Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([NH2:39])[C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([NH:39][C:1](=[O:3])[CH3:2])[C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3N)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(-c2ccc(Cl)cc2)cnc1C#Cc1ccc(OCCN2CCC(C)CC2)cc1

Procedure:
125 μL (1.345 mmol) of acetic anhydride was added at RT to a solution of 100 mg (0.224 mmol) of 5-(4-chlorophenyl)-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridin-3-ylamine (Example 19.1d) and 62 μL (0.448 mmol) of triethylamine in 5 mL of DCM and the mixture was refluxed for 72 hours. The reaction mixture was diluted with DCM, and the organic phase was washed with saturated aqueous sodium bicarbonate solution, water, and 12% aqueous HCl, dried over magnesium sulfate, and evaporated down in vacuo. The residue was triturated with DIPE, and the precipitate was filtered off and dried in vacuo. The crude product was purified by HPLC-MS (Zorbax Stable Bond C18, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). Yield: 23 mg (21% of theoretical); C29H30ClN3O2 (M=488.020); calc.: molpeak (M+H)+: 488/490 (Cl); found: molpeak (M+H)+: 488/490 (Cl); HPLC-MS: 5.01 minutes (method B).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.N1([C:29](=O)[C:28]2N(C)C=N[C:23]=2N(C)C1=O)C.C1(C)CCC(C(C)C)C(O)C1>O>[CH:28]([O:15][C:14](=[O:16])[C@H:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:2])([CH3:29])[CH3:23]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Br
Agent: CC1CCC(C(C)C)C(O)C1
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
HBr (120 g) and tryptophan (5 g) were dissolved in water (1 L). Caffeine (100 g) and menthol (10 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.Cl[CH2:15][CH:16]=O.O.C([O-])(O)=O.[Na+]>CCO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:15]=[CH:16][N:13]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: O=CCCl
Reactant: Cn1cc(-c2ccc(N)nn2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2ccc3nccn3n2)cn1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
6-(1-Methyl-1H-pyrazol-4-yl)-pyridazin-3-ylamine (Stage 8.3, 2.41 g, 13.8 mmol) was dissolved in EtOH (18 mL). Chloroacetaldehyde 55% in H2O (1.61 mL, 13.8 mmol) and NaHCO3 (2.3 g, 27.5 mmol) were added. The RM was stirred at 80° C. for 5 h. The solvent was removed and a solution of 5% NaHCO3 was added. The mixture was extracted twice with DCM/MeOH (9/1). The combined organic phases were washed with brine, dried over Na2SO4, and the solvent was removed to afford the title compound as a black solid (tR 1.0 min (conditions 2), MH+=200).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]([CH3:17])[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[CH3:17][C@@H:9]([NH2:8])[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C[C@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Add 1.6 M hydrogen chloride in dioxane (120 mL) to a solution of (R)-(1-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.05 mol, 12 g) in dry dichloromethane (75 mL) at 0° C. Warm the reaction mixture to room temperature and stir for 2 h. Filter the precipitate and dry under vacuum to obtain the title compound (9.2 g, 86%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (d, 3H), 3.10 (br s, 2H), 3.38 (br s, 4H), 3.79 (br s, 5H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(OB(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: OB(O)Oc1ccccc1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
1-Bromo-4-methoxy-2-nitrobenzene (2.32 g, 10 mmol) was dissolved in 1,4-dioxane (30 mL) and, thereto, were added phenyl boric acid (2.44 g, 20 mmol), cesium carbonate (26 g, 80 mmol), 1,1-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.82 g, 1 mmol), and purified water (12 mL). The reaction mixture was stirred under a nitrogen flow at 80° C. for 18 hours. The reaction solution was filtered through celite, alumina, and Florisil, and, thereafter, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 4-methoxy-2-nitro-1-phenylbenzene (1.86 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:27]2[CH:28]=[N:29][CH:30]=[C:25]([F:24])[CH:26]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cncc(F)c1
Reactant: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 100 °C
Yield: 32.7 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (150 mg, 0.40 mmol), 5-fluoropyridine-3-boronic acid (70 mg, 0.48 mmol), Pd(PPh3)4 (46 mg, 0.040 mmol) and Cs2CO3 (261 mg, 0.80 mmol) in DMF (4 mL) was heated at 100° C. for 16 h under N2 atmosphere. After cooling the mixture to r.t., brine (10 mL) and EtOAc (40 mL) were added. 1 M HCl was added with stirring until pH was ˜4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by column chromatography (0-35% EtOAc/hexanes) to give 51 mg of the title compound. MS: (+) m/z 391.09 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1cccc(I)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccccc3c2)c1
Reaction time: 24 h
Yield: 76 %

Procedure:
Under an argon gas atmosphere, 243 g (1.41 mol) of 2-naphthaleneboronic acid, 400 g (1.41 mol) of 3-bromoiodobenzene, 3.27 g (28.2 mmol) of tetrakis(triphenylphosphine) palladium(0), 6.4 L of toluene and 3.2 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours while being refluxed. After the reaction in the mixture was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 303 g of 2(3-bromophenyl)naphthalene was obtained with an yield of 76%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].[O:13]1[CH2:25][CH:14]1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20].[OH-].[Na+].C(C1C=CC=CC=1OCC(O)CNCCC(OCCCC)=O)#N>CCOCC>[C:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[O:16][CH2:15][CH:14]([OH:13])[CH2:25][NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6])#[N:20]
Reactant: CCCCCOC(=O)CCN
Reactant: N#Cc1ccccc1OCC1CO1
Agent: CCCCOC(=O)CCNCC(O)COc1ccccc1C#N
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCOC(=O)CCNCC(O)COc1ccccc1C#N

Procedure:
This compound was prepared in accordance with Example 1 using 6.9 g of the hydrochloride of pentyl 3-aminopropanoate, 5.5 g of 2-(2,3-epoxypropoxy)benzonitrile and 1.8 g of NaOH. The crude oil was treated with ether and butyl N-[3-(2-cyanophenoxy)-2-hydroxypropyl]-3-aminopropanoate crystallized. Yield 1.3 g. Melting point 91° C. (HCl). The structure was determined using NMR and equivalent weight.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28](=[O:40])[N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:25]([CH3:41])[NH:24][C:23]=1[CH:42]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28](=[O:40])[N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:25]([CH3:41])[NH:24][C:23]=1/[CH:42]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCC[C@H]1CN1CCCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-[2-oxo-2-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]-1H-pyrrole-2-carbaldehyde (110 mg, 1 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated, triturated with methanol, filtered and washed wit DCM to give the titled compound as a pale orange solid.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7].Cl.[CH2:27](OCC)[CH3:28]>[Cl-].[Zn+2].[Cl-]>[OH:3][CH:4]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=1)[C:6]([O:8][CH2:27][CH3:28])=[O:7]
Reactant: CCOCC
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of zinc chloride (14.7 g, 108 mmol) in diethyl ether (250 ml) was added sodium borohydride (8.2 g, 216 mmol) and the mixture was stirred at room temperature for 2 hrs. The insoluble material was filtered off. To the filtrate was added a solution of 3-oxo-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (22 g, 54 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl (2RS,3RS)-3-hydroxy-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate (15.6 g, 83%) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:61])[N:24]([C@@H:26]([C:38](=[O:60])[N:39]([C@H:41]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:42]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49][N:50]([CH3:52])[CH3:51])=[O:43])[CH3:40])[CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH3:25])[CH:18]=1)C)(C)(C)C>ClCCl>[CH2:53]([C@@H:41]([N:39]([CH3:40])[C:38]([C@H:26]([N:24]([CH3:25])[C:23](=[O:61])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][NH:14][CH3:13])[CH:18]=1)[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)=[O:60])[C:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[CH2:49][N:50]([CH3:51])[CH3:52])=[O:43])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cccc(C(=O)N(C)[C@H](Cc2ccc3ccccc3c2)C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N2CCC[C@H]2CN(C)C)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.1 %

Procedure:
At 0° C., trifluoroacetic acid (7 ml) was added to a solution of N-(3-[N-((1R)-1-{N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]benzyl}-N-methylcarbamic acid tert-butyl ester (523 mg, 0.70 mmol) in dichloromethane (7 ml). The reaction mixture was stirred for 25 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (90 ml), and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 436 mg of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8](O)[CH:9]=[CH2:10])[CH:3]=[CH2:4].Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][CH:8]([CH2:7][CH2:6][CH2:5][CH:2]([OH:1])[CH:3]=[CH2:4])[CH:9]=[CH2:10]
Reactant: CN(C)CCCl
Reactant: C=CC(O)CCCC(O)C=C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CC(O)CCCC(C=C)CCN(C)C
Yield: 57.8 %

Procedure:
A stirred mixture of 3,7-dihydroxy-nona-1,8-diene (181.5 g; 1.16 M), 2-dimethylaminoethylchloride hydrochloride (201 g; 1.4 M), powdered NaOH (163 g; 4.07 M) and toluene (2.4 l) was refluxed during 4.5 h. The reaction mixture was cooled and washed successively with H2O and sat. brine. Work-up and fractional distillation in vacuo (spinning band) gave the title compound as a colourless oil (142 g) (54%) bp. 85°-90°/0.05 Torr, GC (5% Carbowax®) 240°/4.8 min., RF 0.38 [methanol/EtOAc (9:1]; NMR (δ) 1.5 (c, 6H; aliphatic CH2), 2.21 [s, 6H; (CH3)2N], 2.49 (t, J 7 Hz, 2H; CH2N), 3.16* (bs, 1H, OH), 3.15-4.2 [c, 4H, CH2 (O) and CH(O)] and 4.9-6.2 (c, 6H; olefinic H) (*D2O exchange removes this signal); IR (cm-1) 3400 (b), 3080, 1645, 1460, 995 and 920.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.[H-].[Na+].Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:7]=[CH:6]2
Reactant: BrCCc1ccccc1
Reactant: COc1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2CCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of 5-methoxyindoline (175 mg, 1.17 mmol) in 3.6 mL of dry N,N-dimethylformamide was added sodium hydride (55%, 70 mg, 1.6 mmol) at 0° C. After the reaction mixture was stirred at the same temperature for 30 min, (2-bromoethyl)benzene (0.22 mL, 1.6 mmol) was added with additional stirring at room temperature overnight. After the reaction mixture was quenched with water at 0° C., the solution was extracted with diethyl ether (20 mL) twice. The combined extracts were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 85/15) to obtain 5-methoxy-1-phenethylindole (95 mg, 32%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[CH:39]1([NH:42][C:33](=[O:35])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:28])=[O:29])[CH:31]=2)[CH2:41][CH2:40]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 77.2 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 44 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:13]([N:10]1[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCC(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCC(N)C1
Yield: 86.6 %

Procedure:
t-Butyl-1-isopropylpyrrolidin-3-ylcarbamate (0.90 g, 3.9 mmol) obtained in Preparation Example (2-vii-1) was dissolved in dichloromethane (10 ml) in a 50 ml vessel, and trifluoroacetic acid (1.45 ml, 1.95 mmol, 5 eq.) was slowly added dropwise thereto while stirring. The resulting mixture was reacted for 18 hrs. After the completion of reaction, the reaction mixture was distilled and concentrated under reduced pressure, and then subjected to azeotropic distillation with CHCl3 3 times. The resultant was basified with aqueous 2N potassium hydroxide solution (20 ml) and extracted with CHCl3 3 times. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain 433 mg of the title compound as yellow oil (yield 86%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: OC1CCNCC1
Product: OC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 25 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 25% yield; NMR Spectrum: 1.34-1.37 (m, 2H), 1.66-1.69 (m, 2H), 2.15 (t, 2H), 2.76-2.80 (m, 4H), 4.40 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.87-7.91 (m, 2H), 8.29 (s, 1H), 8.47 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH:16]3[CH:18]([OH:19])[CH:13]2[CH2:14][CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>CN(C)C=O>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH2:27][N:11]([CH:12]2[CH2:17][CH:16]3[CH:18]([OH:19])[CH:13]2[CH2:14][CH2:15]3)[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:29][CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=S(=O)(NC1CC2CCC1C2O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN(C2CC3CCC2C3O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 49.4 %

Procedure:
A solution of 2-(4-chlorophenylsulfonamido)bicyclo[2.2.1]heptan-7-ol (604 mg, 2.0 mmol), cesium carbonate (1.30 g, 4.0 mmol), and 4-(bromomethyl)benzonitrile (471 mg, 2.4 mmol) was stirred in 10 mL dimethylformamide for 1 h. The crude reaction product was treated with additional cesium carbonate (261 mg, 0.8 mmol) and 4-(bromomethyl)benzonitrile (94 mg, 0.5 mmol) to complete the reaction. The reaction was partitioned between 50 mL ethyl acetate and 50 mL 0.1 M HCl, concentrated and purified by flash chromatography on 120 g silica gel with 30 to 50% ethyl acetate in hexane to yield N-(4-cyanobenzyl)-N-(7-hydroxybicyclo[2.2.1]heptan-2-yl)-4-chlorobenzenesulfonamide (412 mg, 49%). 1H NMR (400 MHz, CDCl3) δ ppm 7.70-7.77 (2H, m), 7.59 (2H, d, J=8.56 Hz), 7.44-7.50 (4H, m), 4.81 (2H, dd, J=39.53, 17.88 Hz), 4.06 (1H, t, J=7.81 Hz), 3.84 (1H, br. s.), 1.91 (1H, br. s.), 1.75-1.82 (2 Hon), 1.43-1.66 (3H, m), 1.07-1.17 (2H, m). LC/MS R.T.=1.97 min; [M+H]+=417.15.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(F)cc1O
Product: O=C(Nc1ccccc1)Nc1ccc(F)cc1O
Yield: 91 %

Procedure:
N-(2-Hydroxy-4-fluorophenyl)-N′-phenyl urea was prepared from 2-amino-5-fluoro phenol (200 mg, 1.57 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (352 mg, 91%). mp: 195.5-195.7° C.; 1H NMR (CD3OD/CDCl3): d 7.70 (m, 1H), 7.3 (d, 2H, J=8.25 Hz), 7.15 (t, 2H, J=8.25 Hz), 6.89 (t, 1H, J=8.25 Hz), 6.50-6.38 (m, 2H); EI-MS m/z 246 (M+H)+; Anal. (C13H11N2O2F) C, H, N.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=C(C)C(=O)OCCO
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of 2,5-di-t-butylhydroquinone (polymerization inhibitor) were added. The mixture was heated to keep about 130° C. for 3 hours in nitrogen atmosphere with distilling 23.5 ml (0.40 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 64.8 g (yield 52.4%) of 2-ethoxalyloxyethyl methacrylate (bp 95°-125° C./0.3 mmHg).