Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH2:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH3:29]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9]([NH:33][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Product: CCS(=O)(=O)Nc1ncc(OCC2CC2)c(-c2cn(C)c(=O)c3ccccc23)n1

Procedure:
The title compound of Example 152, step 5 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.00 (s, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.38 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.69 (m, 2H), 7.57 (t, J=7.6 Hz, 1H), 3.86 (d, J=6.8 Hz, 2H), 3.70 (s, 3H), 3.63 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.13 (m, 1H), 0.57 (m, 2H), 0.25 (m, 2H). LCMS: 415.0 (M+1)+
Reaction SMILES: [H-].[Na+].[C:3]12([N:13]3[C:17]4[CH:18]=[C:19]([O:22][CH2:23][CH3:24])[CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:25])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1[S:37](Cl)(=[O:39])=[O:38].O>C1COCC1.CN(C=O)C>[C:3]12([N:13]3[C:17]4[CH:18]=[C:19]([O:22][CH2:23][CH3:24])[CH:20]=[CH:21][C:16]=4[N:15]([S:37]([C:29]4[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=4[O:27][CH3:26])(=[O:38])=[O:39])[C:14]3=[O:25])[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: CCOc1ccc2[nH]c(=O)n(C34CC5CC(CC(C5)C3)C4)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc2c(c1)n(C13CC4CC(CC(C4)C1)C3)c(=O)n2S(=O)(=O)c1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
0.35 g of sodium hydride as a 60% dispersion in oil is added in portions to a suspension of 2.5 g of 3-(adamant-1-yl)-5-ethoxy-1,3-dihydro-2H-benzimidazol-2-one in 10 ml of THF and 20 ml of DMF and the mixture is stirred for 30 minutes at RT. 2.2 g of 2-methoxy-4-nitrobenzenesulfonyl chloride are then added and the formation of a yellow precipitate is observed. The reaction mixture is poured into iced water and the precipitate obtained is filtered off and washed with water, with 95° EtOH and with ether to give 3.8 g of the expected product. M.p.=231° C.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[C:5](OCC)=[O:6])(=O)[CH3:2].[ClH:32].[NH2:33][C:34]1[N:35]=[CH:36][NH:37][C:38]=1[C:39](=[O:41])[NH2:40]>>[ClH:32].[C:39]([C:38]1[N:37]=[CH:36][N:35]2[C:5]([OH:6])=[C:4]([CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][C:15](=[C:18]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[C:1]([CH3:2])=[N:33][C:34]=12)(=[O:41])[NH2:40]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CCOC(=O)C(CCN1CCC(=C(c2ccccc2)c2ccc(C)cc2)CC1)C(C)=O
Agent: Cl
Product: Cc1ccc(C(=C2CCN(CCc3c(C)nc4c(C(N)=O)ncn4c3O)CC2)c2ccccc2)cc1

Procedure:
This compound was prepared from ethyl 2-acetyl-4-{4-[(4-methylphenyl)phenylmethylene]-1-piperidyl}-butyrate and 4-amino-5-carbamoyl imidazole hydrochloride according to the process described in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:30][CH3:31])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CC
Temperature: 55 °C
Yield: 36 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (210 mg, 0.49 mmol), potassium carbonate (82 mg, 0.59 mmol) and ethyl iodide (44 μl, 0.54 mmol) in DMF was heated at 55° C. for 2 hours. The mixture was allowed to cool to ambient temperature then evaporated. The residue was partitioned between EtOAc (50 mL) and water (15 mL). The organic phase was separated, dried (Na2SO4), filtered and evaporated to give an oil. The oil was purified by flash column chromatography on silica (Si-PPC, pentane:EtOAc, gradient 100:0 to 40:60) to provide the title compound as a yellow solid (80 mg, 36%). LCMS (method B): RT=2.52 min, M+H+=454.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: CSc1ccc(CO)cc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(CBr)cc1F
Reaction time: 1 h
Yield: 99 %

Procedure:
The mixture of [3-fluoro-4-(methylsulfanyl)phenyl]methanol (9.00 g, 52.26 mmol) and carbon tetrabromide (19.06 g, 57.49 mmol) in CH2Cl2 (200 mL) was added triphenylphosphine (15.08 g, 57.49 mmol) at 0° C. After 1 hour, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/10) to provide the subtitle compound (12.16 g, 94% yield) as an oil.
Reaction SMILES: O.[O:2]1[CH2:7][CH:6]=[C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[N:11]=[C:10]([N:23]3[CH:28]4[CH2:29][CH2:30][CH:24]3[CH2:25][O:26][CH2:27]4)[N:9]=2)[CH2:4][CH2:3]1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH:24]12[N:23]([C:10]3[N:9]=[C:8]([C:5]4[CH2:6][CH2:7][O:2][CH2:3][CH:4]=4)[N:13]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=4)[N:11]=3)[CH:28]([CH2:29][CH2:30]1)[CH2:27][O:26][CH2:25]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(C3=CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(C3=CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A mixture of iron powder (0.071 g, 1.27 mmoles) in acetic acid (2 ml) was heated to 55° C. for 15 minutes. Water (2 ml) was then added and oil bath was turned off. A solution of 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.100 g, 0.253 mmol) in ethyl acetate (2 ml) was then added to this warm solution over 5 minutes. The mixture was cooled to RT and allowed to stir for 16 hours. The mixture was extracted with ethyl acetate by decantation (4×) into a sep. funnel containing saturated aqueous sodium carbonate. The combined organic extracts were washed with water, brine, dried, and concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3,6-dihydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)aniline (0.068 g, 74%), which was used in the next step without purification. (M+H) 366.4.
Reaction SMILES: [K+].[CH2:2]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[C:16]([S:20]([O-:23])(=[O:22])=O)[CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:5]1=[O:26])[CH3:3].S(Cl)(Cl)=O.[CH3:31][N:32]([CH2:34][CH2:35][NH2:36])[CH3:33]>CN(C=O)C>[CH2:2]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[C:16]([S:20]([NH:36][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:5]1=[O:26])[CH3:3]
Reactant: CN(C)CCN
Reactant: CCn1c(=O)c2[nH]c(-c3cccc(S(=O)(=O)[O-])c3)nc2n(CC)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCn1c(=O)c2[nH]c(-c3cccc(S(=O)(=O)NCCN(C)C)c3)nc2n(CC)c1=O
Temperature: 0 °C
Yield: 18 %

Procedure:
A mixture of 3-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid monopotassium salt (4.6 g, 0.01 moles) and DMF (250 ml) is prepared and cooled to 0° C. To this solution is added thionyl chloride (7.14 g, 0.06 mole) and the mixture allowed to come to ambient temperature with vigorous stirring. To this slurry is added unsym dimethylethylenediamine (17.6 g, 0.2 moles). The resulting solution is concentrated on a rotary evaporator, the residue taken up in water, filtered, recrystallized twice from ethanol and dried at 48° to yield 0.78 grams of 3-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)-N-[2-(dimethylamino)ethyl]benzenesulfonamide, mp, 250°-251° C.
Reaction SMILES: [Zn]([CH2:4][CH3:5])CC.[C:6]1([CH:12]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1>>[C:6]1([C@@H:12]([OH:13])[CH2:4][CH3:5])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: CC[Zn]CC
Reactant: O=CC1=CCCCC1
Product: CC[C@H](O)C1=CCCCC1
Yield: 90 %

Procedure:
The product was prepared by General procedure L using 0.28 mL (0.55 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 55 mg (0.50 mmol) cyclohexenecarboxaldehyde. The crude product was purified by column chromatography on silica (10% ethyl acetate in hexanes) to afford the title compound in 90% yield (104 mg, 0.39 mmol) as a colorless oil, [α]D20=−3.4 (c=0.005, CHCl3, 99% ee); 1H NMR (CDCl3, 500 MHz): δ 0.8 (t, 3H, J=7.5 Hz), 1.3 (br s, 2H), 1.5-1.6 (m, 4H), 1.8 (s, 1H), 2.0 (s, 4H) 3.84 (q, 1H, J=10.0 Hz), and 5.63 (s, 1 H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 10.1, 22.6, 23.3, 24.9, 27.6, 29.6, 78.1, 123.2, and 139.6 ppm; IR (neat) 3500, 2962, 2922, 2874, 2360, 1732, 1456, and 1260 cm−1. HRMS-CI m/z 123.1174 [(M−OH)+; calcd for C9H15: 123.1173].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[N:34]#[C:35]Br>C(Cl)Cl>[C:35]([N:17]1[CH2:16][CH2:15][CH:14]([C@H:12]2[CH2:13][C@H:11]2[CH2:10][CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:3][C:2]=2[CH3:1])[CH2:19][CH2:18]1)#[N:34]
Reactant: N#CBr
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of tert-butyl (5-methyl-6-{2-[(1S,2R)-2-piperidin-4-ylcyclopropyl]ethoxy}pyridin-3-yl)acetate (770 mg, 2.1 mmol) in 15 mL of DCM was added K2CO3 (3 eq., 852 mg, in 5 mL of water) at room temperature followed by addition of cyanogen bromide (1.2 eq., 0.85 mL of 3M soln in DCM) at room temperature. The mixture was then stirred for 30 min at room temperature and then diluted with 20 mL DCM. The solution was washed with sat'd NaHCO3 aq. soln, separated, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by ISCO column (40 g silica gel) using ethyl acetate in hexane (0-60%, 700 ml) to give the title compound. LCMS (ESI) m/z 400 [M+H]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][Cl:15].CCN(CC)CC>O1CCOCC1.CCOCC>[Cl:15][CH2:14][CH2:13][CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: ClCCCBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: ClCCCN1CCCc2ccccc21
Temperature: 70 °C
Reaction time: 17 h
Yield: 23.5 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (505 mg, 3.79 mmol) and 1-bromo-3-chloro propane (1.77 g, 11 mmol) in 1,4-dioxane (6 mL) was added Et3N (1.90 g, 19 mmol). The reaction mixture was stirred at 70° C. for 17 h, and quenched by addition of H2O (2 mL). Reaction was diluted with Et2O (100 mL) and washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (hexanes:EtOAc 49:1) yielded 1-(3-chloropropyl)-1,2,3,4-tetrahydroquinoline (187 mg, 24%) as a colorless oil. The title compound was isolated as a yellow oil (22 mg, 43%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-(3-chloropropyl)-1,2,3,4-tetrahydroquinoline (51 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.77-2.19 (m, 10H), 2.24-2.41 (m, 2H), 2.61-2.69 (m, 1H), 2.75-2.84 (m, 3H), 2.91-3.02 (m, 1H), 3.10-3.21 (m, 2H), 3.26-3.34 (m, 5H), 3.52-3.61 (m, 1H), 3.77-3.96 (m, 1H), 6.49-6.65 (m, 3H), 6.85 (d, 1H, J=7.3 Hz), 6.92-6.96 (m, 2H), 6.99-7.05 (m, 1H) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)(=[O:5])[CH3:4].CN(C)C=O.[CH3:25][O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[CH3:25][O:26][C:27](=[O:36])[CH:28]([N:12]1[C:11](=[O:15])[CH:10]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:3](=[O:5])[CH3:4])[CH:14]=[N:13]1)[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(C)=O)cc1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Sodium hydride in mineral oil (3.65 g) was added to a solution of 5-(2-acetyl-phenoxy)-2H-pyridazin-3-one (16.3 g, 0.07 mol) in tetrahydrofuran (340 mL) at 0° C. The resulting mixture was stirred at 0° C. for 10 min and then was warmed to 20° C., where it stirred for 50 min. After this time, N,N-dimethylformamide (45 mL) and 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 25 g, 0.11 mol) were added to the reaction. The reaction was then warmed to 50° C. overnight. After this time, the reaction was concentrated in vacuo. Silica gel column chromatography afforded 2-[4-(2-acetyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (23.4 g, 86%); ESI-MS 385 [M+H+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6]2.[O:14]=[C:15]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:34]=[C:33]([N:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)[CH2:8]1)[CH2:32][N:16]1[CH2:17][CH2:18][C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]1=[O:14]
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Reaction time: 8 h

Procedure:
A solution of 5-(trifluoromethyl)isoindoline (0.035 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.54-7.61 (m, 1H), 7.20-7.49 (m, 12H), 4.82-4.88 (m, 4H), 4.24 (s, 2H), 3.61 (td, J=6.5, 1.6 Hz, 2H), 2.85 (t, J=6.6 Hz, 2H); MS (ESI+) m/z 465 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[OH:18][CH:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)[C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[CH3:26])=[CH:21][CH:20]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
1 g of the compound [25-1] was dissolved in 10 mL of methanol, then 200 mg of a carbon catalyst of 20% palladium hydroxide was added thereto, and the mixture was stirred for 1 hour at room temperature under hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure, to obtain 710 mg of tert-butyl ((1S)-1-{4-[hydroxy(piperidin-4-yl) methyl]phenyl}ethyl)carbamate [37-1]. The compound [37-1] (hereinafter, referred to as the compound [37-1]) was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][O:20][CH2:21][CH2:22][OH:23]>C1COCC1>[Si:5]([O:23][CH2:22][CH2:21][O:20][CH2:19][C:15]1[S:14][CH:18]=[CH:17][N:16]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOCc1nccs1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCc1nccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 544.8 %

Procedure:
TBDMS-Cl (2.4 g, 15.7 mmol) and imidazole (1.10 g, 16.9 mmol) were added to a sol. of 2-(thiazol-2-ylmethoxy)ethanol (2.45 g, 15.39 mmol) in THF (80 mL). The reaction mixture was stirred at rt over 15 h, partitioned between aq. sat. NH4Cl and Et2O. The phases were separated and the aq. layer was extracted with Et2O (2×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil (22.93 g, 87%) that was not further purified. LC-MS: tR=1.06 min, ES+: 274.24.
Reaction SMILES: C([O-])C.[Na+].[Cl-].[F:6][C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1.[C:33]([O:40][CH2:41][CH3:42])(=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])=O.C(OCC)(=O)C.CCCCCC>C(O)C>[CH2:41]([O:40][C:33](=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])=[CH:11][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:32][CH:31]=1)[CH3:42]
Reactant: CCOC(=O)CCC(C)=O
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(C)=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium ethanolate (0.836 g, 12 mmol) was added under cooling (0° C.) to a solution of 4-fluorobenzyl triphenylphosphonium chloride ([3462-95-1], 5.00 g, 12 mmol) in ethanol, and the mixture was stirred for 45min at r.t. Ethyl levulinate ([539-88-8], 1.77 g, 12 mmol) was added, and the light-orange mixture was refluxed (36 h). After the usual workup, 5-(4-fluoro-phenyl)-4-methyl-pent-4-enoic acid ethyl ester was obtained by column chromatography (silica gel, ethyl acetate/hexane) from the reaction mixture. MS: m/e=237.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1I.[C:13]([C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1)#[CH:14].C(#N)C>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.[Cu]I.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:14]#[C:13][C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1
Reactant: COc1ccc(I)c(OC)c1F
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C#Cc2cnn(C)c2)c(OC)c1F
Reaction time: 1 h
Yield: 86 %

Procedure:
To a mixture of (0.95 mmol) of 2,4-dimethoxy-3-fluoro-iodo benzene, 0.122 g (1.15 mmol) of 4-ethynyl-1-methyl-1H-pyrazole, 0.028 g (0.04 mmol) of dichlorobis(triphenylphosphine)palladium (II) and 8 mg (0.042 mmol) of copper (I) iodide 4 mL of anhydrous acetonitrile and 2 mL of triethylamine were added under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 hour, when TLC indicated a consumption of the iodobenzene. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography (silica gel; dichloromethane:ethyl acetate 9:1) to give the title compound in an 86% yield as creamy crystals. H1 NMR(CDCl3) 3.88 (s, 3H, Me); 3.89(s, 3H, MeO); 4.05 (d, 3H, MeO, J=1.34 Hz); 6.62 (tr, 1H, CH, J=8.2 Hz); 7.12 (dd, 1H, CH, J=8.2 Hz, J=2.55 Hz); 7.53 (s, 1H, CH pyr); 7.62 s, 1H, CH pyr).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1
Reactant: CN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1
Product: CNc1nc(N(C)c2ccc(OC)cc2)c2cc([N+](=O)[O-])ccc2n1

Procedure:
The title compound was prepared from (2-chloro-6-nitro-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine and methyl amine by a procedure similar to example 14. 1H NMR (CDCl3): 8.11 (dd, J=9.3, 8.0, 1H), 7.73 (d, J=2.4, 1H), 7.33 (m, 1H), 7.15 (m, 2H), 6.98 (m, 2H), 5.29 (s, broad, 1H), 3.86 (s, 3H), 3.55 (s, broad, 3H), 3.14 (d, J=4.8, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C.O>CS(C)=O>[Cl:8][C:4]1[CH:3]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Clc1cc(Br)ccn1
Reactant: Fc1ccc(C2CCCN2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(C2CCCN2c2ccnc(Cl)c2)cc1
Temperature: 200 °C
Yield: 57.8 %

Procedure:
4-Bromo-2-chloro-pyridine (0.17 mL, 1.5 mmol), 2-(4-fluoro-phenyl)-pyrrolidine (250 mg, 1.5 mmol) and triethylamine (0.22 mL, 1.6 mmol) are mixed in DMSO (5.0 mL). The reaction mixture is heated at 120° C. for 30 min and 200° C. for 40 min in a microwave reactor. Then water (35 mL) is added and the mixture is extracted with EtOAc (3×30 mL). The organic layers are combined, washed with water (3×20 mL) and concentrated to give the crude product. Purification by silica flash column chromatography using EtOAc in heptane (gradient from 10% to 90%) followed by Gilson preparative HPLC affords 240 mg of desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CO>C1COCC1.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CCNCC2)cc1)N1Cc2ccncc2C1
Temperature: 25 °C
Reaction time: 38 h

Procedure:
N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (2.0 g, 6.24 mmol) in 80 mL of 1:1 THF:methanol was added to 5% Pd on carbon (wet) (0.500 g) in a 250 mL SS pressure bottle and the mixture was stirred for 38 hours at 30 atm and 25° C. The mixture was filtered through a nylon membrane, concentrated and suspended in ether. Filtration with ether washes provided the title compound.