Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.C(#N)C.[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>CCOCC>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH2:28][CH3:29])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CCN1CCCC1CN
Solvent: CC#N
Solvent: CCOCC
Product: CCN1CCCC1CNC(=O)CCn1cnc2c(=O)[nH]cnc21
Reaction time: 17 h
Yield: 43.1 %

Procedure:
3-(1.6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (250 mg. 1.06 mol) (AIT-0027) was placed into a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser and CaCl2 drying tube. Then 3 ml acetonitrile and 280 mg (2.18 mmol) 2-(aminomethyl)-1-ethyl-pyrrolidine were added and the solution was heated to reflux. Not all of the ester dissolved at reflux, but as the reaction proceeded, the solution became homogeneous. Reflux was continued for 17 hours, at which time the solvent had completely evaporated. The residue was treated with acetonitrile and allowed to cool. A white precipitate had formed. Ether was added and the solution was stirred to wash the precipitate. The solution was filtered by Buchner vacuum filtration and the precipitate was washed with ether. Upon drying, 300 mg (0.94 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]propanamide (AIT-0029) was obtained as an off-white solid.
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[Cl:5][C:6]1[C:11]2[CH2:12][NH:13][CH2:14][CH2:15][S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.Cl.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:11]2[CH2:12][N:13]([S:2]([CH3:1])=[O:3])[CH2:14][CH2:15][S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cccc2c1CNCCS2
Reactant: CS(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphinyl chloride (0.98 g) in dichloromethane (10 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane/ethanol (98:2) as eluent gave 6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethylacetate/hexane. Yield 2.1 g (m.p. 82°-84° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH:9]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][OH:15])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>C(#N)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:15][CH2:14][CH2:13][N:12]([CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: CC(C)N(CCO)C(C)C
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Solvent: CC#N
Product: CC(C)N(CCOc1cc(Cl)ncn1)C(C)C
Temperature: 180 °C
Yield: 20.2 %

Procedure:
A mixture of 4,6-dichloropyrimidine (0.5 g, 3.4 mmol), 2-(diisopropylamino)ethanol (0.44 g, 3.0 mmol), and cesium carbonate (2.18 g, 6.7 mmol) in butyronitrile (4 mL) was heated in a microwave oven at 180° C. for 20 min. Filtration followed by purification using preparative HPLC (XTerra®PrepMS C8 column 10 μm, 30×150 mm; 0.1 M NH4OAc buffer/acetonitrile, (80:20-20:80), as the eluent) gave 0.156 g (20% yield) of the title compound: MS (ESP) m/z 258 (M++1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([CH3:32])[NH:27]1>>[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([CH3:32])[N:27]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1
Reactant: C[C@@H]1CCC[C@H](C)N1
Product: C[C@@H]1CCC[C@H](C)N1CCCOc1ccc(-c2ccc(C(=O)N3CCCC3)cc2)cc1

Procedure:
The product from Example 11A and (2R,6S)-2,6-dimethylpiperidine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)[CH2:3][C:4]#[N:5].[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19]>>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=1)[CH2:3][C:4]#[N:5]
Reactant: CCCCC=O
Reactant: N#CCC(O)c1cccc([N+](=O)[O-])c1
Product: CCCCCNc1cccc(C(O)CC#N)c1

Procedure:
Hydrogenation of nitrobenzene 11 (0.8 g, 4.2 mmol) and pentanal (0.45 ml, 4.2 mmol) following method described in Example 11 gave 3-hydroxy-3-(3-(pentylamino)phenyl)propanenitrile as a light yellow oil. Yield (0.90 g, 77%).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:16][CH3:17])(=O)C.P(Cl)(OCC)(OCC)=O.[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][NH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.CO.C(Cl)Cl.C(N(CC)CC)C>[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][N:31]([C@H:32]1[CH2:33][CH2:34][C@H:35]([CH3:38])[CH2:36][CH2:37]1)[C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:14]=[CH:15][C:5]([OH:4])=[C:6]([O:16][CH3:17])[CH:7]=1
Reactant: COc1cc(C=CC(=O)O)ccc1OC(C)=O
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)ccc1O

Procedure:
Using 2.5 g of 4-acetoxy-3-methoxycinnamic acid, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), 0.5 g of 4-dimethylaminopyridine, 100 ml of methanol, and 3 g of potassium carbonate, a reaction similar to that conducted in Example 73 was carried out. As a result, 1.8 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1.S(Cl)([Cl:39])=O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:39])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Solvent: c1ccncc1
Product: Cc1cc(C(Cl)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Yield: 75 %

Procedure:
At room temperature, 8.0 g of N-[2,6-dimethyl-4-{1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl}phenyl]3-(benzoylamino)benzamide and 1.0 g of pyridine were introduced to 40 ml of thionyl chloride. Thereafter, the mixture was heated and stirred under a reflux condition. After disappearance of the starting raw material was confirmed by means of TLC, the reaction solution was cooled down and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography using an eluent (development solvent; hexane:ethyl acetate=3:1) to obtain 6.2 g of the desired product (Yield: 75%) in the form of powder.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[NH:9][CH:8]=1)C.CO.[OH-].[Na+].Cl>O1CCCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH:5]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:4]([OH:32])=[O:3]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(Br)cc23)C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(Br)cc23)C(=O)O)cc1
Reaction time: 10 h
Yield: 93.9 %

Procedure:
2-(4-But-2-ynyloxy-benzenesulfonylamino)-3-(5-bromo-1H-indol-3-yl)-propionic acid ethyl ester (0.100 g, 0.193 mmol) was dissolved in 0.5 mL tetrahydrofuran. To the solution was added MeOH (0.5 mL) and 1 N NaOH (0.4 mL, 0.4 mmol). The reaction mixture was placed in a shaker for 10 hours at room temperature. The solution was acidified with 1N HCl and extracted with ethyl acetate (3×3 mL). The organic solution was concentrated and the residue was purified by RP-HPLC to give 0.089 g (94%) of the title compound as a pale yellow solid. 1H NMR (DMSO-d6): 400 MHz δ 12.65 (bs, 1H), 11.01 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.48 (m, 3H), 7.26 (d, J=8.8 Hz, 1H), 7.13 (m, 2H), 6.89 (d, J=9.2 Hz, 2H), 4.77 (q, J=2.8 Hz, 2H), 3.82 (q, J=8.4 Hz, 1H), 3.01 (dd J=14.6, 6.4 Hz, 1H), 2.82 (dd J=14.6, 8.0 Hz, 1H), 1.83 (t, J=2.4 Hz, 3H); HRMS: calcd for C21H20BrN2O5S (ESI+, Br79, [M+H]1+), 491.0271; found 491.0287; LCMS m/z (ESI) [M−H] 489 (Br79), retention time=2.75 min.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][N:27](C)[C:28]1C=CC(C#N)=CC=1.N[C@H](C(O)=O)CS>>[CH3:26][N:27]([CH3:28])[C:4]1[CH:5]=[CH:6][C:1]([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[N:11]=2)=[CH:2][CH:3]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Reactant: CN(C)c1ccc(C#N)cc1
Agent: N[C@@H](CS)C(=O)O
Product: COc1cc(C(=O)c2csc(-c3ccc(N(C)C)cc3)n2)cc(OC)c1OC

Procedure:
(2-(4-(Dimethylamino)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (2o) was prepared using the same method as used of compound 1h from 4-(dimethylamino)benzonitrile and cysteine. 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.88 (d, 2H), 7.80 (s, 2H), 6.73 (d, 2H), 3.96 (s, 3H), 3.95 (s, 6H), 3.05 (s, 6H); MS (ESI) m/z 421.1 (M+Na)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][N:15]=[C:14]4[CH:21]=[CH:22][S:23][C:13]=34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O.[OH-].[Na+]>CC(C)=O>[N+:18]([C:17]1[C:12]([NH:11][CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[C:13]2[S:23][CH:22]=[CH:21][C:14]2=[N:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1NC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
A mixture of N-1,4-dioxaspiro[4.5]dec-8-yl-6-nitrothieno[3,2-b]pyridin-7-amine (0.45 g, 1.3 mmol) and 3.0 M hydrogen chloride in water (9 mL, 30 mmol) in acetone (20 mL) was stirred at room temperature for 20 min and then at 60° C. for 1 h. The mixture was basified with aq. 5M NaOH solution at 0° C., then extracted with EtOAc. The combined organic layers were dried over sodium sulfate, concentrated and purified on silica gel column (eluting with 0-30% of EtOAc in methylene chloride) to give the desired product (0.2 g, 51% in 2 steps). LCMS calculated for C13H14N3O3S (M+H)+: m/z=292.1. Found: 292.0.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18](OC)=[O:19])[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH3:24]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH2:24])=[O:19])[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12
Reactant: N
Product: NC(=O)c1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12

Procedure:
Following standard procedure C, the acetate salt of methyl 2-(3′-trifluoromethylphenyl)-1-H-benzimidazole-4-carboxylate (134.8 mg, 0.358 mmol) was treated with excess liquid ammonia in a sealed vessel. The product was purified by recrystallisation from methanol, to yield off-white needles. (78 mg, 72%). mp 268-270° C.; Found C 57.68 H 3.82 N 12.96 C15H10F3N3O.0.6CH3OH Requires C 57.74 H 3.82 N 12.95; vmax(cm−1) 3488.83, 3348.86, 3176.45, 1667.66, 1600.93, 1329.63; δH 7.44-7.52 (1H, t), 7.88-8.04 (5H, m), 8.66-8.70 (1H, d), 8.70 (1H, s, 2′ H), 9.3 (1H, br s, NH), 13.6 (1H, br s, NH); m/z (EI) 305 (M+), 288, 260, 145.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5](=[O:18])[C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH3:9])[CH3:8].[BH4-].[K+]>CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C@H:5]([OH:18])[C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)CC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl ester 45 (2.4 g, 8.70 mmol) in HPLC MeOH (100 mL), cooled to −78° C., potassium borohydride (1.4 g, 26.1 mmol) was added in portions. The reaction mixture was stirred at −78° C. for 10 min, warmed to −20° C. for 30 min and then to 0° C. for 10 min. The reaction was quenched with acetic acid to pH=7 and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with NaHCO3 (50 mL, sat), NaCl (50 mL, sat), dried (Na2SO4), filtered, and evaporated. The alcohol 46 was obtained as a colorless oil (2.2 g, 92%) and used directly in the next step. 1H-NMR (500 MHz, CDCl3): 0.88 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 1.44 (s, 9H), 2.03-2.17 (m, 1H), 2.41-2.52 (m, 1H), 2.58-2.63 (m, 1H), 3.50-3.55 (m, 1H), 3.71 (s, 3H), 3.89-3.93 (m, 1H), 3.38-3.41 (m, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:8][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:10][CH:11]=1)=O)C.C(OC(=O)C(C(=O)C1C=CC(C)=CC=1)=[CH:32][N:33](C)[CH3:34])C.Cl.FC1C=CC(CC(N)=N)=CC=1.CCN(CC)CC>CCO.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:9]2[N:8]=[C:7]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[C:6]([CH2:4][N:33]([CH3:34])[CH3:32])=[CH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cnc(Cc2ccc(F)cc2)nc1-c1ccc(C)cc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C)cc1
Agent: Cl
Agent: N=C(N)Cc1ccc(F)cc1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc(Cc3ccc(F)cc3)ncc2CN(C)C)cc1
Yield: 74 %

Procedure:
2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidine-5-carboxylic acid ethyl ester. To solution of 3-dimethylamino-2-(4-methyl-benzoyl)-acrylic acid ethyl ester (Tetrahedron, 2002, 58, 8581-8589; 0.567 g, 2.15 mmol) in EtOH (10 mL) was added 2-(4-fluoro-phenyl)-acetamidine hydrochloride (0.405 g, 2.15 mmol) and Et3N (0.90 mL, 6.5 mmol). The mixture was heated at reflux for 18 h, and then was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (5-20% EtOAc/hexanes) to give 0.560 g (74%) of the title compound. MS (ESI): exact mass calcd. for C21H19FN2O2, 350.14; m/z found, 351.4 [M+H]+. 1H NMR (CDCl3): 8.97 (s, 1H), 7.51 (d, J=8.2, 2H), 7.38-7.35 (m, 2H), 7.27-7.26 (m, 2H), 7.01-6.97 (m, 2H), 4.32 (s, 2H), 4.23 (q, J=7.1, 2H), 2.42 (s, 3H), 1.16 (t, J=7.1, 3H). Step B. [2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-yl]-methanol. To a 0° C. solution of the product from Step A (0.606 g, 1.73 mmol) in THF (8 mL) was added DIBAL-H (1.5 M in toluene; 2.5 mL, 3.8 mmol). The mixture was allowed to warm to rt, and was stirred for 18 h. The mixture was diluted with 20% aq. sodium potassium tartrate and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (40-60% EtOAc/hexanes) to give 0.330 g (62%) of the title compound. MS (ESI): exact mass calcd. for C19H17FN2O, 308.13; m/z found, 309.4 [M+H]+. 1H NMR (CDCl3): 8.77 (s, 1H), 7.58 (d, J=8.0, 2H), 7.38-7.35 (m, 2H), 7.29 (d, J=7.9, 2H), 6.99-6.96 (m, 2H), 4.70 (s, 2H), 4.29 (s, 2H), 2.42 (s, 3H). Step C. The title compound was prepared using the methods described in Example 112, Step C. MS (ESI): exact mass calcd. for C21H22FN3, 335.18; m/z found, 336.4 [M+H]+. 1H NMR (CDCl3): 8.67 (s, 1H), 7.69 (d, J=8.1, 2H), 7.40-7.36 (m, 2H), 7.29 (d, J=7.9, 2H), 7.01-6.96 (m, 2H), 4.29 (s, 2H), 3.36 (s, 2H), 2.42 (s, 3H), 2.22 (s, 6H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10]3([CH2:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](Br)[CH:18]=4)[O:13]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O>>[CH3:29][O:28][C:24](=[O:27])/[CH:25]=[CH:26]/[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[O:13][C:10]1([CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]1)[CH2:21][C:20]2=[O:22]
Reactant: O=C1CC2(CCN(c3ccccc3)CC2)Oc2ccc(Br)cc21
Reactant: C=CC(=O)OC
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(c3ccccc3)CC1)O2

Procedure:
(E)-3-{1′-Phenyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester was synthesized starting from 1′-phenyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one (650 mg, 1.75 mmol) and methyl acrylate (541 mg, 6.2 mmol) according to the procedure described for Intermediate 1, Step B, giving 541 mg of the product.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)C.[ClH:32].[OH:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[OH:43])[CH2:37][CH2:38][NH2:39].C(O)CCC>O>[ClH:32].[CH2:22]([O:21][C:19]([N:6]([CH2:5][CH:4]1[C:40]2[C:36](=[CH:35][C:34]([OH:33])=[C:42]([OH:43])[CH:41]=2)[CH2:37][CH2:38][NH:39]1)[C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1cc(OC)c(OC)c(OC)c1)OCC
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: COc1cc(N(CC2NCCc3cc(O)c(O)cc32)C(=O)OCc2ccccc2)cc(OC)c1OC
Yield: 70.1 %

Procedure:
N-benzyloxycarbonyl-3,4,5-trimethoxyanilinoacetaldehyde diethyl acetal (21 g) and 3,4-dihydroxyphenethylamine hydrochloride (8.3 g) were added to a mixture of n-butyl alcohol (210 ml) and water (30 ml) and then the mixture was refluxed for 11 hours in a stream of nitrogen. In the course of the reaction, amounts of the above-mentioned acetal (2.1 g, 2.1 g and 4.2 g) were added to the mixture after 5 hours, 6 hours and 7 hours, respectively, from the beginning of the reaction, respectively. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ether and acetone to give 1-(N-benzyloxycarbonyl-3,4,5-trimethoxyanilinomethyl)-6,7-dihydroxy,1,2,3,4-tetrahydroisoquinoline hydrochloride (16.3 g). The product was recrystallized from a mixed solvent of ethanol and ether to give a pure product, mp 197° to 199° C. (dec).
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=3[F:23])[CH2:10][CH2:9]2)[O:5][C:4]1=[O:24])[CH3:2].O.O.Cl[Sn]Cl>CO>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:6]3[O:5][C:4](=[O:24])[N:3]([CH2:1][CH3:2])[N:7]=3)[CH2:9][CH2:10]2)=[C:15]([F:23])[CH:16]=1
Reactant: CCn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)oc1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CCn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Yield: 571.3 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.23 g, 4 mmol) on reacting with C2H5Br (0.53 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-ethyl-5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6e, 1.27 g, 95%). Nitro compound (6e, 1.34 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution, is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 g, 1.05 g, 86%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzo triazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7g, 0.3 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-3-fluorophenyl-5-nitro-2-furamide (8 g, 391 mg, 88%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40](NC1N=C(C2C=CC=C(C)N=2)C=C(C2C=NC=C(Br)C=2)C=1)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:40])[N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2cc(-c3cncc(Br)c3)cc(NCc3ccccc3)n2)n1
Reactant: CC(C)(C)N1CCN(CC#Cc2cncc(-c3cc(NCc4ccccc4)nc(-c4ccccn4)c3)c2)CC1
Product: Cc1cccc(-c2cc(-c3cncc(C#CCN4CCN(C(C)(C)C)CC4)c3)cc(NCc3ccccc3)n2)n1

Procedure:
This compound is prepared analogously to Benzyl-{5″-[3-(4-tert-butyl-piperazin-1-yl)-prop-1-ynyl]-[2,2′;4′,3″]terpyridin-6′-yl}-amine (Example 2.138) by replacing Benzyl-(5″-bromo-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 1.25) with Benzyl-(5″-bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 2.40, step1).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[CH2:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:38][S:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[Cl:28])(=[O:37])=[O:36])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)O)ccc32)c1
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: CC(C)COC(=O)Nc1cccc(Cn2ccc3cc(C(=O)NS(=O)(=O)c4ccccc4Cl)ccc32)c1

Procedure:
Using a similar procedure to that described in Example 29, the carboxylic acid (Example 28) was reacted with 2-chlorobenzene sulphonamide to give N-{1-[3-(isobutoxycarbonylamino)benzyl]indol-5-ylcarbonyl}-2-chlorobenzene sulphonamide.