Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:19]1([C:25]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=2[C:27](Cl)=[O:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:25]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=2[C:27]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:8]=3[C:9]#[N:10])[CH2:2][CH2:3]2)=[O:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCNCC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCN(C(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-Piperazin-1-yl-5-trifluoromethyl-benzonitrile and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (69%, yellow solid, MS (m/e): 490.2 (M+H, 100%)
Reaction SMILES: [F:1][C:2]([F:34])([CH2:31][CH2:32][CH3:33])[C:3](=[O:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C:11](=[O:12])[CH2:10][C@H:9]([O:13]C2CCCCO2)[C@@H:8]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(O)(=O)C.C1COCC1.O>[F:1][C:2]([F:34])([CH2:31][CH2:32][CH3:33])[C:3](=[O:30])[CH2:4][CH2:5][CH2:6][C@H:7]1[C:11](=[O:12])[CH2:10][C@H:9]([OH:13])[C@@H:8]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: CCCC(F)(F)C(=O)CCC[C@H]1C(=O)C[C@H](OC2CCCCO2)[C@@H]1C/C=C\CCCC(=O)OC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC(F)(F)C(=O)CCC[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)OC

Procedure:
The diketone (42) (0.188 g) was dissolved in a mixed solvent of acetic acid, THF and water (3:1:1, 25 ml) and the resultant mixture was kept at 40° C. for 3.5 hours. The crude product obtained after the usual work-up was subjected to silicagel column chromatography to give the titled compound (43).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)[O:18][CH2:19]2)[C@@H:12]1[O:34][CH3:35]>C1COCC1.N1C=CC=CC=1.F.N1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]([CH2:19][OH:18])[C@@H:13]([OH:14])[C@@H:12]1[O:34][CH3:35]
Reactant: CO[C@H]1[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@H]2O[C@H]1n1cnc2c(Cl)ncnc21
Agent: F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CO[C@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 6-chloro-9-[(6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methoxytetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purine (1.31 g, 2.41 mmol) in THF/pyridine (12 mL, 1:1) was added approximately 20 drops of hydrofluoric acid in pyridine. This solution was stirred at r.t. overnight. The reaction was diluted with EtOAc (10 mL) and quenched with saturated aq NaHCO3. The aq layer was extracted with EtOAc (3×40 mL) and the combined organics were dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography (0 to 10% MeOH/DCM) to afford the title compound (0.690 g, 74%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25].O>CN(C)C=O>[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([N:8]1[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])=[O:26]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)c(C)c1
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 523 mg) at room temperature, and the mixture was stirred for 1 hr. Mesitylsulfonyl chloride (2.42 g) was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3→3:2) to give the title compound as a pale-yellow oil (yield 1.76 g, 49%).
Reaction SMILES: [C:1]([N:9](C)[C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C1C=CC=CC=1)=O.[H][H]>C(O)(=O)C.Cl.[C].[Pd]>[NH:9]([CH3:1])[C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C(=O)c1ccccc1)[C@@H](Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A 12.66 g portion of the BzMePhe was dissolved in 120 ml of acetic acid and 47 ml of HCl, and the solution was subjected to hydrogen catalytic reduction (room temperature, 8 hours) with addition of 5.0 g of 10% palladium-carbon catalyst. After separating off the catalyst by filtration, the filtrate was concentrated in vacuo, and the concentrate was recrystallized from ethanol (50 ml)-ether (500 ml) to give 7.93 g of MePhe, yeild 94.1%. M.p. 225° C.
Reaction SMILES: N1C=CC=C1/C=C1\C(=O)N(C#C)C2C\1=C[C:13]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12]C=2.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:34]\[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41].C[Si](C#C)(C)C.C(N(CC)CC)C>[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.CN(C=O)C>[CH3:41][O:40][C:39]1[CH:38]=[CH:37][NH:36][C:35]=1/[CH:34]=[C:27]1\[C:28](=[O:33])[NH:29][C:30]2[C:26]\1=[CH:25][C:24]([C:12]#[C:13][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:32][CH:31]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(Br)cc21
Reactant: C#CN1C(=O)/C(=C\c2ccc[nH]2)c2cc([Si](C)(C)C)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(C#C[Si](C)(C)C)cc21

Procedure:
This compound was prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)-ethynyl-2H-indol-2-one in Example 81 above. In this example, (Z)-5-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (740 mg, 2.32 mmol) (from Example 91) was coupled with (trimethylsilyl)acetylene (640 mg, 6.52 mmol) (Aldrich) using CuI (40 mg, 0.21 mmol) (Aldrich) and (Ph3P)2PdCl2 (90 mg, 0.13 mmol) (Aldrich) as catalyst in 10 mL DMF and 10 mL triethylamine at 70° C. for 22 hours to give (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)ethynyl-2H-indol-2-one. (Yield 410 mg, 52%).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=1.C(=O)([O-])O.[Na+]>O>[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])=[O:26])=[CH:23][N:22]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCOC(=O)c1ccc(N)nc1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To 7 ml of N,N-dimethylformamide were dissolved 0.92 g (4.0 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.72 g (5.2 mmol) of 6-aminonicotinic acid, followed by the addition of 1.30 g (16 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 0.85 g (yield: 78%) of 6,6-difluoro-5-methyl-5-hexenyl 6-aminonicotinate.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][OH:10].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.C(=O)([O-])O.[Na+]>ClCCl>[CH3:21][O:22][CH2:23][O:10][CH2:9][C:6]1[CH:7]2[CH2:8][CH:3]([CH2:4][CH:5]=1)[C:2]2([CH3:11])[CH3:1]
Reactant: CC1(C)C2CC=C(CO)C1C2
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCC1=CCC2CC1C2(C)C
Yield: 100 %

Procedure:
rac-(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methanol (10.0 g, 65.7 mmol), diisopropylethylamine (17.0 mL, 97.6 mmol) and chloromethyl methyl ether (6.5 mL, 85.6 mmol) were stirred in dichloromethane (100 mL) at room temperature for 1 day. After completion of the reaction, the reaction solution was mixed with saturated sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate=10/1) to give the desired product (100% yield).
Reaction SMILES: C[O:2][C:3](=[O:49])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[N:33]([CH3:34])[C:32]3[CH:35]=[C:36]([O:39][C:40]4[CH:45]=[C:44]([CH3:46])[C:43]([NH2:47])=[C:42]([CH3:48])[CH:41]=4)[CH:37]=[CH:38][C:31]=3[N:30]=2)=[CH:23][CH:22]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[OH-].[Li+].[ClH:53].Cl.O1CCOCC1>O1CCCC1.O>[ClH:53].[ClH:53].[NH2:47][C:43]1[C:42]([CH3:48])=[CH:41][C:40]([O:39][C:36]2[CH:37]=[CH:38][C:31]3[N:30]=[C:29]([CH2:28][O:27][C:24]4[CH:23]=[CH:22][C:21]([CH2:20][C@@H:4]([C:3]([OH:49])=[O:2])[NH:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[C:12](=[O:19])[C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:26][CH:25]=4)[N:33]([CH3:34])[C:32]=3[CH:35]=2)=[CH:45][C:44]=1[CH3:46]
Reactant: COC(=O)[C@H](Cc1ccc(OCc2nc3ccc(Oc4cc(C)c(N)c(C)c4)cc3n2C)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc3nc(COc4ccc(C[C@H](Nc5ccccc5C(=O)c5ccccc5)C(=O)O)cc4)n(C)c3c2)cc(C)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine methyl ester (0.25 g), lithium hydroxide monohydrate (0.04 g), tetrahydrofuran (5 ml) and water (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was chromatographed on LiChroprepDIOL (Merck) using ethyl acetate as the eluant to give a yellow material. To a solution of the material in tetrahydrofuran (3 ml) was added 4N hydrogen chloride/dioxane (1 ml) to give crystals. The crystals were isolated by filtration to afford the title compound (0.11 g, mp 148-155° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].I[C:30]1[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=1>>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][C@@:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:13][C:12](=[O:28])[N:11]([C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=3)=[CH:8][CH:7]=2)[CH3:10])[CH2:16][CH2:15]1
Reactant: O=c1cc(I)cc[nH]1
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Product: C[C@@H](c1ccc(C#Cc2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-ethynylphenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 28 Step 3. LC-MS Method 1 tR=1.3 min, m/z=471 (M+1). 1H NMR (CD3OD) 7.44-7.28 (m, 8H), 6.97 (d, 2H), 6.64 (s, 1H), 6.44 (dd, 1H), 5.54 (q, 1H), 3.02 (dt, 1H), 2.49 (m, 2H), 2.21 (m, 1H), 2.15 (s, 2H), 1.53 (d, 3H), 1.26 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:11]=1[CH3:19].C(Cl)(Cl)Cl>CO.[Pd]>[Cl:1][C:2]1[C:37]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(N)cccc1OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 75 %

Procedure:
(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(2-methyl-3-nitro-phenoxy)-propyl]-amine (300 mg, 0.51 mmol) was dissolved in methanol (100 ml), and hydrogenated with 10% Pd/C (40 mg) at 60 psi at room temperature. After 2.5 h, the reaction mixture was filtered and concentrated in vacuo to give an amber oil, 0.25 g (89%). Flash silica gel chromatography (Supelco Discovery DSC-Si) (CHCl3) afforded the title compound as a pure oil (75%). MS (ESI) 552.5 (M−H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[CH:10][C:11](I)=[N:12][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[N:12][CH:13]=1
Reactant: C1CSCCN1
Reactant: Brc1ccc(I)nc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCSCC2)nc1
Temperature: 98 °C
Reaction time: 3 h

Procedure:
A mixture of thiomorpholine (1.03 g, 10.0 mmol), 5-bromo-2-iodopyridine (3.69 g, 13 mmol), Pd2(dba)3 (200 mg, 0.2 mmol), xantphos (510 mg, 0.6 mmol) and t-BuONa (1.44 g, 15 mmol) in toluene (50 ml) was stirred under argon at 98° C. for 3 hours. After cooled to room temperature, the mixture was filtered through celite and washed with ethyl acetate. The filtrate was evaporated and the residue was subjected to silica gel column chromatography with 0-5% ethyl acetate in hexanes as eluent to give 4-(5-bromopyridin-2-yl)thiomorpholine 219-2 as solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[I-].[NH2:15][N+:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)=[CH:6][CH:7]=1
Reactant: N[n+]1ccccc1
Reactant: COC(=O)C#Cc1ccc(F)cc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: [I-]
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of methyl 3-(4-fluorophenyl)propiolate (8.02 g, 45 mmol) and 1-aminopyridinium iodide (10 g, 45 mmol) in dry acetonitrile (150 mL) was cooled to about 0° C. A solution of 1,8-diazabicycloundec-7-ene (13.7 g, 90 mmol) in dry acetonitrile (50 mL) was added dropwise over 1 h. The mixture was allowed to stir at room temperature for about 18 h. The reaction mixture was cooled in an ice bath for about 30 min and the precipitate was collected by filtration and washed with cold acetonitrile (10 mL). The solid was dried under reduced pressure to give the title compound as a white solid, 8.48 g (70%). 1H NMR (CDCl3) δ 8.50 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz), 7.78 (m, 2H), 7.42 (t, 1H, J=8.4 Hz), 7.13 (t, 2H, J=8.8 Hz), 6.97 (td, 1H, J=6.8, 1 Hz). MS (+ve ion electrospray) 271 (100), (MH+).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[OH-].[Li+:25].O1CCCC1>O.C(#N)C>[Li+:25].[C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][C:3]([O-:23])=[O:2])[CH2:8][CH2:9]2)=[CH:18][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)CCCC1CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(N2CCC(CCCC(=O)[O-])CC2)cc1
Yield: 138.1 %

Procedure:
To 4-[1-(4-tert-butyl-phenyl)-piperidin-4-yl]-butyric acid methyl ester (385 mg; 1.21 mmol, prepared in accordance with Example 135) is added lithium hydroxide (72 mg; 3.00 mmol) dissolved in water (6.5 mL). After dilution with tetrahydrofuran (10 mL) the reaction mixture is stirred for 2-4 hours. The mixture is then diluted with acetonitrile until a precipitate is formed. The solid is collected by filtration and dried under high vacuum to afford the desired product (517 mg) which is used in the next step without further purification.
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[S:7][CH:8]=1.[CH2:13]([OH:15])[CH3:14]>>[CH2:13]([O:15][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[S:7][CH:8]=1)[CH3:14]
Reactant: CCO
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: [Na]
Product: CCOCc1csc(NC(C)=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
The sodium metal (16 mg, 0.681 mmol) was dissolved in 2 ml of anhydrous ethanol. To this solution was added a suspension of N-(4-(chloromethyl)thiazol-2-yl)acetamide (100 mg, 0.521 mmol) in ethanol (1 ml). The reaction was stirred at room temperature for 1 hour and then heated at 63° C. for 1 hour. The reaction was concentrated and the residue was purified via preparative HPLC to afford N-(4-ethoxymethyl-thiazol-2-yl)-acetamide as a yellow amorphous solid (44 mg, 42%). LC/MS m/z 199.16 (M-1)+; HPLC Rt: 1.79 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.080 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)=[O:2].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[CH:1]([N:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)=[O:2]
Reactant: O=CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(CN2CCN(C=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A mixture comprising 9 g of 1-formyl-4-(4-nitrobenzyl)-piperazine, 180 ml of methanol and 14.6 of nickel chloride hexahydrate, was cooled in ice bath, and 4.6 g of sodium borohydride was slowly added thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 30 minutes. The reaction solution was distilled off under reduced pressure, and the residue was dissolved by an addition of 200 ml of 10% hydrochloric acid, and adjusted to pH 10 with 28% aqueous ammonia. Then, the mixture was extracted with ethyl acetate. The extract solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether to obtain 8.0 g of the above-identified compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[NH2:11][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cnc3c(N)nc(Cl)nc32)c1
Temperature: 60 °C
Yield: 85.5 %

Procedure:
To a solution of 2-chloro-6-aminopurine (1) (10 g, 58.97 mmol) and potassium carbonate (10 g, 744 mmol) in DMF (100 mL) was added methyl 3-(bromomethyl)benzoate (13.5 g, 58.93 mmol). The reaction mixture was heated to 60° C. for 90 minutes at which time the reaction was quenched by adding water. The quenched reaction mixture was extracted with ethyl acetate (3×50 mL) giving 16 g (86%) of Compound (2) as a white solid, which was used in the next step without further purification. 1H NMR (300 MHz, DMSO) δ 3.83 (s, 3H), 5.42 (s, 2H), 7.53 (m, 2H), 7.89 (m, 2H), 8.29 (s, 1H). LCMS: m/z for C14H12ClN5O2++H observed 318.1 at 1.99 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 440 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Methyl indole-5-carboxylate (1.40 g) was dissolved in 10 ml of dimethylformamide, followed by addition of 212 mg of sodium hydride (content: 95%) under ice-cooling and stirring for one hour. To the mixture, there was added 1.51 g of benzyl bromide, followed by stirring the mixture for 2 hours, pouring the reaction solution into 140 ml of a 5% ammonium chloride aqueous solution and extraction with ethyl acetate (50 ml×2). The resulting organic phase was washed with water (50 ml×2), dried over anhydrous sodium sulfate and the solvent was removed through evaporation under reduced pressure to give 2.09 g of methyl 1-benzylindole-5-carboxylate as orange-colored crystals. The yield thereof was found to be 99%.