Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:18].[K+].[K+].O>CS(C)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:11])([CH3:12])[CH2:8][C:9]([NH2:10])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)(CC#N)Oc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(CC(N)=O)Oc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 3-(4-chlorophenoxy)-3-methylbutyronitrile (60.4 mmol) in DMSO (75 mL) is treated with H2O2 (50% w/w) (434 mmol) and potassium carbonate (121 mmol) at zero degrees Celsius. The reaction mixture is stirred at room temperature over the weekend. The reaction mixture is transferred into a separatory funnel using water (100 mL) and CH2Cl2 (200 mL). The mixture is equilibrated and the CH2Cl2 layer is removed. The aqueous layer is extracted two additional times with CH2Cl2 (2×300 mL). The combined CH2Cl2 extracts are washed 5 consecutive times with water (5×200 mL) followed by a brine (500 mL) wash, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure, which affords 3-(4-chlorophenoxy)-3-methylbutyramide.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: ON=C(Cl)Cc1ccc(CCC2CCCO2)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(CCC3CCCO3)cc2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (43.7 mg, 0.37 mmol) was added (4-(2-tetrahydrofuran-2-yl-ethyl) phenyl)-acetohydroximoyl chloride (300 mg, 1.12 mmol) described in Manufacturing Example 82-1-6 under nitrogen atmosphere at room temperature. Triethylamine (0.31 mL, 2.24 mmol) was then added dropwise and stirred for 2 hours at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:9 then 3:7) to obtain the title compound (68 mg, 53%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[NH:23]1[C:24]2[C:20](=[C:19]([NH:18][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)[CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(Nc2cccc3[nH]ccc23)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-aminoindole (38 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (6 mg, 9%). 1H NMR (CDCl3): 9.75–9.74 (m, 1H), 8.77–8.73 (m, 1H), 8.69 (dd, J=1.8, 5.1 Hz, 1H), 8.57 (s, 1H), 8.08 (s, 1H), 7.44–7.38 (m, 2H), 7.31–7.23 (m, 3H), 6.85 (s, 1H), 6.50–6.48 (m, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](O)(=[O:25])C.CCCCCC>CO.ClCCl>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([O:25][CH3:23])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)n2nc(SCc3ccccc3)nc2c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)cc2nc(SCc3ccccc3)nn12
Reaction time: 4 h

Procedure:
A mixture of 2-benzylthio-5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridine (5.0 g, 0.017 mol), sodium methoxide in methanol (16 mL of 25 percent, 3.7 g, 0.070 mol) and methanol (100 mL) were heated at reflux with stirring for 4 hours. The reaction mixture was then cooled, acidified with acetic acid (10 mL), and concentrated by evaporation under reduced pressure. The residue obtained was dissolved in dichloromethane and the resulting solution was washed well with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue obtained was mixed with hexane and filtered to recover the solids. The solids were dried to obtain 4.7 g (97 percent of theory) of the title compound as a tan powder melting at 85°-87° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:15]1([CH2:20][C:21](O)=[O:22])[CH:19]=[CH:18][N:17]=[CH:16]1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[N:15]1([CH2:20][C:21]([NH:1][C:2]2[C:3]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:22])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: O=C(O)Cn1ccnc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cn1ccnc1)Nc1cccnc1Nc1ccccc1
Yield: 25.3 %

Procedure:
To a mixture of 3-amino-2-anilinopyridine (0.5 g), 2-(imidazol-1-yl)acetic acid (0.38 g) and pyridine (0.24 ml) in chloroform (5 ml) was dropwise added phosphorus oxychloride (0.28 ml) and the mixture was refluxed for 1.5 hours. After being cooled, the reaction mixture was decanted and the residue was poured into saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The combined extract was dried over magnesiumsulfate and the solvent was evaporated under reduced pressure. The resultant residue was triturated in ethyl acetate (10 ml) to give 2-(imidazol-1-yl)-N-(2-anilinopyridin 3-yl)acetamide (200 mg).
Reaction SMILES: C([O:8][CH:9]1[C:10](=[O:41])[NH:11][C:12]2[C:17]([C:18]3[CH:19]=[CH:20][N:21]=[C:22]([CH:35]=3)[C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:24][CH:25]=[CH:26]1)=[CH:16][CH:15]=[C:14]([NH:36][C:37]([O:39][CH3:40])=[O:38])[CH:13]=2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[OH:8][CH:9]1[C:10](=[O:41])[NH:11][C:12]2[CH:13]=[C:14]([NH:36][C:37]([O:39][CH3:40])=[O:38])[CH:15]=[CH:16][C:17]=2[C:18]2[CH:35]=[C:22]([C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:24][CH:25]=[CH:26]1)[N:21]=[CH:20][CH:19]=2
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)C(OCc1ccccc1)C=CC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Agent: [Pd+2]
Agent: COC(=O)Nc1ccc2c(c1)NC(=O)C(O)/C=C/C[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Agent: COC(=O)Nc1ccc2c(c1)NC(=O)C(OCc1ccccc1)/C=C/C[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Solvent: CO
Product: COC(=O)Nc1ccc2c(c1)NC(=O)C(O)C=CC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 65 °C

Procedure:
To a solution of 123A (770 mg, 1.378 mmol) in MeOH (125.00 mL) under Ar was added palladium hydroxide on carbon (77 mg, 0.551 mmol) and ammonium formate (3477 mg, 55.1 mmol). The mixture was refluxed at 65° C. overnight. The reaction mixture was filtered through Celite, rinsed with MeOH, and concentrated. The residue was purified by silica gel chromatography to yield 123B (360 mg, 0.765 mmol, 55.5% yield). MS (ESI) m/z: 471.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:37][CH:36]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5ccccc5CN(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.019 g, 18%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (d, J=6.5 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.45-7.39 (m, 2H), 7.35 (t, J=7.2 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.00-6.94 (m, 3H), 6.81 (d, J=7.7 Hz, 1H), 6.68 (t, J=7.2 Hz, 1H), 6.60 (s, 1H), 4.36 (s, 2H), 3.18-3.13 (m, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.
Reaction SMILES: FC(F)(F)C([O-])=O.[Tl+].FC(F)(F)C(O)=O.[CH:16]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]([F:29])=[CH:26][C:27]=2[F:28])=[CH:20][C:19]([C:30]([OH:32])=[O:31])=[C:18]([OH:33])[CH:17]=1.[I-:34].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>O>[F:28][C:27]1[CH:26]=[C:25]([F:29])[CH:24]=[CH:23][C:22]=1[C:21]1[CH:20]=[C:19]([C:30]([OH:32])=[O:31])[C:18]([OH:33])=[C:17]([I:34])[CH:16]=1
Reactant: [I-]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=C([O-])C(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Reaction time: 0.5 h

Procedure:
A mixture of 20.6 g of thallium trifluoroacetate (TTFA, 31.9 mmol) and trifluoroacetic acid (TFA, 50 ml) was stirred in a flask until the TTFA dissolved. This solution was added at room temperature to a flask containing 51 g (205 mmol) of diflunisal and it was stirred for 30 min. A solution of potassium iodide (KI, 40.9 g, 245.6 mmol) in 120 ml of water was slowly added to the mixture. After the reaction finished, the product was worked up. First, sodium metabisulphite (NaS2O5, 5.01 g, 26.4 mmol) was added to reduce the species of TI (III) to TI (I), and then a solution of sodium hydroxide was added to neutralize the TFA. It was extracted with dichloromethane and the organic phase was washed with water and dried over magnesium sulphate. The solvent was evaporated at low pressure and a crude was obtained of 96% purity, which was purified by chromatography on a silica gel column using the appropriate eluents.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:7])=[O:6].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.O>CC(C)=O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:22]([NH2:21])=[S:23]
Reactant: COc1ccc(C(N)=O)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(N)=O)cc1NC(N)=S
Temperature: 25 °C

Procedure:
To a solution of 3-amino-4-methoxybenzamide (2.49 g, 15.0 mmol, Alfa) in acetone (30 mL) at reflux was added benzoyl isothiocyanate (2.22 mL, 16.5 mmol) and the mixture was stirred at reflux for 30 min, then was poured into water. The precipitate was collected by vacuum filtration and was treated with 10% aq. NaOH (15 mL). The mixture was heated to reflux for 40 min, cooled to room temperature, and poured into a mixture of ice and 6 N aq. HCl. The mixture was basified to pH 10 with conc. aq. NH4OH and the resulting white solid precipitate was collected by vacuum filtration, affording the crude title compound, which was used without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:46]([O:53][C:54]([NH:56][C:57](N1C=CC=N1)=[NH:58])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][C:57]([NH2:58])=[N:56][C:54]([O:53][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:55])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNC(N)=NC(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (70 mg) in tetrahydrofuran (3 mL) was added N-(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.27 g), and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate-ethyl acetate/ethanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(N′-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl)methyl}-5-isopropyl-1H-pyrazole (50 mg). This material was dissolved in methanol (1 mL). To the solution was added sodium methoxide (28% methanol solution, 0.01 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 4-({4-[3-(N′-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (35 mg). This material was dissolved in methanol (2 mL). To the solution was added 10% palladium-carbon powder (15 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (27 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[N:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:17]1([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:4]3[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=4)[N:3]=3)[CH2:11][CH2:12]2)[CH2:19][CH2:18]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(Cl)nc(N2CCN(CC3CC3)CC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCN(CC3CC3)CC2)c1
Temperature: 100 °C

Procedure:
The nitrile 25D (2.4 g, 8.67 mmol), 4-trifluoromethylphenylboronic acid (2.05 g, 1.1 mol eq), palladium acetate (45 mg), cesium carbonate (4.5 g, 2 mol eq), and XPhos (190 mg) were mixed, placed under a nitrogen atmosphere and dioxane (10 mL) was added. The mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through a celite pad, washed with dioxane (2×20 mL) and concentrated under reduced pressure. The residue was used for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[NH:8]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH:9]2[NH:8][CH:7]([CH2:5][NH:4][CH2:3][CH2:2][OH:1])[CH2:12][CH2:11][CH2:10]2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(C2CCCC(C(=O)NCCO)N2)cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CCCC(CNCCO)N2)cc1OC
Temperature: 60 °C
Yield: 101.9 %

Procedure:
A solution of 1.5 g (5.0 mmoles, 1 eq) of 6-(3,4-Dimethoxy-phenyl)-piperidine-2-carboxylic acid (2-hydroxy-ethyl)-amide in 18 mL of THF is added slowly into 15 mL of 1 M LiAlH4 solution in THF. The reaction is heated at 60° C. under N2 for 6 hours. At that time there is no starting material shown on TLC. Cooled in ice bath, to the reaction are added 0.5 ml water, 0.5 mL 15% NaOH and 1.5 mL water slowly in order. Finally, some anhydrous MgSO4 is added, and the reaction mixture is filtered through Celite. Upon the removal of the solvent, the residue is taken in ethyl acetate, washed with brine, dried over Na2SO4 and concentrated to afford 2-{[6-(3,4-dimethoxy-phenyl)-piperidin-2-ylmethyl]-amino}-ethanol as an oil (1.5 g, 68%), which is used in the next step without purification. Analysis: MS (LC-MS): Calculated for C16H26N2O3 294.39, found 295.37 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](Cl)=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][N:3]12.O1CCOCC1.[NH3:25]>C(O)(=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:25])=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][N:3]12
Reactant: N
Reactant: O=C(Cl)c1ccc2nc3ccccn3c(=O)c2c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC(=O)c1ccc2nc3ccccn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10 gm of 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxylic acid chloride, prepared as in Example 12, were introduced into a mixture consisting of 200 ml of dioxane and 50 ml of concentrated ammonia, and the resulting mixture was stirred for 5 hours at room temperature. Thereafter, the reaction mixture was acidified with dilute acetic acid, and the crystals precipitated thereby were collected by suction filtration, yielding the compound of the formula ##STR22##
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:9][CH2:8][CH2:7]2.[F:22][C:23]1([CH:43]=[CH:42][CH:41]=[CH:40][CH2:39]1)[CH2:24][N:25]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)[C:26](=[O:29])[CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:22][C:23]1([CH:39]=[CH:40][CH:41]=[CH:42][CH2:43]1)[CH2:24][N:25]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)[C:26](=[O:29])[CH2:27][C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:13]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:8][NH:9]1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)NCC2
Reactant: O=C(CBr)N(CC1(F)C=CC=CC1)C1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1OC)C(CC(=O)N(CC1(F)C=CC=CC1)C1Cc3ccccc3C1)(c1ccccc1)NCC2
Temperature: 80 °C
Yield: 77.8 %

Procedure:
A mixture of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (160, 153 mg, 0.5 mmol), N-(1-fluorobenzyl)-N-indan-2-yl-2-bromoacetamide (161, 180 mg, 0.5 mmol) and potassium carbonate (500 mg) in acetonitrile is heated at 80° C. overnight. After cooling, the mixture is filtered and concentrated. The resulting residue is purified by column chromatography eluting with 5% methanol in chloroform to provide the title product (162) as a thick oil (215 mg, 78%). 1H NMR (CDCl3) 6.8–7.3 (m, 14H), 6.60(s, 1H), 6.05 (s, 1H),
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44]Cl)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].[CH2:46]1[C:51]2([CH2:56][CH2:55][CH2:54][NH:53][CH2:52]2)[CH2:50][CH2:49][N:48]([C:57](=[O:67])[CH2:58][NH:59][C:60]([NH:62][CH2:63][CH:64]([CH3:66])[CH3:65])=[O:61])[CH2:47]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(OC(=O)C)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1.C(OC[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](OC(=O)C)[C@H](N2C3C(=C(C)C=CC=3)C(CC3C=CC(OCCCCl)=CC=3)=C2)O1)(=O)C.C(N(CC)CC)C.CO.CCOC(C)=O>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][N:53]4[CH2:52][C:51]5([CH2:50][CH2:49][N:48]([C:57](=[O:67])[CH2:58][NH:59][C:60](=[O:61])[NH:62][CH2:63][CH:64]([CH3:65])[CH3:66])[CH2:47][CH2:46]5)[CH2:56][CH2:55][CH2:54]4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCCl)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCNC2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCN4CCCC5(CCN(C(=O)CNC(=O)NCC(C)C)CC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a stirred solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-(3-chloropropoxy)phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (143.38 mmoles; 118.40 g) in acetonitrile (829 mL) add 1-[2-(3,8-diazaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-3-isobutyl-urea (143.38 mmoles; 47.35 g), potassium carbonate (286.75 mmoles; 39.63 g), and potassium iodide (143.38 mmoles; 23.80 g). Heat the mixture at reflux under nitrogen overnight. Cool the reaction mixture to room temperature and add acetic acid anhydride (1.43 moles; 135.53 mL) and N,N-dimethyl-4-pyridinamine (14.34 mmoles; 1.75 g). Stir the mixture for 1 hour. Concentrate the mixture under reduced pressure and partition the residue between water and EtOAc. Separate the organic layer and wash with brine, dry over MgSO4, filter, and concentrate under reduced pressure. The residue is combined with another lot prepared in a similar manner starting from [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-(3-chloropropoxy)phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (6.2 mmol). Purify by flash column chromatography on silica gel (1.5 kg) eluting with 99:1 EtOAc:triethylamine (1cv), EtOAc (3cv's) and 190:10:1 EtOAc:MeOH:triethylamine (5cv's) to afford the title compound (68.2 g; 49% yield) mass spectrum (m/z): 918.6 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C(N(CC)CC)C.Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[BH4-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CCNCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thiophene aldehyde (11.2 g) was dissolved in 100 mL of methanol, then 12.1 g of triethylamine and 16.1 g of ethyl 3-aminopropionate hydrochloride were added thereto in this order and the mixture was stirred overnight at room temperature. The reaction solution was cooled down to 0° C., 2.27 g of sodium borohydride was slowly added thereto little by little and the mixture was stirred at room temperature for 1 hour.