Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>O1CCCC1>[O:13]1[CH2:14][CH2:15][N:10]([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: O=C(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Dissolve t-butyl bromoacetate (leq) in tetrahydrofuran and add morpholine (2.2 eq) via syringe. Stir the reaction mixture at room temperature for 2 hours, filter and wash the filter cake with ethyl ace tare. Combine the organic filtrates and wash with saturated sodium bicarbonate (2×), water (2×) and brine. Dry (Na2SO4), filter and evaporate the solvent in vacuo. Take up the oily residue in ethyl acetate, cool in ice and bubble hydrogen chloride gas into the solution. Stir at room temperature overnight, cool and filter to give morpholinoacetic acid (85%); mp 169°-170° C.; 1H NMR (D2O) δ3.75-4.29 (br m, 6), 3.59 (br s, 2), 3.28 (br s, 2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>C(#N)C>[CH3:20][N:21]([CH3:25])[C:22](=[O:23])[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(C)C)nc(C(Cl)(Cl)Cl)n1
Yield: 48 %

Procedure:
A mixture of 5.7 g (0.025 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 5.1 g (0.05 mole) triethylamine, and 100 ml acetonitrile was stirred and 5.4 g (0.05 mole) dimethylcarbamoyl chloride was added to the mixture. The reaction mixture was stirred 2 hours under reflux, and allowed to cool. A solid was filtered out after cooling and washed with water to give 3.6 g (48% yield; mp 83.5°-84.5° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]([CH2:21][CH3:22])[CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH:12]2[CH2:23][OH:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.N#N.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][N:35]([CH3:39])[C:36](=[O:37])[O:24][CH2:23][CH:12]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:20]([CH2:21][CH3:22])[CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13]1
Reactant: CCC1CC2(CC(CO)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CC2(CC(COC(=O)N(C)C)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Reaction time: 0.08 h
Yield: 136.6 %

Procedure:
(8-(4-Chlorophenylsulfonyl)-9-ethyl-1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol (111; 1.19 g, 3.18 mmol) and triethylamine (2.21 ml, 15.9 mmol) were added to CH2Cl2 (15 mL) in a flame-dried flask and placed tinder N2. DMAP (77.8 mg, 0.637 mmol) was added and the mixture stirred for 5 minutes. Dimethylcarbamoyl chloride (0.88 mL, 1.54 mmol) was added dropwise and the reaction stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and equal portions of EtOAc and water were added. The aqueous layer was extracted with several more portions of EtOAc. The combined organic layers were washed with a dilute NaOH solution, 10% citric acid, brine, dried over Na2SO4 and concentrated to yield 940 mg of 112 as a yellow oil. The material was purified by column chromatography using EtOAc/hexanes gradients to yield 836 mg (59%) of a mixture of cis/trans isomers.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1c(F)cccc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cccc(F)c1-c1nc(-c2cccnc2)no1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,6-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.29 (t, J=8.6 Hz, 2 H), 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.77 (tt, J=8.6, 6.1 Hz, 1 H), 8.57 (ddd, J=8.3, 1.9, 1.7 Hz, 1 H), 8.75 (dd, J=4.7, 1.7 Hz, 1 H), 9.30 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:11]>COCCOC>[ClH:9].[NH:7]([C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:11])[C:6]([NH2:8])=[NH:5]
Reactant: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1ccnc2ccccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc2c(c1)c(C(=O)NC(=N)N)cn2-c1ccnc2ccccc12
Temperature: 22 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
0.365 g (15.9 mmol) of sodium is added at 22° C. under an argon atmosphere to 45 cm3 of methanol. After complete dissolution, 1.4 g (15 mmol) of guanidine hydrochloride are added. After stirring at 22° C. for 2 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 25 cm3 of 1,2-dimethoxyethane. 1 g of 3-chlorocarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole, suspended in 20 cm3 of 1,2-dimethoxyethane, is subsequently added at 22° C. under an argon atmosphere. After stirring at 22° C. for 19 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 20 cm3 of water. After stirring at 22° C. for 1 hour, the suspension is filtered and dried to give a beige-coloured powder which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume) and then dichloromethane/methanol/20% aqueous ammonia (18/3/0.5 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.1 g of a beige-coloured solid are obtained, which solid is triturated in 10 cm3 of N hydrochloric acid for 1 hour. After filtering off, the residue is recrystallised under hot conditions from 180 cm3 of methanol to give 0.66 g of 3-guanidinocarbonyl-5-methyl-1-(quinol-4-yl)-1H-indole hydrochloride in the form of pale yellow crystals melting at 268° C. (Analysis C20H17N5O.HCl; % calculated C, 63.24, H: 4.78, Cl: 9.33, N: 18.44, O: 4.21, % found C: 63.26, H: 4.72, Cl: 9.47, N: 18.57).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1.[Cl:23][C:24]1[N:35]=[CH:34][CH:33]=[CH:32][C:25]=1[C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27]>>[ClH:23].[F:22][C:2]([F:1])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:24]2[N:35]=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27])[CH2:15][CH2:16]1
Reactant: CON(C)C(=O)c1cccnc1Cl
Reactant: NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Product: CON(C)C(=O)c1cccnc1NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Product: Cl

Procedure:
substituting 3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propylamine and 2-chloro-N-methoxy-N-methylnicotinamide gave 2-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propylamino)-N-methoxy-N -methylnicotinamide hydrochloride, m.p. 161°-177° C.; Anal.: Calcd. for C23H30F3N5 O3.(HCl)1.75.(C4H8O)0.1 : C, 55.79; H, 7.04; N, 14.78%; Found: C, 55.83; H, 6.92; N, 14.69%;
Reaction SMILES: [N:1]([C@@H:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][C@@H:4]([NH2:1])[CH3:21])[CH3:20]
Reactant: CCOC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: CCOC1=C2C=c3c(cnn3C[C@H](C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
0.53 g (1.87 mmol) of (S)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 25 ml of anhydrous ethanol was hydrogenated on 55 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 50 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 217 mg (1.87 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.54 g (77%) of (S)-2-(7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 157° was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=2)=[N:19][CH:20]=1.C(N(CC)CC)C>C(O)C>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:32])([F:13])[F:31])=[CH:20][N:19]=2)=[CH:27][CH:26]=1
Reactant: Fc1cccc2c(Cl)ncnc12
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1cccc2c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)ncnc12
Yield: 58.4 %

Procedure:
A mixture of 4-chloro-8-fluoroquinazoline (1.82 g, 0.01 mol), 2-(4-(5-trifluoromethyl-2-pyridinyloxy)-phenyl)ethylamine (2.82 g, 0.01 mol), triethylamine (1.1 g, 0.011 mol) and ethanol (50 mL) was heated under reflux for three hours and allowed to cool. Solvent was evaporated under reduced pressure, and the residue dissolved in dichloromethane. This was washed with 0.5M sodium hydroxide solution and water, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallization from ethyl acetate:hexane gave 2.5 g of product. MP 152° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[Cl-:19].[Cl-].[Cl-].[Cl-].[Zr+4:23]>C1(C)C=CC=CC=1>[Cl-:19].[Cl-:19].[C:10]1([Zr+2:23][C:17]2[C:13]3[NH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:14]=[CH:15][CH:16]=2)[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: [Li]CCCC
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1c([Zr+2]c3cccc4c3[nH]c3ccccc34)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Complex Preparation (Steps 1 and 2). Carbazole (5.0 g, 30 mmol) is stirred in a flask under an atmosphere of nitrogen in a dry box for 15 min. Toluene (120 mL) is added, and the mixture is stirred for 30 min. n-Butyllithium (12 mL of 2.5 M solution in hexane, 30 mmol) is added by syringe over 5 min. to the stirred carbazole solution. The mixture is stirred at room temperature for 2 h. The mixture turns light pink, and the slurry becomes thick, requiring vigorous stirring. Zirconium tetrachloride (3.50 g, 15 mmol) and more toluene (25 mL) are added to the flask, and the mixture turns brown. Stirring is continued at room temperature for another 18 h, after which the mixture is black-brown-green. Solvents are removed under a flow of nitrogen, and the residue is vacuum dried for 3 h. A yellow solid (9.25 g) that contains 81 wt. % of the desired bis(carbazolyl) complex (15.1 wt. % Zr) is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.[NH2:54][OH:55]>CN(C=O)C.ClCCl>[OH:55][NH:54][C:14](=[O:15])[CH:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19]
Reactant: NO
Reactant: CCC(C)(C)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(C)(C)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
The product of step 1 (0.116 g), EDC hydrochloride (0.076 g, 1.1 equivalent), hydroxybenzotriazole (0.054 g, 1.1 equivalent), and diisopropylethylamine (0.143 g, 3 equivalent) are mixed with dichloromethane (20 mL) to give a homogeneous solution. Hydroxylamine hydrochloride (0.051 g, 2 equivalent) is added as a solid. DMF (3 mL) is added to solubilize the hydroxylamine hydrochloride. The reaction is allowed to stir at room temperature overnight. The solvents are then removed under reduced pressure and the residue partitioned between ethyl acetate and 1N HCl. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product is loaded onto a reverse phase column as a DMSO solution. The column is eluted with a step gradient, starting at 20% acetonitrile/water, and raised in 10% increments. The appropriate fractions are combined to give 22 mg of the title compound. 1H NMR (DMSO, 300 MHz): 10.4, 7.69-7.65, 7.43, 7.01-6.98, 3.80, 1.20-1.17, 0.77, 0.75, 0.69 .
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH3:20])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]([O:17]CC)=[O:16].O.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH3:20])[C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1ncn2c3cccc(Cl)c3c(=O)n(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c2c(Cl)cccc2n2cnc(C(=O)O)c12
Temperature: 0 °C
Yield: 102.2 %

Procedure:
Ethyl 6-chloro-4,5-dihydro-4-methyl-5-oxo-imidazo(1,5-a)-quinazoline-3-carboxylate (2.27 g,7.4 mmol) in a mixture of 50 ml of ethanol, 25 ml of water and 4.6 ml of 4M aqueous sodium hydroxide was refluxed for 1 h. Then the mixture was cooled to 0° C. and neutralized by addition of 4.6 ml of 4M hydrochloric acid. The precipitate was filtered off, rinsed with water and dried to give 2.1 g (100%) of 6-chloro-4,5-dihydro-4-methyl-5-oxo-imidazo(1.5-a)quinazoline-3-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:9])=[O:8].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:8])=[O:9]
Reactant: C1CCNCC1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Yield: 35.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.318 g, 0.564 mmol) was dissolved in acetonitrile (10.0 mL), and the solution was treated with piperidine (1.10 mL, 11.3 mmol), acetic acid (0.646 mL, 11.3 mmol) and sodium triacetoxyborohydride (0.359 g, 1.69 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.126 g, 35%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:57][CH2:58]C=O)[N:45]=[C:46]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)[C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:57][CH2:58][CH2:6][N:8]3[CH2:9][CH2:10][N:11]([C:14]4[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:23])[CH2:12][CH2:13]3)[N:45]=[C:46]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:55])([F:56])[F:54])=[CH:51][CH:52]=3)[C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2[N+](=O)[O-])CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (940 mg, 2.75 mmol) in 10 mL of CH2Cl2 was treated with 5 mL of trifluoroacetic acid and stirred at 25° C. for 1 h. The volatiles were then removed. The residue was taken up in CH2Cl2 (60 mL) and KOH (4 N, 20 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The yellow oil was dissolved in CH2Cl2 and added into the 996 mg (2.35 mmol) of 1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxy lic acid tert-butyl ester. The yellow solution was treated with glacial acetic acid (0.8 mL, 6 eq) and stirred at 25° C. for 1 h. NaBH(OAc)3 (1.5 g, 7.05 mmol) was added and stirred under nitrogen for 2 h. Then saturated NaHCO3 (20 mL) was added and stirred for 30 min, and the layers were separated. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Column chromatography (silica, 2-5% MeOH/CH2Cl2) afforded 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester as a white solid (1.40 g, 92%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C31H36ClF3N6O4, 648.24; m/z found 649.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.69 (d, J=8.2 Hz, 1H), 7.60-7.50 (m, 1H), 7.45-7.37 (m, 4H), 7.02 (t, J=8.2 Hz, 1H), 4.58 (br s, 2H), 4.04 (t, J=6.7 Hz, 2H), 3.73-3.65 (m, 2H), 3.05-2.95 (m, 4H), 2.71 (t, J=5.6 Hz, 2H), 2.50-2.35 (m, 4H), 2.30 (t, J=6.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[C:11](=[O:20])[CH:12]=[C:13]([CH:16]([OH:19])[CH2:17][NH2:18])[O:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:21]1([CH:27](C)[C:28](=O)[CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].[C-:34]#N.[Na+]>CO>[ClH:1].[CH2:2]([O:9][C:10]1[C:11](=[O:20])[CH:12]=[C:13]([CH:16]([OH:19])[CH2:17][NH:18][CH:29]([CH3:34])[CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCC(O)c1cc(=O)c(OCc2ccccc2)co1
Reactant: [C-]#N
Reactant: CC(=O)C(C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CCc1ccccc1)NCC(O)c1cc(=O)c(OCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 1-(5-Benzyloxy-4H-pyran-4-on-2-yl)-2-amino ethanol hydrochloride (1.94 g, 0.0065 m) and 3-phenyl-2-butanone (0.97 g, 0.0065 m) in methanol was added 65 ml of 0.1N NaOH followed by NaCN BH2 (0.25 g, 0.004 m). The mixture was stirred for 2 days at room temperature after concentration, chromatography on silica gel 60 (E. Merck) eluting with 5% CH3OH/CH2Cl2 saturated with NH3 afforded the desired product as its free base. The hydrochloride salt was prepared by dissolving in ethanol and adding aqueous HCl. Filtration of the solid upon attempted ether extraction gave a poor yield of the desired salt A; m.p. 205°-208° C.
Reaction SMILES: C(O[CH2:5][CH:6]1[CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=O)[O:19][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=O)C.[N:36]1C(C)=CC(C)=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>ClCCl>[N:60]1([CH2:5][CH:6]2[CH2:35][CH2:34][N:9]3[C:10]4[C:15]([C:16]([C:17]5[C:18](=[O:19])[NH:36][C:20](=[O:32])[C:21]=5[C:22]5[C:30]6[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=6)[N:24]([CH3:31])[CH:23]=5)=[C:8]3[CH2:7]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1
Reactant: Cc1cc(C)nc(C)c1
Reactant: C1CCNCC1
Reactant: CC(=O)OCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CN3CCCCC3)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 2.5 h

Procedure:
A solution of 0.64 g of the product of Example 1 and 0.4 ml of 2,4,6-collidine in 20 ml of dichloromethane was added dropwise to a solution of 0.75 g of trifluoromethanesulfonic anhydride in 10 ml of dichloromethane at 0° C. After 2.5 hours, the mixture was treated with 3 ml of piperidine and stirred for 16 hours. Concentration and chromatography of the residue on silica gel with dichloromethane/methanol (gradient from 98:2 to 50:50) gave 340 mg of 3-[6,7,8,9-tetrahydro-8-[(1-piperidino)methyl]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione. This was converted into the hydrochloride of melting point 294° C. (decomposition), by treatment with a saturated solution of hydrogen chloride in ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[C:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:12])([CH3:1])[CH2:11][CH2:10]2)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of 2,2-dimethylchroman (Compound 214, 15 g, 19.4 mmol) in dry CH2Cl2 (100 mL) was added acetyl chloride (1.52 ml, 21.3 mmol) followed by AlCl3 (2.84 g, 21.3 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then poured into ice water. Extraction (CH2Cl2), drying (Na2SO4), and concentration under reduced pressure afforded a yellow oil. Column chromatography (EtOAc:hexanes 1:9) yielded 2.15 g (54%) of the title compound as a yellow solid. 1H NMR δ 7.73 (2H, m), 6.80 (1H, d, J=8.3 Hz), 2.83 (2H, t, J=6.9 Hz), 2.54 (3H, s), 1.84 (2H, t, J=6.9 Hz), 1.36 (6H, s). Anal. (C13H16O2) C, H.
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([CH3:18])=[N+:6]([O-:17])[C:7]([CH3:16])=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1)#[N:3].[OH-:19].[Na+]>>[CH3:18][C:5]1[C:4]([C:2]([NH2:3])=[O:19])=[C:9]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH:8]=[C:7]([CH3:16])[N+:6]=1[O-:17]
Reactant: [OH-]
Reactant: Cc1cc(N2CCSCC2)c(C#N)c(C)[n+]1[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(N2CCSCC2)c(C(N)=O)c(C)[n+]1[O-]

Procedure:
3 g (0.012 mol) of 3-cyano-2,6-dimethyl-4-(4-thiomorpholinyl)pyridine 1-oxide hydrochloride (from Example 1) were dissolved in 10 ml of 10 N sodium hydroxide solution, and the solution was heated under reflux for 6 hours. It was then evaporated until a precipitate formed, the mixture was cooled, and the solid was filtered off and recrystallized from methanol.