Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C(=O)N(Cl)C(=O)C1>[Br-].C([N+](C)(C)C)C1C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1.ClCCl>[CH:9](=[O:10])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(CO)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(C=O)cc1
Yield: 82.1 %

Procedure:
p-Methoxybenzyl alcohol (2.0 g, 14.5 mmol), sodium carbonate (0.9 g, 8.7 mmol), TEMPO (23 mg, 0.15 mmol), benzyltrimethylammonium bromide (0.3 g, 1.5 mmol) and dichloromethane (15 ml) were put in a 50-ml egg plant type flask. The suspension was cooled to less than 10° C. in an ice bath and thereto was added NCS (2.1 g, 16 mmol) divided in two portions. The insoluble materials were filtered off and the filtrate was washed with 5% aqueous sodium bicarbonate solution. The crude product was purified by distillation to give p-anisaldehyde (1.62 g, yield 82%).
Reaction SMILES: C1(C2N=C(/C=C/C3C=C(N)C=CC=3)SC=2)CCC1.[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25](CC(O)=O)=[C:24]([O:32][CH3:33])[CH:23]=1>C(Cl)Cl>[CH3:19][O:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:32][CH3:33])[CH:23]=1
Reactant: COC(=O)c1ccc(CC(=O)O)c(OC)c1
Agent: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(OC)c1
Reaction time: 16 h

Procedure:
A solution composed of 0.49 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.43 g of 4-carboxymethyl-3-methoxybenzoic acid methyl ester, 0.4 g of N-ethyl-N-(dimethylaminopropyl)carbodiimide and 25 ml of methylene chloride was sealed in a flask and stored at 25° C. for 16 hr. The reaction mixture was then washed with 10 ml of water, dried (MgSO4) and the solvent removed by rotary evaporation. The residual material was purified by silica gel chromatography using ethyl acetate as the eluant to yield 0.62 g of (E)-4-[2-[3-[2-(4-cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]-3-methoxybenzoic acid methyl ester; m.p., 156°-157° C. from ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][NH:4][C:5]([C:7]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2Br)[N:11]2[CH:12]=[N:13][CH:14]=[C:10]2[CH2:9][CH2:8]1)=[O:6].CNCCNC.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.C1COCC1>[O:6]=[C:5]1[C:7]2([N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][CH2:8]2)[C:15]2[C:20](=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[N:4]1[CH2:3][C:2]([F:25])([F:24])[F:1]
Reactant: N#Cc1ccc(C2(C(=O)NCC(F)(F)F)CCc3cncn32)c(Br)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)N(CC(F)(F)F)C(=O)C21CCc2cncn21
Temperature: 110 °C

Procedure:
A suspension of 5-(2-Bromo-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (2,2,2-trifluoroethyl)amide (0.168 g, 0.405 mmol), given in example 9, CuI (0.004 g, 0.021 mmol), N,N′-dimethylethylene diamine (0.005 mL, 0.042 mmol), Cs2CO3 (0.198 g, 0.609 mmol), and THF (15 mL) is heated to 110° C. for 60 h. The mixture is then filtered and concentrated. The residue is purified via flash chromatography (EtOAc/hexanes) to give 1,2,6′,7′-Tetrahydro-2-oxo-1-(2,2,2-trifluoroethyl)spiro[3H-indole-3,5′-[5H]pyrrolo[1,2-c]imidazole]-6-carbonitrile. MS (ESI) m/z 333.1 (M+H); NMR (400 MHz, CDCl3) δ ppm 2.85-2.96 (m, 1H), 3.03-3.18 (m, 2H), 3.27-3.39 (m, 1H), 4.20-4.34 (m, 1H), 4.43-4.57 (m, 1H), 6.86 (s, 1H), 7.04 (s, 1H), 7.30 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.52 (dd, J=7.6, 1.3 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 0.25 h

Procedure:
Triethylamine (10 cc) is added with stirring to a solution, cooled to a temperature in the region of 5° C., of 10-(1-hydroxy-2-propyl)-2-phenothiazinecarbonitrile, L series (12.6 g) in methylene chloride (126 cc), a solution of methanesulphonyl chloride (5.6 cc) in methylene chloride (56 cc) is then added dropwise during 25 minutes, and stirring is continued for 1 hour 15 minutes at a temperature in the region of 10-15° C. The reaction mixture is washed successively with distilled water (2×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40 C. 2-(2-cyano-10-phenothiazinyl)-1-propyl methanesulphonate, L series (16.2 g) is thereby obtained in the form of an orange oil.([α]20D =+29.9±0.3°; 2.4%; chloroform), which is used without further purification for the next stage of the synthesis.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:52][CH3:53])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:34][C:35]2[CH:36]=[C:37]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=2)[O:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].[OH-].[Na+:55]>C(O)C>[Na+:55].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:52][CH3:53])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:34][C:35]2[CH:36]=[C:37]([CH:45]=[C:46]([C:48]([F:51])([F:49])[F:50])[CH:47]=2)[O:38][CH2:39][CH2:40][CH2:41][C:42]([O-:44])=[O:43])[C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(OCCCC(=O)O)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(OCCCC(=O)[O-])cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
4-(3-{[(5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyric acid (69 mg) is dissolved in ethanol (1 ml) and thereto is added a 1M-aqueous sodium hydroxide solution (92 μl) and the mixture is stirred at room temperature for 3 minutes, and concentrated under reduced pressure to give 4-(3-{[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyric acid sodium salt (66 mg). MS (m/z): 745 [M−Na]+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:44]I>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][I:44])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(OCc1ccccc1)N1CCC(CCI)CC1
Temperature: 0 °C

Procedure:
A solution of 3-2(263 g, 116 mmol) was treated with triphenylphosphine (33.5 g, 128 mmol), imidazole (11.9 g, 175 mmol) and cooled to 0° C. Iodine (32.4 g, 128 mmol) was added and the ice bath was removed. The reaction was filtered into a separatory funnel and the solution was washed with H2O and brine, dried over MgSO4 and concentrated. The residue was chromatographed (10% EtOAc/Hexanes) to give 3-3 as a colorless oil. Rf (20% EtOAc/Hexanes) 0.56 1H NMR (300 MHz, CDCl3) δ 7.4-7.1 (m, 5H), 5.2-5.05 (bs, 2H), 4.3-4.1 (bs, 2H), 3.2 (t, 2H), 2.8 (bs, 2H), 1.8-1.5 (m, 5H), 1.15 (m, 2H). ##STR31## 2(N-t-Butyloxycarbonylaminopiperidin-4-yl)ethanol (4-1)
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH3:16].[Li+].[OH-]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:17])=[O:2])=[C:7]([O:13][CH2:14][CH2:15][CH3:16])[CH:8]=1
Reactant: CCCOc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCCOc1cc(F)ccc1C=CC(=O)O
Yield: 92.7 %

Procedure:
3-(4-Fluoro-2-propoxy-phenyl)-acrylic acid methyl ester (134 mg, 0.563 mmol) was reacted with aqueous 1N LiOH (5 ml) as described above to yield title compound (117 mg, 92%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:16]=[C:15](Cl)[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:16]=[C:15]([C:22]4[CH:21]=[CH:20][C:19]([Cl:18])=[C:24]([Cl:25])[CH:23]=4)[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Clc1ccc2ncnc(N3CCOCC3)c2n1
Product: Clc1ccc(-c2ccc3ncnc(N4CCOCC4)c3n2)cc1Cl
Yield: 97 %

Procedure:
The reaction of 4-morpholino-6-chloro-pyrido[3,2-d]pyrimidine and 3,4-dichlorophenylboronic acid afforded the pure title compound (yield 97%) as a yellowish solid which was characterized by its mass spectrum as follows: MS (m/z): 361.2 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:20][CH3:21])[C:3](=[O:19])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][N:7]1CC1C=CC=CC=1)=[O:5]>CCO.[Pd]>[CH3:1][C:2]([CH3:22])([CH2:20][CH3:21])[C:3](=[O:19])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][NH:7]1)=[O:5]
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1

Procedure:
1 g 10% Pd/C was added to a solution of 3,3-dimethyl-1-[2-benzylperhydropyridazinyl]pentane-1,2-dione (7.0 g, 20.2 mmol) in 70 ml EtOH. The mixture was under hydrogenation at room pressure (1 atm) overnight. The product was obtained as white solid after filtering Pd catalyst and concentration (3.8 g, 89%). 1H NMR (CDCl3, 400 MHz) δ 0.88 (t, 3H, J=7.0); 1.19 (s, 6H); 1.65 (m, 4H); 1.79 (m, 2H); 2.85 (m, 2H); 3.42 (m, 1H); 3.56 (m, 1H).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([C:40]2[CH:44]=[CH:43][S:42][C:41]=2[CH:45]=O)(=[O:39])=[O:38])[CH:32]=1>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:45][C:41]2[S:42][CH:43]=[CH:44][C:40]=2[S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])=[C:20]1[CH3:29]
Reactant: O=Cc1sccc1S(=O)(=O)c1cccnc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2cccnc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.7 %

Procedure:
A mixture of triethylsilane (0.42 g), trifluoroacetic acid (0.25 g) and 1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.055 g), 3-(pyridine-3-sulfonyl)thiophene-2-carbaldehyde (0.075 g) and 1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred at room temperature for 20 hours. The mixture was treated with additional triethylsilane (0.42 g) and trifluoroacetic acid (0.25 g), and stirred at room temperature for 3 hours and then at 50° C. for 20 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of diethyl ether and ethyl acetate (1:0 to 0:1 by volume), followed by trituration with diethyl ether to afford the title compound as a white solid (0.027 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]([OH:15])[OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>[OH-].[Na+].O1CCOCC1>[CH2:20]([O:19][C:17]([NH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]([OH:15])[OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(Cc1ccc(B(O)O)cc1)C(=O)O)OCc1ccccc1

Procedure:
3.0 g (14.4 mmol) of 2-amino-3-(4-boronophenyl)propionic acid were dissolved in 120 ml 0.4 N NaOH solution and diluted with 120 ml 1,4-dioxane. 2.05 ml benzyl chloroformate (14.4 mmol) in 15 ml 1,4-dioxane were added slowly at −15° C. The reaction mixture was allowed to come to room temperature over night and the organic solvent was removed under reduced pressure. After extracting the acidified remaining aqueous phase with ethyl acetate and drying this organic phase over Na2SO4 the solvent was removed under reduced pressure. The crude product was recrystallized from acetonitrile.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:30]([OH:32])[CH3:31])[C:26]([F:29])=[N:27][CH:28]=1>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[C:25]([C:30](=[O:32])[CH3:31])[C:26]([F:29])=[N:27][CH:28]=1
Reactant: CC(O)c1cc(Br)cnc1F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.9 %

Procedure:
A solution of pyridinium dichromate (55.4 g, 147 mmol) in DCM (100 mL) was brought to 0° C. and a solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethanol (10.8 g, 49.1 mmol) in DCM (30 mL) was added. The reaction was allowed to warmed to room temperature and stirred for 48 h. The mixture was filtered through Celite, washed with DCM and concentrated to afford 1-(5-bromo-2-fluoropyridin-3-yl)ethanone (11 g, 51 mmol, 100% yield) as a light yellow solid. LC/MS (ESI+) m/z=218 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[N:29]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(N1CCN2CCN(CCCC)P1N(CCCC)CC2)CCC.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:37][CH2:36][CH2:35][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: NCCN1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(NCCN4CCOCC4)ccc2OCC3)c(F)c1
Temperature: 120 °C
Reaction time: 0.1 h
Yield: 12.8 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), 2-Morpholin-4-yl-ethylamine (200 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 6 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 47 mg of 132. (yield=13%). 1H NMR (CDCl3, 400 MHz): δ8.01 (s, 1H), 7.50-7.44 (m, 1H), 7.05-6.97 (m, 4H), 6.23-6.21 (d, J=8.4 Hz, 1H), 4.76-4.74 (m, 1H), 4.17-4.14 (m, 2H), 3.68-3.66 (m, 4H), 3.30-3.26 (m, 2H), 3.04-3.02 (m, 2H), 2.55-2.52 (m, 2H), 2.48-2.42 (m, 4H). LC-MS (ESI): m/z=511 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[CH:22]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH2:42])[CH2:35]2)[N:20]=1>C1COCC1>[NH2:18][C:19]1[N:20]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH:42][S:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:16])=[O:15])[CH2:35]2)[CH:22]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[N:24]=1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (0.05 mL, 0.36 mmol) and benzenesulfonyl chloride (0.04 mL, 0.31 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (99 mg, 0.29 mmol) in THF (3 mL), and the mixture was stirred at room temperature under nitrogen for 45 minutes. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a yellow oil. LC-MS (ES) m/z=483 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:5]([CH:9]=[N:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=NCCc2ccccc2)c1OCCCN1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CNCCc2ccccc2)c1OCCCN1CCOCC1
Yield: 80.5 %

Procedure:
N-[[3-Methoxy-2-[3-(4-morpholinyl)propoxy]-phenyl]methylene]benzeneethanamine (49.7 g) is reduced with 14.8 g of sodium borohydride in 225 ml. of methanol following the procedure described in Example 1C, yielding 40.2 g of the title compound, boiling point 0.2-0.3 mm of Hg.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16].C(N(CC)CC)C>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:17][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C#CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 22 h
Yield: 87 %

Procedure:
p-Toluenesulfonyl chloride (21.4 g, 112 mmol) was added slowly to a stirred solution of 4-pentyn-1-ol (11.5 mL, 124 mL) and triethylamine (17.2 mL, 124 mmol) in dichloromethane (100 mL) at room temperature. After 22 hours, the solution was diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 95:5 to 85:15 hexanes/ethyl acetate) to afford the product pent-4-ynyl 4-methylbenzenesulfonate (23.4 g, 87%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cl)cc1Oc1ccc(C=O)c2ccccc12
Yield: 55.2 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.31 g, 2.0 mmol), 4-hydroxy-1-naphthaldehyde (0.34 g, 2.0 mmol) and cesium carbonate (0.64 g, 2.0 mmol) were heated with stirring in dry DMF (4 mL) at ambient temperature for 10 days. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(4-formylnaphthalen-1-yloxy)benzonitrile (0.34 g, 56%) as a tan solid, which was used without further purification.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:12]1
Reactant: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 12 h
Yield: 82 %

Procedure:
To a 23° C. solution of 8.66 g (33.7 mmol) 3-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-indole and 200 mL THF was added 200 mL of 1N HCl. After stirring for 12 h, the organics were evaporated and the resulting slurry was extracted with 2×150 mL EtOAc. The combined organics were washed with 2×100 mL of 1N NaOH, dried over MgSO4, filtered and evaporated to an off-white solid. Flash chromatography on silica gel, eluting with hexanes/EtOAc (1/1) gave 5.89 g (27.6 mmol, an 82% yield) of the title compound as a white solid. mp 123-125° C.; MS (ES) m/z (relative intensity): 214 (M++H, 100.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=O)[CH2:6][CH2:5]1.[C:15]1(C)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:4]12[CH2:3][CH2:2][C:7]([C:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[OH:12])([CH2:6][CH2:5]1)[CH2:8][CH2:9]2
Reactant: CCOC(=O)C1CCN(CCCl)CC1
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Temperature: -15 °C
Yield: 57 %

Procedure:
Ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (199 g, for example, as prepared by Example 1) in water (800 ml) was added to toluene (2000 ml) and potassium carbonate (118 g) in water (800 ml) and rinsed in with water (400 ml). The mixture was stirred until a biphasic solution was obtained. The aqueous layer was separated and extracted with toluene (3000 ml). The combined organic layers were concentrated to 4000 ml by vacuum distillation. This solution was added to 0.5 M potassium hexamethyldisilazide in toluene (1700 ml) and toluene (2000 ml) at 40° C. Acetic acid (178 ml) was added, the mixture concentrated to 4000 ml by vacuum distillation and added to an 18% w/w aqueous potassium carbonate solution (2432 g). The layers were separated, the organic layer was concentrated to 3000 ml by vacuum distillation and toluene (1000 ml) added. The solution was cooled to −15° C. and 2M phenyl lithium in dibutyl ether (800 ml) added. Water (2000 ml) and n-butanol (700 ml) were added and the mixture heated to 75° C. The aqueous layer was removed and the organic layer washed with water (1000 ml). Toluene (1000 ml) was added and mixture distilled until 3000 ml of solvent had been removed, then cooled to 20° C. and stirred overnight. The product was filtered, washed with toluene (2×200 ml) and dried under vacuum at 40° C. to give a white solid (131 g, 57%). EI-MS m/z 294 (M+H+) Rt (3.6 min).