Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 3-methoxypyridine-5-boronic acid pinacol ester (Aldrich, Buchs, Switzerland, 30 mg, 0.125 mmol) to give the title compound as an off-white solid. (HPLC: tR 2.17 min (Method A); M+H=401 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.39-8.26 (m, 2H), 8.21-8.07 (m, 2H), 8.04-7.96 (m, 1H), 7.66-7.56 (m, 1H), 7.45-7.36 (m, 1H), 3.91 (s, 6H), 3.60 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.N1([C:16]([N:18]2[CH:22]=[CH:21]N=C2)=[O:17])C=CN=C1.Cl.NCC([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=1)=O>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=4)[CH2:22][NH:18][C:16]3=[O:17])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: NCC(=O)c1ccc(F)c(F)c1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Product: O=C1NCC(c2ccc(F)c(F)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), di(1H-imidazol-1-yl)methanone (0.713 g, 4.4 mmol), TEA (1.84 mL, 13.2 mmol), aminomethyl-(3,4-difluorophenyl)ketone hydrochloride (0.911 g, 4.4 mmol), TEA (1.23 mL, 8.8 mmol), PdC (10%, 0.02 g) as described in method 1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1.O>CS(C)=O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: ClCc1ccc2ccccc2c1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc2ccccc2c1
Reaction time: 1.8 h
Yield: 56 %

Procedure:
A 21.5g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 44.3 g (0.25 mole) of 2-(chloromethyl)-naphthalene. The reaction mixture was heated to 105° over 0.3 hours, held at 105°-110° for 1.8 hours and poured with rapid stirring into 1.5 l of water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated to dryness to give 31.5 g (56%) of a light yellow solid, m.p. 102 soften, 120°-138°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[CH3:25][O:26][C:27](=[O:40])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:49](=[O:50])[CH2:48][N:45]3[C:46]([CH3:47])=[C:42]([Cl:41])[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44]3)[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 4-Piperazin-1-yl-benzoic acid methyl ester and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.78 (d, 2H), 6.98 (d, 2H), 5.38 (s, 2H), 3.71 (s, 3H), 3.60 (m, 4H), 3.46 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) expect M+H=445.1, found 445.0.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(O)(=O)C.C(OCC)C>O>[C:21]([NH:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of glutathione (1 g, 3.25 mmole) in 10 ml of water was added over 1 hr to a mixture of acetic anhydride (10 ml) and acetic acid (10 ml) at room temperature. After the addition was complete, the reaction mixture was chilled on ice. Additional acetic anhydride (5 ml) was added and the reaction mix was stirred while it gradually warmed to room temperature overnight. The reaction mixture was treated with 300 ml of ethyl ether and cooled overnight to obtain crystallized product. A white solid was obtained by filtering the reaction mix, and washing with more ether. More crystallized product was generated in the filtrate. The filtration and washing were repeated a second time and the white solids were combined and air-dried (585 mg, yield 51.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[CH2:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc3sc(C)nc3c2Cl)cc1
Yield: 52 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-propylbenzoyl chloride (90 μL, 0.56 mmol) in presence of triethylamine (0.5 mL) according to method A gave N-(4-Chloro-2-methyl-benzothiazol-5-yl)-4-propyl-benzamide (44 mg, 0.13 mmol, 52% yield) as a orange powder after crystallisation in hexane and methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:22][CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[OH:22][CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=3)[N:6]=[CH:5]4)=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1
Reactant: O=C(O)c1ccc2c(ccn2CCO)c1
Reactant: CCOC(=O)c1ccc(-n2ncc3cc(N)ccc32)cc1
Product: CCOC(=O)c1ccc(-n2ncc3cc(NC(=O)c4ccc5c(ccn5CCO)c4)ccc32)cc1

Procedure:
Compound 1039 was prepared according to the procedure described in Scheme IV from ethyl 4-(5-amino-1H-indazol-1-yl)benzoate and 1-(2-hydroxyethyl)indole-5-carboxylic acid. [M+H]+ calcd for C27H24N4O4: 469.18; found 469.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-amino-1-methylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=543.99 (M+H+); retention time=0.53 minutes.
Reaction SMILES: Cl[Si:2]([Cl:5])([CH3:4])[CH3:3].[F:6][C:7]1[CH:15]=[CH:14][C:10](C[Mg]Cl)=[CH:9][CH:8]=1.CCCCCC>C1COCC1>[Cl:5][Si:2]([CH3:3])([CH3:4])[C:10]1[CH:14]=[CH:15][C:7]([F:6])=[CH:8][CH:9]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: Fc1ccc(C[Mg]Cl)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(Cl)c1ccc(F)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
First, 6.45 g of dichlorodimethylsilane was dissolved in dry THF and cooled to 0° C. Next, 100 ml of 4-fluorobenzylmagnesium chloride (0.25 M) was slowly added dropwise thereto. After the completion of the addition, the reaction mixture was allowed to further react at low temperature for about 3 hours. Next, an excessive amount of hexane was added to the reaction mixture to precipitate a magnesium salt. The magnesium salt was removed via filtration and the organic solvent was evaporated under reduced pressure. By doing so, chlorodimethyl(4-fluorophenyl)silane was obtained with a yield of 80% via vacuum distillation. In a separate container, 3.0 g of 4-bromo-4′-n-propylbiphenyl and 250 mg of Mg was added to 20 ml of dry THF to provide a Grignard reagent, to which 2.3 g of chlorodimethyl(4-fluorophenyl)silane was added at room temperature. The reaction mixture was heated to 60° C. for about 10 hours, and worked up with water and hexane, and then purified by silica gel column chromatography to obtain the silicon-containing compound represented by the above formula (yield: 91%). 400 MHz 1H-NMR, CDCl3, δ (ppm): 0.30 (s, 6H), 0.99 (t, 3H), 1.65˜1.74 (m, 2H), 2.30 (s, 2H), 2.65 (t, 2H), 6.89 (d, 4H), 7.26˜7.28 (m, 2H), 7.50 (d, 2H), 7.54 (d, 2H), 7.58 (d, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]=3[C:12](I)=[CH:11]2)[O:7][C@@H:6]1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])#[CH:47]>CN(C=O)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]=3[C:12]([C:47]#[C:46][Si:48]([CH3:51])([CH3:50])[CH3:49])=[CH:11]2)[O:7][C@@H:6]1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)O[C@H]1C[C@H](n2cc(I)c3c(CCc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1C[C@H](n2cc(C#C[Si](C)(C)C)c3c(CCc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
To a suspension of (2R,3S,5R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(5-iodo-4-phenethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydrofuran-3-yl acetate 9 obtained from example 132, step d) (0.36 g, 0.578 mmol), CuI (0.022 g, 0.0116 mmol), Pd(PPh3)2Cl2 (0.040 g, 0.0570 mmol) and DIPEA (0.20 mL, 1.15 mmol) in DMF was added ethynyltrimethylsilane (0.230 g, 2.34 mmol). The mixture was stirred at r.t. for 12 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with H2O, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) to give the title compound (0.305 g, 58%).
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.[NH:8]1[CH2:11][CH:10]([S:12][C:13]2[CH:18]=[CH:17][C:16](/[C:19](/[C:26]3[N:31]=[C:30]([O:32][CH3:33])[C:29]([CH3:34])=[CH:28][CH:27]=3)=[CH:20]\[CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=2)[CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O>[CH:21]1(/[CH:20]=[C:19](/[C:26]2[N:31]=[C:30]([O:32][CH3:33])[C:29]([CH3:34])=[CH:28][CH:27]=2)\[C:16]2[CH:15]=[CH:14][C:13]([S:12][CH:10]3[CH2:11][N:8]([CH2:1][CH3:2])[CH2:9]3)=[CH:18][CH:17]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC=O
Reactant: COc1nc(/C(=C/C2CCCC2)c2ccc(SC3CNC3)cc2)ccc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCN1CC(Sc2ccc(/C(=C\C3CCCC3)c3ccc(C)c(OC)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
90% acetaldehyde (31 μL) and acetic acid were added to a solution of 6-{(E)-1-[4-(azetidin-3-ylsulfanyl)phenyl]-2-cyclopentylethenyl}-2-methoxy-3-methylpyridine in chloroform (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled and sodium triacetoxyborohydride (206 mg) was added, after which the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0→93:7) to give 6-[(E)-2-cyclopentyl-1-{4-[(1-ethylazetidin-3-yl)sulfanyl]phenyl}ethenyl]-2-methoxy-3-methylpyridine as a colorless oil (78 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:68][CH2:69][CH2:70][CH2:71][C:72]([O:74][CH3:75])=[O:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:68][CH2:69][CH2:70][CH2:71][C:72]([O:74][CH3:75])=[O:73])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: COC(=O)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (Example 115) (200 mg, 0.45 mmol) in 10 ml of anhydrous DMF were added HATU (190 mg, 0.50 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of methyl 4-aminobutyrate hydrochloride (104 mg, 0.68 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added slowly until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate as white solid. Yield: 220 mg, 90%.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1>>[N:5]1([CH2:3][CH2:2][CH2:1][NH2:4])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: c1c[nH]cn1
Reactant: C=CC#N
Product: NCCCn1ccnc1
Reaction time: 9 h

Procedure:
In accordance with Method IIB, acrylonitrile (8) and an imidazole (9) are reacted with heat for about 2-4 hours, concentrated to an oil and then hydrogenated with Raney nickel catalyst in methanol and ammonium hydroxide for a period of about 8-10 hours, giving 1H-imidazole-1-propanamine derivatives (10).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(Cl)Cl.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>CC#N.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([O:1][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[C:8]([CH3:10])[C:5]=1[CH:6]=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(O)cc(C)c1C=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(Oc2ccccc2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A suspension of 4-hydroxy-2-methoxy-6-methyl-benzaldehyde (1.00 g, 6.02 mmol), powdered 4A molecular sieves (4 g) in CH3CN (40 mL) and DCM (40 mL) was treated with phenylboronic acid (1.47 g, 12.06 mmol), followed by copper (II) acetate (1.09 g, 6.00 mmol). Pyridine (2.40 mL, 29.70 mmol) was added to the green suspension and the resulting mixture was stirred at rt overnight in an open flask. The mixture was filtered through a pad of Celite and the filtrate was concentrated to a green oil. The residue was purified by column chromatography (SiO2, EtOAc/hexanes; 1:9) to afford 2-methoxy-6-methyl-4-phenoxy-benzaldehyde (0.92 g, 63%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 7.41 (t, J=7.42 Hz, 2H), 7.22 (t, J=7.42 Hz, 1H), 7.08 (d, J=7.42 Hz, 2H), 6.43 (d, J=2.34 Hz, 1H), 6.31 (d, J=2.34 Hz, 1H), 3.83 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.[CH3:8][Si:9]([CH2:12][CH2:13][O:14][CH2:15]Cl)([CH3:11])[CH3:10].[Br:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([S:28](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:30])=[O:29])=[CH:23]2.CC(C)([O-])C.[Li+].C1COCC1>CN(C=O)C>[Br:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([S:28]([N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1)[CH2:15][O:14][CH2:13][CH2:12][Si:9]([CH3:11])([CH3:10])[CH3:8])(=[O:29])=[O:30])=[CH:23]2
Reactant: Nc1ccncn1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cccc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(c1ccncn1)S(=O)(=O)c1ccc2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of pyrimidin-4-amine (0.944 g, 9.93 mmol) in 10 mL DMF was treated with SEM-Cl (1.761 ml, 9.93 mmol) and was allowed to stir at room temperature 30 minutes. Perfluorophenyl 5-bromonaphthalene-2-sulfonate (INTERMEDIATE M; 4.50 g, 9.93 mmol) was added and the reaction mixture was treated with lithium tert-butoxide 1N in THF (19.86 ml, 19.86 mmol) drop wise. After stirring for one hour, the reaction mixture was concentrated. The crude residue was diluted with DCM, washed with water, the organics dried over MgSO4 and concentrated. The material (INTERMEDIATE CCC) was carried forward crude without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].[CH3:10][OH:11].[OH-:12].[Na+]>[Pd]>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([C:4]2[CH:9]=[CH:8][C:10]([OH:11])=[CH:2][C:1]=2[OH:12])[CH3:2])[CH:5]=1
Reactant: [OH-]
Reactant: CC(=O)c1cccnc1
Reactant: CO
Agent: [Pd]
Agent: [Na+]
Product: CC(c1cccnc1)c1ccc(O)cc1O
Reaction time: 96 h

Procedure:
Pd/C (10%, 50% wet) (2 g; 50% by mass) is added to a solution of compound (16) (4 g; 70% by mass; 6.8 mmol, 1.0 eq) in a methanol/1 M aqueous HCl solution mixture (120 ml/40 ml). The suspension is stirred for 4 days under hydrogen atmosphere and then filtered using a Buchner funnel. The filtrate is evaporated under reduced pressure. The oil obtained is taken up in 1 M aqueous sodium hydroxide solution (160 ml) and washed with ethyl acetate (2×80 ml). The aqueous phase is neutralized by adding solid NaH2PO4 and then filtered using a Buchner funnel. The solid obtained is washed thoroughly with water and then dried under strong vacuum to lead to compound 3 (0.5 g; 35%) obtained as a beige solid.
Reaction SMILES: CN(C=[N:5][N:6]=[CH:7][N:8]([CH3:10])[CH3:9])C.[CH2:11]([N:18]1[CH2:23][CH2:22]C(N)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:10]([N:8]2[CH:7]=[N:6][N:5]=[CH:9]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=NN=CN(C)C
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(n3cnnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2-bis[(dimethylamino)methylene]hydrazine (660 mg) in toluene (10 ml) was added 1-benzylpiperidin-4-amine (0.8 ml) and p-toluenesulfonic acid (75 mg) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was refluxed for 8 hours and then evaporated to dryness. The residue was purified by chromatography on silica eluting with a gradient of methanol/ethyl acetate to give 1-benzyl-4-(4H-1,2,4-triazol-4-yl)piperidine. Yield 220 mgs. NMR (d6 DMSO): 2.0 (m, 4H), 2.1 (m, 2H), 2.9 (m, 2H), 3.5 (s, 2H), 4.2 9m, 1H), 7.35 (m, 5H), 8.65 (s, 2H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[C:13]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:12]=3[N:11]=[C:10]([CH3:28])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[C:13]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[C:12]=3[N:11]=[C:10]([CH3:28])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21
Yield: 78.3 %

Procedure:
Activated manganese dioxide (47 mg, 0.54 mmol) was added to a solution of 1-(1-ethylpropyl)-6-mesityl-4-methyl-2,3-dihydro-1H-pyrrolo(3,2-c][1,5]naphthyridine (40 mg, 0.11 mmol) in toluene (4.0 mL) and the mixture was heated under reflux for one day. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (32 mg) as white crystals.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[Li][CH2:8][CH2:9][CH2:10]C.CCCCCC.BrCC#C.OS([O-])(=O)=O.[K+]>C1COCC1>[O:5]=[C:4]1[NH:6][CH2:1][CH2:2][N:3]1[CH2:10][C:9]#[CH:8]
Reactant: [Li]CCCC
Reactant: O=C1NCCN1
Agent: C#CCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CCN1CCNC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a suspension of ethylene urea (2.0 g, 23.2 mmol) in THF (80 mL) was added dropwise 1.47 N n-BuLi in hexane (15.8 mL, 23.2 mmol) at room temperature. 3-Bromopropyne (2.0 mL, 22.4 mmol) was added and the mixture was stirred for 30 min at room temperature then for 2 h at 50° C. Aqueous 5% KHSO4 was added and the mixture was extracted with ethyl acetate. The Organic layers were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 1:1 to 0:1 hexane/ethyl acetate to give the title compound (641 mg, 22%).