:24]=[CH:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=[C:19]3[C:18]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:17][CH:16]=2)=[CH:11][N:10]=1)=[O:5])C.C1CCN2C(=NCCC2)CC1.O.Cl>CC1C=CC=CC=1C>[O:39]1[CH2:40][CH2:41][N:36]([C:18]2[C:19]3[N:20]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:8]4[N:42]=[C:4]([OH:5])[O:6][N:7]=4)=[N:10][CH:11]=3)=[CH:16][N:17]=2)[CH2:37][CH2:38]1
Reactant: [H]/N=C(/NOC(=O)OCC)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=Cc4ccc5ccccc5n4)cn23)cn1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1nc(-c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cn2)no1
Temperature: 25 °C
Yield: 27.2 %

Procedure:
To a solution of compound 4b (200 mg, 0.350 mmol) in o-xylene (4 mL) was added DBU (300 mg, 1.97 mmol). The reaction mixture was stirred in a 10 mL sealed tube at 120° C. for 2 h. After cooling to rt, water (20 mL) was added, and the pH of the solution was adjusted to 7 using 1N HCl solution. The solids were collected by filtration and washed with DCM/MeOH (50:1 v/v, 3×10 mL) to obtain the title compound 95 as an orange solid (49.4 mg, 26% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 13.32 (s, 1H), 9.06 (s, 1H), 8.82-8.60 (m, 1H), 8.44-8.40 (m, 2H), 8.30-8.05 (m, 5H), 8.05-7.92 (m, 1H), 7.82 (s, 1H), 7.75 (d, J=9.9 Hz, 1H), 7.65 (s, 1H), 4.55-4.30 (m, 4H), 4.00-3.80 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H22N8O3: 519.2 (M+H). Found 519.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:13]=3[N:12]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:48]1[CH:52]=[CH:51][N:50]=[C:49]1[NH:53][C:54]([C:56]1([NH2:61])[CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:55]>>[NH:48]1[CH:52]=[CH:51][N:50]=[C:49]1[NH:53][C:54]([C:56]1([NH:61][C:20]([C:18]2[CH:17]=[CH:16][C:14]3[NH:15][C:11]([C:3]4[N:2]=[CH:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[N:12][C:13]=3[CH:19]=2)=[O:22])[CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:55]
Reactant: O=C(O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1
Reactant: NC1(C(=O)Nc2ncc[nH]2)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NC1(C(=O)Nc2ncc[nH]2)CCCC1)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1
Yield: 10.3 %

Procedure:
145 mg (0.5 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid (Synthesized in Example 1, step 3) was reacted with 280 mg (0.75 mmol) of HBTU and 1-amino-cyclopentanecarboxylic acid (1H-imidazol-2-yl)-amide HCl salt (120 mg, 0.5 mmol) as described in general procedure A. A solid precipitated from the solution and was collected by filtration, washed with H2O and EtOAc, to give 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-(1H-imidazol-2-ylcarbamoyl)-cyclopentyl]-amide (24 mg, 10%). LCMS: 466 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:33]([OH:35])[CH3:34]>CS(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:34][CH2:33][OH:35])[N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)n[nH]1
Reactant: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)nn1CCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A mixture of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-methyl-1H-pyrazol-3-yl)-benzamide (5.0 g, 13.8 mmol) and cesium carbonate (9.0 g, 27.7 mmol) in dimethylsulfoxide (50 mL) was stirred at room temperature for 10 minutes. Bromoethanol (1.9 g, 15.2 mmol) was added and the resulting mixture was stirred at 80° C. for 12 h. The mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (300 mL), washed with water and brine, dried, filtered and concentrated in vacuo. The residue was triturated with dichloromethane-ethyl acetate-diethyl ether (1:1:1, 100 mL) and washed with ethyl acetate to afford the title compound (3.3 g). LCMS (m/z) 406.1 M+1.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[C@H:23]([CH:24]=O)[CH2:22][C@H:21]2[C@@H:17]1[CH2:18][CH2:19][CH2:20]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(O)(=O)C>[C:9]([O:13][C:14]([N:16]1[C@H:23]([CH2:24][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][C@H:21]2[C@@H:17]1[CH2:18][CH2:19][CH2:20]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)C[C@@H]2CCC[C@@H]21
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1[C@H](CNCc2ccccc2)C[C@@H]2CCC[C@@H]21
Reaction time: 0.08 h

Procedure:
Benzylamine (2.76 mmol, 2.3 eq) is added to a solution of (1S,3S,5S)-3-formyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester (1.2 mmol, 1.0 eq) in chloroform (10 mL). The mixture is stirred for 5 min, treated with sodium triacetoxyborohydride (4.8 mmol, 4.0 eq) and acetic acid (0.05 mL), stirred for additional 14 h and poured into sat. NaHCO3 solution. DCM is added, the layers are separated and the aqueous layer is extracted with DCM. The combined organic layers are washed with water (100 mL) and concentrated in vacuo. The residue is dissolved in ether and extracted three times with hydrochloric acid (0.1 M). The combined aqueous layers are extracted once with ether, made basic (pH 9-10) by addition of NaOH solution (1.0M) and extracted three times with ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired benzylamine which is used without further purification. LC-MS: tR=0.89 min; [M+H]+=331.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[O:34][CH2:33][C:27]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:25]=2[CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:30]3[CH2:31][CH2:32][C:27]4([C:25]5[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=5[O:34][CH2:33]4)[CH2:28][CH2:29]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: Fc1ccc2c(c1)C1(CCNCC1)CO2
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CC3)COc3ccc(F)cc34)cnc12
Yield: 64.3 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.416 g, 1.66 mmol) obtained in Example 19, step 2 and 5-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.500 g, 1.99 mmol) obtained in Reference Example 3, the title compound (0.470 g, 54%) was obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[ClH:18]>O>[ClH:18].[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: Cl
Solvent: O
Product: FC(F)(F)c1cccc(C2=CCNCC2)c1
Temperature: 25 °C

Procedure:
In a round-bottomed flask equipped with a mechanical stirrer, 50 g of 4-(3-trifluoromethylphenyl)-4-piperidinol are charged to 377 ml of water and 514 ml of concentrated hydrochloric acid. The mixture is left to react at reflux for 5 hours and is then cooled to ambient temperature. A white solid precipitates. It is filtered off through a Büchner funnel and dried in an oven. 37 g of a white solid are isolated. M.p. 203-204° C.
Reaction SMILES: Cl[Sn]Cl.[F:4][C:5]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]1[CH:17]=[CH:16][C:12]([N:13]([CH3:15])[CH3:14])=[CH:11][C:10]=1[N+:18]([O-])=O>Cl.C(O)(=O)C>[F:4][C:5]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]1[CH:17]=[CH:16][C:12]([N:13]([CH3:14])[CH3:15])=[CH:11][C:10]=1[NH2:18]
Reactant: CN(C)c1ccc(/C=C/c2c(F)cccc2F)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Product: CN(C)c1ccc(/C=C/c2c(F)cccc2F)c(N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
A solution of 5 g (26.4 mmol, 8.5 equiv) of SnCl2 in 7 mL of conc HCl was added dropwise to a solution of 0.95 g (3.1 mmol) of 6 in 100 mL of glacial acetic acid. The mixture was stirred for ca. 12 h at 25° C. A precipitate was collected by filtration, washed with 5 mL of glacial acetic acid, and suspended in 200 mL of water. The aqueous suspension was adjusted to pH 9-1° with NaOH and was extracted with Et2O. The combined ethereal extracts were washed with water, dried over anhydrous MgSO4 and concentrated. The residue was recrystallized from ethanol to afford 590 mg (69%) of 7 as yellow crystals: mp 97-98° C. NMR (DMSO-d6): δ 7.41 (d, 1H, J=16.4 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.24-7.18 (m, 1H), 7.12-7.05 (m, 2H), 6.61 (d, 1H, J=16.4 Hz), 6.10 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 6.03 (d, 1H, J=2.8 Hz), 5.05 (br.s, 2H), 2.87 (s, 6H). 13C NMR (DMSO-d6): δ 160.25 (dd, J1=246.0 Hz, J2=7.9 Hz, two C), 151.95, 147.98, 132.39 (t, J=7.1 Hz), 127.45 (t, J=11.1 Hz), 127.06, 116.11 (t, J=15.1 Hz), 112.20 (dd, J1=18.7 Hz, J2=6.8 Hz, two C), 111.39, 108.21, 103.52, 99.07, 40.28 (two C). MS: m/z (%) 275 (21), 274 (100), 273 (33), 257 (15), 211 (16). Anal. Calcd for C16H16F2N2: C, 70.06; H, 5.88. Found: C, 70.18; H, 5.94.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH:50]CC3C=CC(OC)=CC=3OC)=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH3:39])=[O:37])=[N:34][CH:35]=5)=[CH:26][CH:25]=4)[C:19]=3[O:40]CC3C=CC(OC)=CC=3)=O)[CH:12]=2)[CH2:7]1>C(O)(=O)C>[OH:40][C:19]1[C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH3:39])=[O:37])=[N:34][CH:35]=3)=[CH:26][CH:25]=2)=[N:21][N:22]([CH3:23])[C:18]=1[C:16]1[NH:50][C:10]2=[CH:9][C:8]3[CH2:7][NH:6][CH2:14][C:13]=3[CH:12]=[C:11]2[N:15]=1
Reactant: CNC(=O)c1ccc(-c2ccc(-c3nn(C)c(C(=O)Nc4cc5c(cc4NCc4ccc(OC)cc4OC)CN(Cc4ccc(OC)cc4OC)C5)c3OCc3ccc(OC)cc3)cc2)cn1
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(-c2ccc(-c3nn(C)c(-c4nc5cc6c(cc5[nH]4)CNC6)c3O)cc2)cn1
Temperature: 120 °C

Procedure:
A solution of 5-(4-(5-(2-(2,4-dimethoxybenzyl)-6-(2,4-dimethoxybenzylamino)isoindolin-5-ylcarbamoyl)-4-(4-methoxybenzyloxy)-1-methyl-1H-pyrazol-3-yl)phenyl)-N-methylpicolinamide T-14 (410 mg, 0.45 mmol) in acetic acid (4 mL) was heated in a microwave reactor at 150° C. for 50 minutes. Solvent was evaporated under reduced pressure and trifluoroacetic acid (4 mL) was added. The reaction mixture was heated in microwave reactor at 120° C. for 30 minutes. Solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired 5-(4-(4-hydroxy-1-methyl-5-(1,5,6,7-tetrahydroimidazo[4,5-f]isoindol-2-yl)-1H-pyrazol-3-yl)phenyl)-N-methylpicolinamide T-15 (143 mg, 0.31 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:14][CH2:13]2)[C:5]=1[C:6]#[N:7])([O-])=O.[H][H]>[Pd].C(Cl)Cl.C(O)C>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14]2)[C:5]=1[C:6]#[N:7]
Reactant: [H][H]
Reactant: N#Cc1c(C2CC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1c(N)cccc1C1CC1
Reaction time: 48 h
Yield: 39 %

Procedure:
A slurry of palladium on carbon (10%; 0.025 g) in DCM (5 mL) was added to a solution of 2-nitro-6-cyclopropylbenzonitrile (Intermediate 11, 0.25 g) in ethanol (15 mL) under nitrogen. The nitrogen atmosphere was exchanged for hydrogen and the mixture was stirred for 48 hours. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless oil (0.082 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])([CH3:3])[CH3:2]>CCO.[Ni]>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH2:9])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C#N)c1
Agent: [Ni]
Solvent: CCO
Product: CC(C)Oc1cccc(CN)c1
Reaction time: 3 h

Procedure:
A 500 mL Parr bottle was flushed with argon, then 3-isopropoxybenzonitrile (32 g, 198 mmol) was added and diluted with 150 mL EtOH. The reaction was charged with ˜2 mL of an aq. slurry of Raney Nickel, then affixed to a Parr hydrogenation apparatus. The flask was evacuated and flushed with N2 three times before being charged with 40 psi H2. The flask was allowed to shake for 3 hr over which time the flask was recharged to 40 psi and consumption of gas ceased. HPLC/MS showed no starting material so the catalyst was carefully filtered without drying and washed with EtOH. The filtrate was concentrated and purified on an Isco automated system affixed with a Biotage Flash 40(M) cartridge eluted with 0-5% (MeOH+0.5M NH3) in CH2Cl2 over 30 min at 40 mL/min to give the product.
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](C)[NH:15][N:14]=2)[N:3]=1.[CH2:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1ccc(N)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: CCCCOc1ccc(Nc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 273 was used, starting (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-butoxy-phenylamine to give N1-(4-butoxy-phenyl)-N3-(1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 374(MH+).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:7])=[C:4]([CH3:28])[N:3]=1.C(N1CCNCC1)(=O)C>>[CH3:28][C:4]1[N:3]=[CH:2][CH:27]=[CH:26][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1
Agent: CC(=O)N1CCNCC1
Product: Cc1ncccc1C(N)=O

Procedure:
6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)-2-methylnicotinamide (0.16 mmol) was used in general procedure 3 with 1-acetylpiperazine (0.83 mmol). The product was purified by RP-HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl))phenyl)-2-methylnicotinamide. MS (Q1) 526.1 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([F:16])([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+:18].O1CCCC1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([F:16])([C:13]([O-:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Li+:18]
Reactant: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)[O-])C1
Temperature: 45 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a solution of #168 (50 mg, 0.21 mmol, 1 eq.) in methanol (0.2 mL) was added a solution of lithium hydroxide (9.2 mg, 0.38 mmol, 1.8 eq.) dissolved in water (0.1 mL). Next, tetrahydrofuran (0.3 mL) was added and the reaction was stirred at 45° C. for 18 hours. The reaction was concentrated in vacuo and the material was azeotroped (3×) with toluene (2 mL) to obtain #170 (51 mg, 100%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]3[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)=[N:12][N:11]=2)=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)=[N:12][N:11]=2)=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCc3ccc(OCC(=O)OCC)cc3)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(CSc2nnc(SCc3ccc(OCC(=O)O)cc3)s2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 79.2 %

Procedure:
In 2 ml of 90% methanol was suspended 0.20 g of ethyl [p-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]methyl]phenoxy]acetate obtained in Example 26. Further 1 ml of a 1N aqueous sodium hydroxide solution was added to the suspension followed by stirring at room temperature for 1 minute. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with a 1N hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off. The resultant solids were recrystallized from isopropyl alcohol to give 0.15 g of [p-[[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]methyl]phenoxy]acetic acid.
Reaction SMILES: [C:1]([N:8]1[C:16]2[CH:15]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:13]=[CH:12][C:11]=2[C:10](I)=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.CO.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>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:10]1[C:11]2[CH:12]=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:15][C:16]=2[N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[N:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cnc(Oc3ccc(F)cc3F)cc21
Reactant: OB(O)c1ccccc1Cl
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: c1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2Cl)c2cnc(Oc3ccc(F)cc3F)cc21
Yield: 66 %

Procedure:
A solution of 1-BOC-6-(2,4-difluorophenoxy)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.071 g) and 2-chlorophenylboronic acid in 5 mL of benzene and 1 mL of methanol was stirred at room temperature for 15 minutes. To this solution was added tetrakis(triphenylphosphine)palladium catalyst (52 mg) and 0.3 mL of 1 M sodium carbonate. The resulting mixture was heated to reflux for five hours, cooled, filtered and the organic layer was separated. The organic layer was washed, dried and concentrated. The residue was purified via chromatography using 5% ethyl acetate in hexane as the eluent to afford 45 mg of 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-pyrazolo[4,3-c]pyridine-1-carboxylic acid, tert-butyl ester (66% yield). Mass. Spec. M+H=458.