Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:18][C:7]2[S:8][CH2:9][CH2:10][CH:11]3[CH2:16][C:15](=[O:17])[NH:14][N:13]=[C:12]3[C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C1(C)C=CC=CC=1>[C:26]([O:1][CH2:2][CH2:3][C:4]1[S:18][C:7]2[S:8][CH2:9][CH2:10][CH:11]3[CH2:16][C:15](=[O:17])[NH:14][N:13]=[C:12]3[C:6]=2[CH:5]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC2CCSc3sc(CCO)cc3C2=NN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OCCc1cc2c(s1)SCCC1CC(=O)NN=C21
Reaction time: 3 h

Procedure:
A mixture of 1.0 g of 9-(2-hydroxyethyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one, 2 ml of triethylamine and 2 ml of acetic anhydride in 20 ml of toluene is kept on a water bath at 80°-85° C. for 3 hours. After cooling, to the mixture is added water, the organic layer is collected by a separatory funnel and concentrated. To the residue is added hexane and the precipitated crystals are collected by filtration. The resulting crystals are recrystallized from isopropyl ether to give 0.5 g of 9-(2-acetoxyethyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 106°-108° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[OH:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1.C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([C:36](=[O:37])[C:35]([OH:34])([CH3:40])[CH3:39])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.33 mmol), 2-hydroxy-2-methylpropionic acid (52 mg, 0.50 mmol), HOBt (50 mg, 0.37 mmol), NMM (81 μL, 0.74 mmol) and EDCI (96 mg, 0.50 mmol) in THF (3 mL) was allowed to stir at r.t. for 4 h. The resulting mixture was diluted with DCM and washed with sat. aq. NaHCO3, dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, THF:EtOAc, 0-50%) then triturated with Et2O/cyclohexane. The resulting solid was collected by filtration and dried in vacuo affording 811 (108 mg, 60%). LCMS (method I): RT 3.21 min, [M+H]+ 535.3. 1H NMR (DMSO, 400 MHz): δ 8.06-8.05 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 5.23 (1 H, s), 5.05 (1 H, d, J=10.74 Hz), 4.67 (1 H, d, J=10.76 Hz), 4.55 (1 H, d, J=10.69 Hz), 4.29 (4 H, brd s), 4.16 (1 H, d, J=10.75 Hz), 3.79 (4 H, t, J=4.62 Hz), 3.73 (3 H, s), 3.29-3.27 (2 H, m), 3.09 (3 H, s), 1.35 (3 H, t, J=7.43 Hz), 1.30 (3 H, s), 1.25 (3 H, s)
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11](O)=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2.CN(C)C=O.[Cl:21]C1N(C2C=CC=CC=2)N=NN=1.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:21].[NH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2
Reactant: NCCc1ccc(O)c2c1CC(=O)N2
Reactant: Clc1nnnn1-c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cl
Product: NCCc1cccc2c1CC(=O)N2
Reaction time: 20 h

Procedure:
A mixture of 2.73 g (10.0 mmoles) of 4-(2-aminoethyl)-7-hydroxy-2(3H)-indolone hydrobromide (U.S. Pat. No. 4,314,944), 200 cc of dimethylformamide, 1.86 g (10.3 mmoles) of 5-chloro-1-phenyl-1H-tetrazole, 10 cc of water and 2.9 g (21 mmoles) of anhydrous potassium carbonate is stirred at room temperature for 2 days or until thin layer analysis indicates that no starting material remains. The reaction is filtered and the filtrate is acidified with dil. hydrochloric acid, concentrated in vacuo and the residue triturated with abs. ethanol. The triturate is clarified with charcoal and evaporated to dryness in vacuo. The hydrochloride salt of 4-(2-aminoethyl)-7-(1-phenyl-1H-tetrazol-5-yloxy)-2(3H)-indolone is hydrogenated directly in 200 cc of glacial acetic acid using 50% by substrate weight of 10% palladium-on-carbon at 50 p.s.i. for 20 hours at 50°. The warm reaction mixture is filtered. The catalyst is washed thoroughly with hot acetic acid. After the filtrate is concentrated in vacuo, the residue is stripped several times from dilute hydrochloric acid and crystallized from ethanol to give 4-(2-aminoethyl)-2(3H)-indolone hydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](Cl)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15](Cl)=[O:16])[CH:8]=2)[CH:3]=1.[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([NH:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([NH:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])[CH:8]=2)[CH:3]=1
Reactant: O=C(Cl)c1ccc2cc(O)c(C(=O)Cl)cc2c1
Reactant: CCCCCCCCCCCCN
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1ccc2cc(O)c(C(=O)NCCCCCCCCCCCC)cc2c1
Temperature: 30 °C
Yield: 29 %

Procedure:
A dispersion of 5.4 g of 2-hydroxy-3,6-dichloro carbonylnaphthalene in 20.0 g of dry tetrahydrofuran was added with 14.8 g of n-dodecylamine solution in 30 g of dry tetrahydrofuran and reacted under reflux for 12 hours. To the reaction mixture, 50 g of water was added and the precipitates were collected by filtration, washed with water and thus obtained crystal was washed with 30 g of methanol under reflux. The obtained mixture was cooled to 30° C. and filtrated, washed with methanol and dried to provide 3.3 g of 2-hydroxy-3,6-di-n-dodecylaminocarbonylnaphthalene (decomposition point: 382.9° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1COCC1.O.[BrH:39]>C(#N)C>[Br-:39].[C:28]([CH:26]1[CH2:27][NH+:24]([CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]3[S:16][C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][N:14]=3)[C:18]=2[CH2:31][CH3:32])[CH2:25]1)([OH:30])=[O:29]
Reactant: Br
Reactant: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CCc1c(C[NH+]2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (50 mg, 0.106 mmol) was added to a mixture of THF (2 mL), water (0.6 mL) and ACN (1 mL), a suspension was obtained to which was added HBr solution (0.016 mL, 40%, wt). A clear solution was obtained and stirred for 30 min at rt. Solvent was removed under the reduced pressure and dried in vacuum to give 3-carboxy-1-(3-(5-(3-chloro-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-ethylbenzyl)azetidin-1-ium bromide (56 mg) as pale yellow solid. δH (DMSO-d6, 600 MHz): 1.08 (3H, t), 1.35 (6H, m), 2.92 (2H, m), 3.67 (1H, m), 4.34 (4H, m), 4.61 (2H, m), 4.85 (1H, dt), 7.39 (1H, d), 7.48 (1H, m), 7.64 (2H, m), 7.97 (1H, d), 8.10 (1H, d), 10.25 (1H, s), 13.17 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56][CH2:55]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56][CH2:55]2)=[O:33])[C:25]=1[CH3:34])(=[O:11])=[O:12]
Reactant: NCCN1CCC(O)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (100 mg, 0.19 mmol), DIPEA (115 mg, 5 eq.) and 1-(2-amino-ethyl)-piperidin-4-ol TFA salt (88 mg, 1.2 eq.) in 2 mL) was stirred at rt for 45 mins. To the mixture was added HATU (83 mg, 1.1 eq.). After stirring for 18 hours, the reaction was concentrated and purified on a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH2:21][OH:22])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([CH:21]=[O:22])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1CCOC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N1CCOC(C=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
A solution of oxalyl chloride (0.097 mL) in dichloromethane (10 mL) was cooled to −78° C. under argon. A solution of dimethylsulfoxide (0.201 mL) in dichloromethane (5 mL) was added dropwise and the mixture was stirred for 5 minutes. A solution of (4-tert-butylmorpholin-2-yl)methanol (175 mg) in dichloromethane (3 mL) was added and the mixture was stirred for 15 minutes. Triethylamine (0.845 mL) was added and the mixture was warmed to room temperature. The reaction was quenched with water and partitioned between water and dichloromethane. The organic layer was dried (Na2SO4), filtered and concentrated to give an orange oil (165 mg). This material was used immediately in the next stage without further purification or analysis.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[S:11][CH:12]=2)=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32])(=[O:24])=[O:23].[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][C:12]1[S:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:9][C:8]=1[C:7]1[C:2]([F:1])=[C:3]([NH:21][S:22]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])(=[O:23])=[O:24])[CH:4]=[CH:5][C:6]=1[F:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCN(c2nc(-c3c(F)ccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)cs2)CC1
Solvent: ClCCl
Product: CN1CCN(c2nc(-c3c(F)ccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(Br)s2)CC1
Temperature: 25 °C
Yield: 73 %

Procedure:
150 mg (0.31 mmol) of N-{2,4-Difluoro-3-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-phenyl}-2,5-difluoro-benzenesulfonamide were suspended in 15 mL of dry DCM and 103 mg (0.62 mmol) of N-bromosuccinimide were added. The reaction was maintained at r.t. for 1 h then diluted with the same solvent and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with petroleum ether and filtered, to afford 128 mg (73%) of N-{3-[5-bromo-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide.
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11]C(=O)C)=[CH:6][C:5]=1F)(=[O:3])[CH3:2].[ClH:16].[OH-].[Na+]>C(O)C>[NH2:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([Cl:16])[CH:6]=1
Reactant: Cl
Reactant: CC(=O)Nc1cc(C)c(C(C)=O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1c(C)cc(N)cc1Cl
Yield: 86 %

Procedure:
An ethanol solution (51 mL) containing N-(4-acetyl-3-fluoro-5-methylphenyl)acetamide (30-2, 5.80 g, 27.7 mmol) and concentrated hydrochloric acid (20.0 mL) was heated at reflux for 15 h. The solution was added with 10% aqueous NaOH and the resultant solids were collected to give 1-(4-amino-2-chloro-6-methylphenyl)ethanone (30-3, 4.00 g, 23.9 mmol) as light yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-d6) δ 6.22 (m, 2 H), 2.37 (m, 3 H), 2.22 (s, 3 H). ESI-MS: m/z 167.8 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:11][C@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12](CC3C=CC=CC=3)[C@H:6]1[CH2:7][CH2:8][C@@:9]2([N:42]=[N+:43]=[N-:44])[O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)(=[O:3])[CH3:2].C(O)(=O)C.[ClH:49]>C(OCC)(=O)C.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:49].[C:1]([NH:4][C@@H:5]1[CH2:11][C@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:12][C@H:6]1[CH2:7][CH2:8][C@@:9]2([N:42]=[N+:43]=[N-:44])[O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(N=[N+]=[N-])OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)N[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@@]2(N=[N+]=[N-])OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-6-Acetamidoazido-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 104; 240 mg, 0.40 mmol) was dissolved in ethyl acetate (10 ml) and glacial acetic acid (1 ml) then 10% palladium hydroxide (30 mg) added and the mixture hydrogenated at 45 psi overnight. The reaction mixture was then filtered and the mixture further hydrogenated with fresh catalyst (30 mg) overnight. The reaction mixture was filtered then concentrated in vacuo, basified (saturated sodium hydrogen carbonate solution), extracted with dichloromethane (×3), dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography [10% methanol in dichloromethane] to give an oil which when concentrated with iso-hexane gave a white solid. The hydrochloride salt was made by dissolving in diethyl ether and adding 1 equivalent of hydrogen chloride in diethyl ether. The title compound was filtered off and dried in vacuo at 60° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@@H:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6]1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(Cl)(Cl)Cl.ClCCl>[ClH:31].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:13]([CH2:12][CH2:11][N:8]2[CH2:9][CH2:10][CH:5]([N:4]3[CH2:3][CH2:2][NH:1][C:33]3=[O:34])[CH2:6][CH2:7]2)[CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C[C@@H](CCN1CCC(NCCN)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CCC(N2CCNC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl
Yield: 121.2 %

Procedure:
A stirred solution of (S)-N-[4-[4-(2-aminoethylamino)-piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide (0.356 g) and 1,1'-carbonyldiimidazole (0.157 g) in chloroform (6 mL) was heated at reflux for 2 hours. The reaction mixture was diluted with dichloromethane, washed (aqueous sodium bicarbonate), dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 90:10) as eluent. The resulting material was dissolved in dichloromethane, precipitated as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound as a white solid (0.244 g); MS: m/z=503(M+1); Analysis for C26H32Cl2N4O2.1.70 HCl.0.20 (C2H5)2O: Calculated: C, 55.47; H, 6.20; N, 9.65; Found: C, 55.47; H, 6.35; N, 9.44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][N:14]=1)[CH2:5][C:6](=O)[CH2:7][C:8](=O)C.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1.[OH-].N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[CH:18]=3)[N:24]=[C:7]([CH3:8])[CH:6]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CC(=O)CC(=O)Cc1ccnc(Cl)c1
Reactant: Cc1cccc(NN)c1
Agent: Cl
Agent: N
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Yield: 72.2 %

Procedure:
To a mixture of 1-(2-chloroisonicotinyl)-1,3-butanedione (1.35 g, 0.068 mol) and 3-methylphenylhydrazine hydrochloride (1.30 g, 0.0082 mol) in ethanol (40 mL) was added ammonia hydroxide (0.96 mL, 0.0082 mol) dropwise. The reaction mixture was heated at reflux overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 1.68 g (87% yield) of product as a yellow oil: Anal. Calcd. for C16H14ClN3: C, 67.72; H, 4.97; N, 14.81; Cl, 12.49. Found: C, 67.91; H, 5.08; N, 14.79; Cl, 12.40.
Reaction SMILES: [CH:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C-:9]#[N:10].[Na+]>C(OCC)(=O)C.O>[OH:8][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]#[N:10]
Reactant: [C-]#N
Reactant: C=CCCCCC=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCCCCC(O)C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyridinium chlorochromate (19.26 g, 0.088 mol) was added to a solution of hept-6-en-1-ol (5.0 g, 0.044 mol) and dichloromethane (600 mL). The resulting mixture was stirred at room temperature for 2 h, then diluted with diethyl ether, filtered through silica gel and concentrated in vacuo below room temperature to yield hept-6-enal as an oil, which was used in the next step without further purification. To a solution of hept-6-enal (4.9 g, 0.044 mol) in ethyl acetate (36 mL) was added a solution of sodium cyanide (6.4 g, 0.13 mol) in water (36 mL) and the resulting mixture was stirred at room temperature for 24 h. The layers were separated and the aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo to yield 2-hydroxyoct-7-enenitrile as a tan oil, which was used in the next step without further purification. A stream of HCl(g) was introduced into a solution of 2-hydroxyoct-7-enenitrile (6.0 g, 0.043 mmol) and methanol (130 mL) at −78° C. for 5 min. The resulting mixture was stored at −10° C. for 18 h, then concentrated in vacuo. The residue was diluted with ethyl acetate (106 mL) and water (106 mL) and the solution was stirred at room temperature overnight. The layers were separated, and the organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield methyl 2-hydroxyoct-7-enoate. 1H NMR (400 MHz, CDCl3) δ 5.48-5.82 (m, 1H), 4.89-5.08 (m, 2H), 4.31-4.52 (m, 1H), 3.79 (s, 3H), 2.78-3.12 (bs, 1H), 2.02-2.28 (m, 2H), 1.75-1.89 (m, 1H), 1.68-1.70 (m, 1H), and 1.38-1.52 (m, 4H).
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:13]([C:15](O)=[O:16])[CH:14]=1.II>CO>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[C:13]([CH:14]=1)[CH2:15][OH:16]
Reactant: Nc1ccc(N2CCOCC2)c(C(=O)O)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOCC2)c(CO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A 50 mL two necked round bottom flask was fitted with a magnetic stirrer bar and a dropping funnel. A suspension of NaBH4 in tetrahydrofuran (100 mg, 2.4 mmol/10 mL) was added, followed by 5-amino-2-morpholinobenzenecarboxylic acid (222 mg, 1.0 mmol) in one portion. A reflux condenser was fitted and the reaction mixture was cooled to 0° C. under nitrogen atmosphere. A solution of iodine in tetrahydrofuran (250 mg, 1.0 mmol/15 mL) was added dropwise to the reaction mixture. After iodine addition was completed and gas evolution had ceased, the reaction mixture was heated at reflux for 6 hours and left stirring at room temperature overnight. Methanol was added slowly until the mixture became clear. The resulting solution stirred at room temperature for 30 minutes then solvent was removed under reduced pressure. The residue was dissolved in 20% KOH (30 mL), stirred for 4 hours and extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 5-amino-2-morpholinobenzyl alcohol as an off-white solid (150 mg, 72% yield). 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J=8.7 Hz, 1H), 6.59 (dd, J=8.4, 2.7 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 5.51 (br s, 1H), 4.71 (s, 2H), 3.84 (t, J=5.1 Hz, 4H), 3.60 (br s, 2H), 2.91 (t, J=5.1 Hz, 4H). LC-ESI-MS (method B): rt 2.31 min.; m/z 209.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>C(O)C>[CH3:15][C:14]1[CH:13]=[C:12]([CH3:16])[NH:11][C:10]=1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:19][N:18]=1
Reactant: NN
Reactant: Cc1cc(C)c(C(=O)c2cccnc2Cl)[nH]1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(-c2n[nH]c3ncccc23)[nH]1
Yield: 46 %

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone (240 mg, 1 mmol) and hydrazine hydrate (0.7 mL) in ethanol (2 mL) was heated at 100–110° C. for overnight. The reaction was concentrated and purified on a silica gel column to give 97 mg (46%) of the titled compound as a light yellow solid.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:28]([CH3:36])[C:29]([C:32]([O:34][CH3:35])=[O:33])=[N:30][N:31]=1.O.OC1N=CN=C2C=1NC(S)=N2>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:28]([CH3:36])[C:29]([C:32]([O:34][CH3:35])=[O:33])=[N:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COC(=O)c1nnc(S)n1C
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: COC(=O)c1nnc(SC2=C(O)CC(CCc3ccc(OC)c(Cl)c3)(C3CCCC3)OC2=O)n1C

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and methyl 5-mercapto-4-methyl-4H-1,2,4-triazole-3-carboxylate, as shown in Example 21, Step 2, was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.50-1.70 (s, 8H) 1.98 (m, 2H) 2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.71 (d, J=18.1 Hz, 1H) 2.90 (d, J=17.6 Hz, 1H) 3.81 (s, 3H) 3.81 (s, 3H) 3.88 (s, 3H) 7.02 (d, J=8.2 Hz, 1H) 7.15 (dd, J=8.2, 1.9 Hz, 1H) 7.27 (d, J=1.9 Hz, 1H). MS (APCI) calcd for C24H28ClN3O6S: 522.02; found M=522.1.