Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[CH2:31]Br>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][O:11][CH2:27][C:28]1[CH:29]=[C:30]([CH3:31])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(COCC(NC(=O)OC(C)(C)C)C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
To a solution of 2-t-butoxycarbonylamino-3,3-diphenylpropan-1-ol (1.0 g, Example 1d) in tetrahydrofuran (5 ml) and dimethylformamide (1 ml) was added sodium hydride (0.11 g, 80% suspension in oil) over 15 minutes. After an additional 10 minutes 3,5-dimethylbenzyI bromide (0.73 g) was added and the solution stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. After washing the organic phase with saturated brine and drying (MgSO4), the solvent was removed in vacuo and the residue chromatographed on silica gel in ethyl acetate/hexane (1:10) to give 2-t-butoxycarbonylamino-1-((3,5-dimethylphenyl)methyloxy)-3,3-diphenylpropane 0.38 g. 1H NMR (360 MHz, CDCl3) δ7.3-6.9 (13H, m), 4.7 (1H, bd), 4.6 (1H, bt), 4.43 (1H, d, J=16.7 Hz), 4.3 (2H, m), 3.4 (1H, dd), 3.2 (1H, dd, J=9.4 Hz and 2.82 Hz), 2.3 (6H, s), 1.3 (9H, s). m/z (CI+) 446 (M+H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C=O.[CH:24](O)=O.[OH-].[Na+]>O.C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH3:24])[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Yield: 94.8 %

Procedure:
16 g (56 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 50 ml of ethanol, 11.9 g (139 mmol, 2.5 equivalents) of a formaldehyde aqueous solution (35%), and 12.8 g (278 mmol, 5 equivalents) of formic acid were charged in a 300 ml four-necked flask. The mixture was reacted at 80° C. for one hour. The raw material was then disappeared. The reaction solution was slowly added to a solution prepared by dissolving 40 g of sodium hydroxide in 200 ml of distilled water. The reaction solution was extracted with 200 ml of chloroform. This operation was repeated twice. The chloroform layer was then dried over anhydrous sodium sulfate. The solvent was then concentrated, thereby obtaining 16 g of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b) as a slightly yellow oily substance (yield: 95%). [HPLC: 99% (HPLC measurement conditions A)]
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=O)=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:61]2[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]2)=[O:40])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 74.7 %

Procedure:
A solution of 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[2-(5-carboxypent-1-yloxy)-4-methylphenyl]benzamide (3.5 g) in ethyl acetate (30 ml) was treated at ambient temperature with triethylamine (575 mg), N-methylpiperazine (569 mg), and diphenylphosphoryl azide (1.56 g). The reaction mixture was stirred at the same temperature for 17 hours. The reaction mixture was washed with brine and dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (SiO2 100 g, 3% methanol in chloroform) to give 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (2.93 g).
Reaction SMILES: [CH2:1]([Zn]CC)[CH3:2].[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>>[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:10])[CH2:1][CH3:2]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC[Zn]CC
Product: CCC(O)(CCCl)c1ccccc1
Yield: 82 %

Procedure:
Diethylzinc addition to 3-chloropropiophenone (0.5 g, 2.97 mmol) was performed according to general procedure B using 10 mol % of Compound B (162.1 mg). The crude product was filtered through a pad of basic alumina with EtOAc (200 mL) to yield 485 mg of 8 (82% yield, 88% ee) as a colorless oil: [α]D 20=−21.0 (c 3.0, MeOH); 1H NMR (CDCl3, 360 MHz) δ 0.76 (dd, J=7.6, 7.6 Hz, 3H), 1.76-1.90 (m, 2H), 2.25-2.34 (m, 2H), 3.20-3.29 (m, 1H), 3.48-3.60 (m, 1H), 7.20-7.39 (m, 5H) ppm; 13C{1H} NMR (CDCl3, 90 MHz) δ 7.55, 36.08, 40.58, 45.46, 77.00, 125.20, 126.92, 128.45, 144.33 ppm; IR (KBr) 3566, 3462, 3087, 3060, 3027, 2969, 2936, 2879, 1602, 1494, 1446, 1340, 1251, 1173, 1124, 1074, 1055, 1031, 1014, 989, 900, 762, 702, 611 cm-1; HRMS calcd for C11H14Cl (—OH)+: 181.0784, found 181.0789 (chlorine splitting pattern observed).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[NH2:16][C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[CH:19][C:18]=1[Cl:28]>>[Cl:28][C:18]1[CH:19]=[C:20]([C:21]2[N:23]=[C:12]([C:10]3[S:11][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([CH3:15])[CH:9]=3)[O:14][N:22]=2)[CH:25]=[C:26]([CH3:27])[C:17]=1[NH2:16]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1N
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(N)c(Cl)c3)no2)cc1C
Yield: 11.6 %

Procedure:
The title compound (20 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (100 mg, 440 μmol) and 4-amino-3-chloro-N-hydroxy-5-methyl-benzamidine (97 mg, 484 μmol) according to Method A; LC-MS: tR=0.61 min; [M+1]+=391.08; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.25 (s, 3H), 2.29 (s, 3H), 2.57-2.70 (m, 4H), 3.72 (s, 2H), 7.65 (s, 1H), 7.78 (s, 1H), 7.98 (d, J=1.5 Hz, 1H).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=O.Cl.O>CO>[CH:9]([N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)([CH3:11])[CH3:10]
Reactant: CC(C)N1CCN(C=O)CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)N1CCNCC1
Yield: 42 %

Procedure:
To a solution of 0.29 g of 1-formyl-4-isopropylpiperazine in 10 ml of methanol were added 0.5 ml of hydrochloric acid and 1 ml of water and the mixture was heated under reflux for 2 hours. The reaction solution was distilled off under reduced pressure, a iN aqueous solution of sodium hydroxide was added and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford 0.1 g of the title compound.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([C:46]([N:48]3[CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)C3)=O)[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.[C:58](=[O:61])(O)[O-].[Na+]>O1CCOCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([CH:46]3[C:50]4[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH2:56][N:48]3[C:58]([N:48]3[CH2:56][C:55]4[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:46]3[C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[C:12]([C:16]6[NH:17][N:18]=[CH:19][N:20]=6)[CH:11]=5)[NH:7][N:8]=4)[CH:41]=3)=[O:61])[CH:43]=[CH:44][CH:45]=2)=[N:20][CH:19]=[N:18]1
Reactant: O=C([O-])O
Reactant: O=C(c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)N1Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N1Cc2ccccc2C1c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1)N1Cc2ccccc2C1c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
To a stirred solution of isoindolin-2-yl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl ketone (0.240 g, 0.327 mmol) was added 4.0 M hydrochloric acid in dioxane (10.0 mL) and the mixture stirred at ambient temperature for 20 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0458 g, 34% yield). 1H NMR (CD3OD) δ 8.74 (s, 1H), 8.50 (br s, 1H), 8.23 (s, 1H), 8.19 (m, 1H), 8.10 (br s, 1H), 7.68 (m, 3H), 7.37 (d, 1H), 7.26 (m, 3H), 5.00 (s, 2H), 4.93 (s, 2H). ES-MS (m/z) 407 [M+1]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:14]3[C:13]([C:11]([NH:10][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:1][CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:3]=4)=[O:12])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:28]=2)[CH:24]=[N:25]1
Reactant: CN1CCC(O)CC1
Reactant: COc1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1O
Product: COc1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1OC1CCN(C)CC1

Procedure:
The title compound was prepared from N-(3-hydroxy-4-methoxyphenyl)[2-(1H-indazol-6-ylamino)(3-pyridyl)]-carboxamide (Example 36) by a method similar to that described in Example 34 using 4-hydroxy-N-methylpiperidine. MS (ES+): 473 (M+H) +; (ES−):471 (M−H). Calc'd. for C26H28N6O3—472.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27]([C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1)[CH3:28]>CN(C=O)C>[CH2:27]([C:29]1([NH:33][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]4)[CH:6]=[N:7][CH:8]=2)[CH2:32][O:31][CH2:30]1)[CH3:28]
Reactant: CCC1(N)COC1
Reactant: CN1C(=O)CCc2cc(-c3cncc(CCl)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(NCc2cncc(-c3ccc4c(c3)CCC(=O)N4C)c2)COC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.1 %

Procedure:
To a stirred solution of 6-(5-chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (190 mg, 0.66 mmol) in DMF (5.0 mL) was added K2CO3 (276 mg, 2.0 mmol) and 3-ethyl-oxetan-3-ylamine (415 mg, 3.0 mmol) at room temperature and the resulting reaction mixture was stirred at room temperature for additional 12 hours. After extraction with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (35 mg, 17.2%) as a light yellow solid. MS: 352.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[N:11]=[CH:10][C:9]=2[C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[N:11]=[CH:10][C:9]=2[C:16]2[S:17][CH:18]=[C:19]([CH2:21][C:22]([NH:32][CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:23])[N:20]=2)=[CH:4][CH:3]=1
Reactant: CC(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCC1CCOCC1
Product: CC(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using the compound obtained in step 4 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C:4](=[O:7])[NH:3]1.CCN(C(C)C)C(C)C.[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[O:7]=[C:4]1[CH2:5][CH2:6][N:2]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[NH:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCNN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)OCc2ccccc2)N1
Reaction time: 3 h

Procedure:
To a suspension of pyrazolidin-3-one hydrogen chloride (5.00 g, 40.8 mmol) in DCM (120 mL) at 0° C. was added DIEA (2.5 eq), followed by CbzCl (1.15 eq). The resulting clear solution was warmed to it and stirred 3 h. The reaction mixture was washed with brine. The aqueous layer was separated and back-extracted with DCM (×2). The combined organic layers were dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-100% EtOAc/Hexanes, Rf=0.35 in 100% EtOAc) to afford the desired product as a white solid (5.31 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]4=[N:1][O:3][C:30]([C:27]5[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=5)=[C:5]4[CH:6]=3)=[CH:11][CH:12]=[N:13]2)=[CH:20][CH:19]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(C(F)(F)F)cc4)c3c2)cc1

Procedure:
The title compound, yellow solid (41 mg, 27%), MS (ISP) m/z=420.2 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(4-trifluoromethyl-phenyl)-acetonitrile.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16](OC)=[O:17])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[CH:3]=1
Reactant: COC(=O)c1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(CO)cc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
A solution (80 mL) of methyl 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (7.1 g) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution (42 mL) of diisobutylaluminum hydride in toluene was added dropwise over 30 min, and the mixture was further stirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, water, saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield 7.1 g, quantitative).
Reaction SMILES: Cl[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]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[OH:48][C@@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@@H](O)CC2)C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(cis-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. Purification: ISCO Combi-flash Rf system, eluting with 0 to 5% MeOH in EtOAc. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 7.47 (br. s., 1H), 7.29 (d, J=8.34 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J=8.08 Hz, 1H), 4.49 (s, 2H), 4.40 (d, J=4.80 Hz, 1H), 3.95-4.07 (m, 4H), 3.91 (br. s., 1H), 3.75 (s, 3H), 3.07 (s, 3H), 1.84-1.97 (m, 2H), 1.77 (d, J=12.38 Hz, 2H), 1.43-1.61 (m, 4H), 1.20 (t, J=6.95 Hz, 6H); MS (ES+): m/z: 678.24 [MH+]. HPLC: tR=3.52 min (ZQ3: polar 5 min).
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[C:4]#[N:5].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[F:23].O>C1COCC1>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:3][C:4]#[N:5])=[CH:17][C:16]=1[F:23]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Cl)c(F)c1
Temperature: 25 °C

Procedure:
Diethylcyanomethyl phosphonate (3.2 ml, 18.9 mmol) was taken up in dry THF (20 ml) at 0° C. under nitrogen, and stirred as a 60% oil dispersion of NaH (756 mg, 18.9 mmol) was added portionwise over ca. 10 min. The resulting grey suspension was then stirred at 0° C. for 1 h, before a solution of 4-chloro-3-fluoro benzaldehyde (Lancaster Synthesis) (3 g, 18.9 mmol) in 5 ml THF was added dropwise. The whole reaction was then allowed to warm to room temperature over 60 h. Water (5 ml) was added, and the mixture extracted with EtOAc (3×50 ml). The combined organics were were dried (MgSO4) and evaporated to a yellow oil which was purified by column chromatography using 5% EtOAc in pentane as eluant to provide the title product as a mixture of geometric isomers (2.4 g, 70%); 1HNMR (400 MHz, CDCl3) δ: 5.82 (d, 1H), 7.19 (d, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.42 (app.t, 1H); LRMS TS+199.1 (M+NH4+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][C:18]([C:20]1[CH:36]=[CH:35][C:23]2[CH2:24][CH2:25][N:26]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:27][CH2:28][C:22]=2[CH:21]=1)=[O:19]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:17][C:18](=[O:19])[C:20]2[CH:36]=[CH:35][C:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:34])[C:30]([F:33])([F:31])[F:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.00 g (4.97 mmol) 4-benzyloxy-1H-pyridin-2-one in THF at 0° C. is added subsequently 613 mg (5.47 mmol) potassium-tert-butylate, 92 mg (0.25 mmol) tetra-butylammonium-iodide and 2.38 g (7.46 mmol) 1-[7-(2-chloro-acetyl)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-2,2,2-trifluoro-ethanone. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is taken up in DCM and aqueous 2M sodium hydroxide solution. The layers are separated, the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via chromatography (silica gel; DCM/MeOH 95:5) and then via reverse HPLC purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[C:9]([C:27]([F:30])([F:29])[F:28])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:14]1([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:27]([F:30])([F:29])[F:28])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(N2CCOCC2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate (1.60 g, 3.73 mmol, 1.00 equiv), dichloromethane (10 mL). Trifluoroacetic acid (3.10 g, 27.2 mmol, 7.30 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 1.00 g (81% yield) of 4-[4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl]morpholine as yellow oil. LCMS (ESI, m/z): 330 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:33][CH3:34])[C:31]=1[CH3:32])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[O:7].CI.[C:37](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:33][CH3:34])[C:31]=1[CH3:32])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[N:22]([CH3:37])[C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)C(F)(F)F)cc(OC)c1C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N(C)C(=O)C(F)(F)F)cc(OC)c1C
Temperature: 50 °C
Yield: 97.1 %

Procedure:
A suspension of compound 1h (1.1 g, 2.3 mmol), methyl iodide (0.72 mL, 11.5 mmol) and potassium carbonate (1.6 g, 11.5 mmol) in acetone (14 mL) was sealed in a pressure tube and heated at 50° C. for 3 h. The reaction mixture was cooled to rt, filtered, and concentrated on a rotary evaporator to give compound 1i (1.1 g, 100%) as a light yellow solid. ESI-MS m/e 493.1 (M+1).