Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O:53][CH3:54])=[CH:5][N:6]=[C:7]2[O:12][C@H:13]1[CH2:52][N:16]2[C:17](=[O:51])[C@@H:18]([NH:43]C(=O)OC(C)(C)C)[C@H:19]([CH3:42])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:41])[CH:24]=[CH:25][C@@H:26]3[CH2:31][C@@:27]3([C:32](=[O:40])[NH:33][S:34]([CH:37]3[CH2:39][CH2:38]3)(=[O:36])=[O:35])[NH:28][C:29](=[O:30])[C@@H:15]2[CH2:14]1.Cl>O1CCOCC1>[ClH:1].[NH2:43][C@@H:18]1[C:17](=[O:51])[N:16]2[CH2:52][C@H:13]([O:12][C:7]3[C:8]4[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=4)[C:4]([O:53][CH3:54])=[CH:5][N:6]=3)[CH2:14][C@H:15]2[C:29](=[O:30])[NH:28][C@:27]2([C:32]([NH:33][S:34]([CH:37]3[CH2:39][CH2:38]3)(=[O:35])=[O:36])=[O:40])[CH2:31][C@H:26]2[CH:25]=[CH:24][CH:23]([CH3:41])[CH2:22][CH2:21][CH2:20][C@H:19]1[CH3:42]
Reactant: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2cccc(Cl)c12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4/C=C\C(C)CCC[C@@H](C)[C@H](N)C(=O)N3C2)c2cccc(Cl)c12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4/C=C\C(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2cccc(Cl)c12
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4C=CC(C)CCC[C@@H](C)[C@H](N)C(=O)N3C2)c2cccc(Cl)c12

Procedure:
A solution of tert-butyl (2R,6S,7R,13aS,14aR,16aS,Z)-2-(5-chloro-4-methoxyisoquinolin-1-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (300 mg, 3.3 mmol) in dioxane.HCl was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to get crude compound (250 mg, 96%). The crude compound was washed with diethyl ether and taken to the next step without further purification. MS: MS m/z 688.2 (M+−36).
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[C:14]=2[CH3:22])=[CH:8][CH:7]=1)=[O:4].[ClH:23]>C(O)(=O)C>[ClH:23].[C:3]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[C:14]=2[CH3:22])=[CH:10][CH:11]=1)([OH:4])=[O:2]
Reactant: COC(=O)Cc1ccc(Nc2cc(C)c(O)c(C)c2C)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(Nc2ccc(CC(=O)O)cc2)c(C)c(C)c1O
Temperature: 50 °C

Procedure:
A mixture of 2.0 g of 4-(4-methoxycarbonylmethylphenylamino)-2,3,6-trimethylphenol (Compound 86), 7.2 ml of 36% hydrochloric acid and 14.2 ml of acetic acid was heated at 50° C. for 14.5 hours. The reaction mixture was cooled to room temperature, and the crystals that precipitated were filtered, washed with acetonitrile and dried, giving 1.6 g of the title compound. The filtrate was concentrated under reduced pressure, and the solid thus obtained was treated similarly, additionally giving 0.4 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[CH:33][N:32]=1>CS(C)=O>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[O:19][C:31]3[N:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]#[N:38])=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21]
Reactant: N#Cc1cccnc1Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(Oc4ncccc4C#N)c3)cc21
Reaction time: 0.33 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-179, 23 mg, 0.07 mmol) in DMSO (2 ml) was charged with Potassium carbonate (20.5 mg, 0.15 mmol, 2.0 eq) and 2-Chloro-3-cyanopyridine (15.4 mg, 0.11 mmol, 1.5 eq). The mixture was irradiated in a microwave at 160 deg C. for 20 min. The resulting dark mixture was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present), providing the title compound, 2-{3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy} nicotinonitrile (2-1), as a tan solid-oil. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, 1H, J=3.3 Hz), 8.03 (d, 1H, J=5.9 Hz), 7.51-7.50 (m, 2H), 7.42 (s, 1H), 7.32 (d, 1H, J=8.2 Hz), 7.20-7.17 (m, 2H), 7.13-7.09 (m, 2H), 3.70 (s, 2H), 3.49 (s, 3H), 1.06 (s, 9H). LRMS m/z: Calc'd for C25H24N4O2(M+H) 413.4, found 413.2.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(S([C:18]([F:21])([F:20])[F:19])(=O)=O)C=CC=CC=1>CN(C=O)C>[F:21][C:18]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([F:19])[F:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccccc1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)C(F)(F)F
Temperature: -30 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
Into a dry 250 mL Schlenk flask under an argon atmosphere, was added 5.14 g Mg turnings (214 mmol) and 32.3 g (214 mmol) t-butyldimethylsilyl chloride in 150 mL DMF at −30° C. Subsequently, 15.0 g (71.4 mmol) of 1 in 10 mL DMF was added slowly via a syringe. The reaction mixture was stirred at room temperature at −30° C. for 1 h, and then at room temperature for another 2 h until all the starting material was consumed (19F NMR showed that the conversion was 75%). The reaction mixture was washed with ice water, followed by extraction with pentane (30 mL×4 ). Combined pentane phase was further washed carefully with cold 98% sulfuric acid (20 mL×4) to remove most of the siloxane and silanol. Then the pentane phase was washed with cold NaHCO3 aqueous solution three times until pH paper indicated neutral pH. The pentane phase was dried over MgSO4 and solvent evaporated to give a crude product that was fractionally distilled to give 7.46 g colorless liquid 16 (95° C./410 Torr), which turned to a transparent crystalline solid at room temperature (m.p. 52˜54° C., sublimes), yield 57%. 1H NMR (500 MHz, CDCl3): δ0.20 (s, 6H); 0.99 (s, 9H). 13C NMR (125 MHz, CDCl3): δ−8.8; 16.0; 26.0; 132.0 (q, 1JC-F=323.8 Hz, CF3). 19F NMR (470 MHz, CDCl3): δ−61.8. 29Si NMR (99 MHz, CDCl3): δ8.4 (q, 1JSi-F=32.8 Hz). GC-MS (m/z): 184 (M+), 127 (M+-tBu), 115 (M+-CF3), 99 (M+-CF3—CH3), 57 (tBu+). High-resolution GC-MS (EI): m/z calculated for C7H15F3Si (M+) 184.0895, found 184.0943.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 66 %

Procedure:
As described for example 162b, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) was converted using 4-amino-tetrahydropyran instead of ethanolamine to the title compound (trituration with tert-butylmethylether, 168 mg, 66%) which was obtained as a white solid. MS: m/e=393.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([OH:29])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([CH:15]=2)[O:29][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:30][CH:31]=1)#[N:2]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 70 °C

Procedure:
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (1.0 g, 2.36 mmol) in 10.0 mL of N,N-dimethylformamide is treated with 60% sodium hydride (100 mg, 2.59 mmol) and ethyl bromoacetate (290 μL, 2.59 mmol), and the mixture is heated at 70° C. overnight; the reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 40-50% ethyl acetate/hexane as the eluent to afford ethyl 5-[5-(4-cyanophenoxy )pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxyacetate as a colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:26]=[C:27]=[O:28])(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:27](=[O:28])[NH2:26])[CH2:20][CH2:21]2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCNCC2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCN(C(N)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of 4-(t-butoxycarbonylamino)-1-(4-piperidinylmethyl)piperidine (590 mg) in methylene chloride (30 ml) is added trimethylsilyl isocyanate (220 mg) under ice-cooling, and the mixture is stirred at room temperature for 8 hours. The reaction mixture is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=10:1) to give 4-(t-butoxycarbonylamino)-1-(1-carbamoyl-4-piperidinylmethyl)piperidine (540 mg).
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:56])=[C:32]([N:38]2[CH2:43][CH2:42][C@@H:41]([O:44][Si](C(C)(C)C)(C)C)[C@H:40]([NH:52][C:53](=[O:55])[CH3:54])[CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1>>[Cl:56][C:31]1[C:30]([NH:29][C:7]2[N:6]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=2)=[CH:35][C:34]([C:36]#[N:37])=[CH:33][C:32]=1[N:38]1[CH2:43][CH2:42][C@@H:41]([OH:44])[C@H:40]([NH:52][C:53](=[O:55])[CH3:54])[CH2:39]1
Reactant: CC(=O)N[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Product: CC(=O)N[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1O

Procedure:
(+/−)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-hydroxypiperidin-3-yl)acetamide was prepared starting from 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 2) and (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-4-((tert-butyldimethylsilyl)oxy)piperidin-3-yl)acetamide using a method analogous to that used to prepare Example 171.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[O:11]=[C:9]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:13][CH:12]=1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Reactant: N#Cc1ccc(/C=C/C(=O)O)cc1
Product: N#Cc1ccc(/C=C/C(=O)N2CCC[C@H]2CN2CCCCC2)cc1

Procedure:
150 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-4-cyanocinnamic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]Cl)[CH2:10][Cl:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[C:19]([O:18][C:16]([N:15]1[CH2:13][C@@H:12]1[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][Cl:11])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]1[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 100.3 %

Procedure:
To a magnetically stirred solution of 2(S)-t-butyldimetylsilyloxy-3(R)-(t-butyloxycarbonyl)amino-1,4-dichlorobutane (375.4 mg, 1.008 mmol) in THF (10 mL) was added NaH slowly at 0° C. under N2. After 5 h, the reaction mixture was slowly added to sat aq ammonium chloride solution (40 mL) and ice (20 g). The resulting solution was extracted with EtOAc (60 mL 4). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated and column chromatographed (10% EtOAc in n-Hex) to provide N-t-butyloxycarbonyl-2(R)-(1(S)-t-butyldimetylsilyloxy-2-chloroethyl)aziridine (339.5 mg) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:28](=[O:43])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)[CH:32]=1)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([N:37]5[CH:41]=[N:40][N:39]=[N:38]5)[CH:32]=4)[CH2:29][C:28](=[O:43])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cnnn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) and 3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (Example H15) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige powder (5.5 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)[nH]2)cc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 2-(4-cyanophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (2.5 g, 7.3 mmol) [See Ex. 96 above] in THF (50 mL) was added LiAlH4 (7.3 mL of 1M solution in THF, 7.3 mmol), and the resulting mixture was heated at reflux for 2 h, at which time tlc analysis indicated that the reaction was incomplete. Additional LiAlH4 (4.0 mL, 4.0 mmol) was added and heating was continued for 30 min. The mixture was allowed to cool, then poured into 2.5N NaOH and extracted with THF. The organic extract was washed with saturated aqueous NaCl and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 9:1 CHCl3 /MeOH, followed by 90:10:1 CHCl3 /MeOH/NH3. The material that was isolated was triturated with Et2O to afford the title compound (1.5 g, 60%): mp 214°-215° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([F:15])[F:14])[CH3:10]>[Cu].CS(C)=O>[CH2:9]([O:11][C:12](=[O:17])[C:13]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([F:15])[F:14])[CH3:10]
Reactant: Brc1ccc(I)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(Br)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 4-bromoiodobenzene (848.7 mg, 3.0 mmol), bromodifluoroacetic acid ethyl ester (Compound 1f; 608.9 mg, 3.0 mmol), copper powder (381 mg, 6.0 mmol) and DMSO (6.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 24 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-bromophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2f) was obtained with a yield of 69%.
Reaction SMILES: [N:1]1([C:8]2[C:17]3[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:19])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[N:1]1([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:27][CH2:26][C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=4)=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:19])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(N2CCCCCC2)c2ccc(I)cc2n1
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: Cc1cc(N2CCCCCC2)c2ccc(NCc3ccc(C(F)(F)F)cc3)cc2n1

Procedure:
In analogy to example 1a), on reaction of 4-azepan-1-yl-7-iodo-2-methyl-quinoline with 4-trifluoromethylbenzylamine there was obtained (4-azepan-1-yl-2-methyl-quinolin-7-yl)-(4-trifluoromethyl-benzyl)-amine a light brown solid. ISP mass spectrum, m/e: 414.3 (M+1 calculated for C24H26F3N3: 414).
Reaction SMILES: C(O)=O.[C:4](OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19]>C1COCC1>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH3:4])=[CH:14][C:13]=1[F:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c(F)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: CNc1ccc(Cl)c(F)c1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Formic acid (1.76 ml) was added to acetic acid anhydride (0.91 ml) at 0° C. The solution was stirred for 10 min at this temperature. The reaction was heated under nitrogen to 55° C. for 2 h. The reaction mixture was cooled to 0° C. 4-Chloro-3-fluoroaniline (1.07 g) dissolved in THF (2 ml) was added and the reaction was stirred over night at RT. The solvent was evaporated in vacuo. The residue was dissolved in THF (4 ml). The solution was cooled to 0° C. and borane tetrahydrofuran complex 1M in THF (16.2 ml) was added slowly. Strong gas evolution was observed. The reaction was heated to reflux for 3 h, then cooled to 0° C. and MeOH (4 ml) was added dropwise. The reaction was stirred for 1 h and 1M aq HCl solution (6 ml) was added. The reaction was stirred over night at RT. The solvent was removed in vacuo and the pH of the aqueous layer was adjusted to 9 with 2N aq NaOH solution. The reaction mixture was extracted twice with diethyl ether and the combined organic layers were dried over sodium sulfate, filtered and the solvent was removed in vacuo to yield (4-chloro-3-fluoro-phenyl)-methyl-amine (1150 mg, 98%) as a light brown oil. 1HNMR (DMSO-d6, 300 MHz): δ 2.65 (d, J=5.1 Hz, 3H), 6.15 (d, J=5.1 Hz, 1H), 6.20 (dd, J=3.0 and J=8.4 Hz, 1H), 6.45 (dd, J=2.4 and 12.3 Hz, 1H), 7.18 (t, J=8.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[C:9]([CH3:12])[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:3]2[C:10]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])=[C:9]([CH3:12])[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1c(I)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2cccc(C#N)c2)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-5-iodo-6-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C6) (300 mg, 0.71 mmol) and (3-cyanophenyl)boronic acid (104 mg, 0.708 mmol) in a mixture of 1,2-dimethoxyethane and water (5:1, 10 mL) was added potassium carbonate (193 mg, 1.40 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 23 μmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. After heating at reflux for 18 hours, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 140 mg, 0.351 mmol, 50%. LCMS m/z 399.2 [M+H+].
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[C:6]([CH:12]=[O:13])=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11]>C1COCC1>[Br:4][C:5]1[C:6]([CH:12]([OH:13])[CH3:1])=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccnc(C=O)c1Br
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccnc(C(C)O)c1Br
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Methylmagnesium chloride (3.0 mol/L) in THF (0.17 mL, 0.525 mmol) was added dropwise to a solution of 3-bromo-4-methyl-pyridine-2-carbaldehyde (100 mg, 0.50 mmol) in THF (2 mL) cooled at −15° C. After 5 min, the reaction was quenched with a few drops of saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a yellow oil (100 mg, 92%), which was used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([O:5]C(=O)OCC(C)C)[CH:2](C)C.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:1](=[O:5])[CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CC(C)COC(=O)OCC(C)C
Product: CC(=O)NCc1ccccc1

Procedure:
After completion of the reaction, 1% hydrochloric acid (23 g) was dropwide added at 10° C. or lower and after stirred for 30 minutes, settled and separated. The obtained organic layer was washed with 9% salt water (7 g) at 5 to 10° C., settled and separated. The obtained organic layer was washed with an aqueous 5% sodium hydrogen carbonate solution (11.8 g) at 15 to 30° C., settled and separated. After that, the organic layer was washed with ion-exchange water (6 g) at 25 to 35° C., settled and separated. The obtained organic layer was evaporated to obtain a solution (10.04 g) of a desired pale yellowish transparent solution or white solid. The content was found 86.5% by gas chromatography analysis. The pure product yield was 8.68 g (yield 87.8% based on acetic acid). The content of impurities are as follows: diisobutylcarbonate: 2.0%, and N-isobutyloxycarbonyl)-benzylamine: 2.5%.