Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-])=O)=[C:7]([CH3:15])[CH:6]=1)([O:3][CH3:4])=[O:2]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([NH2:12])=[C:9]([CH3:11])[CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(N)c(C)c1
Yield: 99.9 %

Procedure:
4-carbomethoxy-2,6-dimethylnitrobenzene (2 g, 9.5 mmol) was dissolved in ethyl acetate (20 ml) and subjected to catalytic hydrogenation using 10% palladium on carbon (300 mg) at 55 psi for 30 min. The catalyst was filtered and solvent removed to give 4-carbomethoxy-2,6-dimethylaniline as a solid (1.7 g, 100% yield).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([S:13][CH3:12])=[CH:15][CH:16]=3)[CH2:2]1)[CH2:8]2
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: CSc1ccc(C(=O)NC2C3CC4CC2CN(C4)C3)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 4-(methylthio)benzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.92-1.98 (m, 2H), 2.11 (s, 1H), 2.31 (d, J=14 Hz, 2H), 2.38 (s, 2H), 2.52 (s, 3H), 3.49 (s, 2H), 3.59 (s, 4H), 4.37 (s, 1H), 7.31-7.35 (m, 2H), 7.74-7.80 (m, 2H); MS (APCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[C:29](Cl)=[O:30].C(N(CC)CC)C>O1CCOCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2([CH2:18][NH:19][C:29]([C:21]3[O:20][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[CH:22]=3)=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: COc1cc(C2(CN)CCCC2)cc(OC)c1OC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C2(CNC(=O)c3cc4ccccc4o3)CCCC2)cc(OC)c1OC
Reaction time: 15 h
Yield: 11.7 %

Procedure:
C-[1-(3,4,5-Trimethoxy-phenyl)-cyclopentyl]-methylamine (53.1 mg, 0.200 mmol) and benzofuran-2-carbonyl chloride (36.1 mg, 0.200 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (84 μL, 0.60 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, and purified by reverse phase preparative liquid chromatography to yield the pure product (9.59 mg, 0.0234 mmol, 11.7%). ESI-MS m/z calc. 409.2, found 410.4 (M+1)+. Retention time of 3.29 minutes.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>>[OH:1][CH:2]([CH2:16][NH:20][CH:17]([CH3:19])[CH3:18])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1
Reactant: O=c1[nH]ncc2ccc(OCC3CO3)cc12
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc2cn[nH]c(=O)c2c1

Procedure:
7-(2,3-Epoxypropoxy)-1(2H)-phthalazinone was reacted with isopropylamine in a similar manner to that described in Example 1(iv) to give 7-(2-hydroxy-3-isopropylaminopropoxy)-1(2H)-phthalazinone, the hydrochloride of which had m.p. 232°-235°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10](Cl)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:5][CH:4]=1.[C:21]([NH:25][NH2:26])(=O)[CH2:22][CH3:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:22]([C:21]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:26][N:25]=1)[CH3:23]
Reactant: CCC(=O)NN
Reactant: COc1ccc(N=C(Cl)c2cccc([N+](=O)[O-])c2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1nnc(-c2cccc([N+](=O)[O-])c2)n1-c1ccc(OC)cc1
Yield: 56.8 %

Procedure:
Using the procedure of Step B of Example 4, 15 g of the product of Step A and 8.8 g of propionic acid hydrazide in 200 ml of toluene and 14 ml of triethylamine were reacted to obtain 9.5 g of 3-ethyl-4-(4-methoxyphenyl)-5-(3-nitrophenyl)-4H-1,2,4-triazole melting at 126° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:22][CH2:21][C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([OH:19])[CH2:25][CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OC1(c2ccccc2)CCNCC1
Product: OC1(c2ccccc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and 4-hydroxy-4-phenylpiperidine via General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-phenyl-piperidin-4-ol.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23](Cl)=[O:24])=[N+:19]=[N-:20].Cl>ClCCCl>[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([N:5]1[CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4]1)=[O:24])=[N+:19]=[N-:20]
Reactant: CC1(C)CCNCC1
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC1(C)CCN(C(=O)CC(C)(C)N=[N+]=[N-])CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a stirred ice cold solution of 4,4-dimethylpiperidine (4.21 g, 1 equiv, 37.2 mmol) and DIEA (9.73 mL, 1.5 equiv, 55.9 mmol) in anhydrous DCE (65 mL) was added 3-azido-3-methylbutanoyl chloride (6.02 g, 37.2 mmol) in small portions. The reaction was stirred and left at 0° C. for 1 h. Aqueous 1 M HCl (100 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with 1 M HCl (100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (7.72 g, 87.1%). The crude oil was purified on an ISCO purification system with gradient elution from 20-50% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a colorless oil (6.00 g, yield: 67.7%). 1H NMR (CDCl3, 400 MHz): δ 0.98 (s, 6H), 1.32-1.39 (m, 4H), 1.45 (s, 6H), 2.52 (s, 2H), 3.42-3.47 (m, 2H), 3.55-3.60 (m, 2H). LRMS (ESI+) for C12H22N4O (238.2); Found: 239 (M+).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[N:16]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>CN(C=O)C>[F:55][C:56]([F:60])([F:59])[CH2:57][NH:58][C:18]([C:14]1[N:15]([CH3:17])[N:16]=[C:12]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH2:21][OH:22])[CH:13]=1)=[O:20]
Reactant: CCCCc1noc(CO)c1COc1cc(C(=O)O)n(C)n1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(CO)c1COc1cc(C(=O)NCC(F)(F)F)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 5-(3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 0.16 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (57 mg, 0.18 mmol), N,N-diisopropyl ethyl amine (138 μL, 0.8 mmol) and 2,2,2-trifluoroethylamine HCl (24 mg, 0.18 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (47 mg, 75%) as a colorless oil. MS: m/e=391.2 [M+H]+.\
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:38]([O-])=[O:39].[NH4+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:20][CH2:21][N:22]([CH:38]=[O:39])[CH2:23][CH2:24]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCNCC3)c2=O)cc1OC
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 97.9 %

Procedure:
A mixture of 0.6 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione obtained in stage 1.6 and 0.113 g of ammonium formate in 5 ml of ACN is irradiated under a microwave field at 140° C. for 1 h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.62 g of the expected product.
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:34]=[C:35]4[CH2:46][CH2:45][NH:44][CH2:43][C:36]4=[N:37][C:38]=3[NH:39][CH:40]([CH3:42])[CH3:41])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.C=O>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:34]=[C:35]4[CH2:46][CH2:45][N:44]([CH3:2])[CH2:43][C:36]4=[N:37][C:38]=3[NH:39][CH:40]([CH3:42])[CH3:41])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCNC2
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCN(C)C2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (6.5 mg, 0.031 mmol) was added to a solution of DIPEA (5 μL, 0.031 mmol), (5-chloro-2-fluorophenyl)(1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone TFA salt (8.4 mg, 0.015 mmol) and formaldehyde (1.5 μL, 0.015 mmol) in MeOH (150 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (4.7 mg, 54.6%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.82-1.93 (m, 2H), 1.97-2.05 (m, 2H), 2.81-3.05 (m, 4H), 3.08 (s, 3H), 3.35-3.54 (m, 4H), 3.72-3.83 (m, 1H), 4.10-4.18 (m, 1H), 4.19-4.40 (m, 2H), 7.25-7.32 (m, 1H), 7.61 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.75 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 446.3.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[C:10]1([CH:9]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1Cl
Solvent: CCO
Product: Clc1ccccc1N=Cc1ccccc1
Temperature: 90 °C
Yield: 81 %

Procedure:
98% 2-chloroaniline (781 g; 6 mol) and 98% benzaldehyde (659.6 g; 6 mol) were dissolved in ethanol (832 g), and the solution was boiled under reflux for 8 h (heating apparatus adjusted to 90° C.). Subsequently, the reaction solution was concentrated on a rotary evaporator at 85° C. and 20 mbar and then fractionally distilled through a distillation apparatus. The main fraction distilled over at 142° C. and 1.3 mbar. 1048 g of the product were obtained in 99% purity.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cu][C:14]#[N:15].[C-]#N.[Na+].C(OCC)(=O)C>O>[C:14]([C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])#[N:15]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)cc1C#N
Temperature: 195 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), copper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 123a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(c2nncc3cc(Br)ccc23)CC1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.12 g, 0.5 mmol), 1-methylpiperazine (0.11 mL, 1.0 mmol) and potassium carbonate (0.07 g, 0.5 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for about 20 min. After about 20 min. all starting material was converted to product (M+1=307, 309). The mixture was concentrated under vacuum and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2M ammonia in MeOH/DCM to give (0.14 g) 6-bromo-1-(4-methylpiperazin-1-yl)phthalazine as a yellow solid. Found MS (ES+): 307, 309(M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([OH:20])[C:6]2[C:7](=[O:19])[C:8]3[C:13]([C:14](=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=3[OH:18].[OH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][OH:27]>CN(C)C=O>[OH:21][CH2:22][CH2:23][N:24]([CH2:2][C:3]1[CH:4]=[C:5]([OH:20])[C:6]2[C:7](=[O:19])[C:8]3[C:13]([C:14](=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=3[OH:18])[CH2:25][CH2:26][OH:27]
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cc(CBr)cc21
Reactant: OCCNCCO
Solvent: CN(C)C=O
Product: O=C1c2cccc(O)c2C(=O)c2c(O)cc(CN(CCO)CCO)cc21
Reaction time: 2 h

Procedure:
A mixture of 3-bromomethyl-1,8-dihydroxy-9,10-anthraquinone (456 mg) and bis(2-hydroxyethyl)amine (600 mg) in N,N-dimethylformamide (20 mL) is stirred for 2 hours, and then partitioned between chloroform (100 mL) and water (100 mL). The organic layer is separated, washed with water (50 mL×3), dried over sodium sulfate, and then concentrated to dryness. The residue is chromatographed on a silica gel column using chloroform-methanol (15:1 v/v) as the eluent. Upon concentration of the major fraction, 3-[N,N-bis(2-hydroxyethyl)amino]methyl-1,8-dihydroxy-9,10-anthraquinone is obtained as a solid: 1H NMR (CDCl3) δ: 2.77 (4H, t, NCH2CH2O), 3.78 (4H, t, NCH2CH2O), 3.78 (2H, s, CH2N=), 7.21-7.79 (5H, m, aromatic H), 11.95 (1H, s, OH), 12.00 (1H, s, OH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH:14]([NH2:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11]C)C.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:16]([CH:14]([CH2:13][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:1])[CH:5]=2)[CH3:15])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOc1ccc(CC(C)N)cc1OCC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(C)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.67 h
Yield: 53.2 %

Procedure:
To a stirred solution of 3-(3,4-diethoxyphenyl)-2-aminopropane (1.95 grams, 10.0 mmol) and sodium carbonate (1.06 grams, 10.0 mmol) in 50 milliliters of water was added N-carbethoxyphthalimide (2.19 grams/10.0 mmol). After 10 minutes the reaction mixture was diluted with 40 milliliters of acetonitrile and the mixture stirred for 40 minutes. The reaction solution was partially concentrated in vacuo to remove the acetonitrile. The resulting mixture of an oil and aqueous layer was extracted with methylene chloride (25 milliliters). The organic extract was dried over sodium sulfate and concentrated in vacuo to afford a crude product which was purified by flash chromatography to afford 1.73 grams (53%) of product as a thick oil which slowly solidified to a white wax: 1H NMR (dmso-d6, 250 MHz) δ 7.7 (m, 4 H, Ar), 6.7 (m, 3 H, Ar), 4.63 (m, 1 H, CH), 3.79 (s, 3 H, Ome), 3.73 (s, 3 H, OMe), 3.28 (dd, 1 H, J=13.8, 9.8 Hz) 3.03 (dd, J=13.8, 6.5 Hz, 1 H), 1.54 (d, J=6.9 Hz, 3 H); 13C NMR (dmso-d6) δ 168.4, 148.6, 147.4, 133.7, 131.8, 130.9, 122.9, 120.9, 111.1, 55.7, 55.6, 48.6, 39.3, 18.3 Anal. Calcd for C19H19NO2. Theoretical C, 70.14; H, 5.89; N, 4.30. Found C, 70.08; H, 5.83; N, 4.30.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2cc[nH]c2cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc2cc[nH]c2cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 90.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5 mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K2CO3 (1.6 g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred at reflux under nitrogen for 40 hours. The cooled reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, washed with brine, dried with MgSO4, and concentrated to yield 4.0 g of a solid. The compound was recrystallized from ethanol to afford 3.3 g. Another recrystallization from ethanol (utilizing a charcoal treatment) provided 2.9 g (66%) of 6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]-propyl]-4-piperidinyl]-1,2-benzisoxzole as a beige solid, m.p.=156°-158° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:16][NH2:17]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:16][NH2:17])=[N:3][CH:4]=[CH:5][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: NN
Reactant: Cc1ccc(-c2ccnc(Cl)c2Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccnc(NN)c2Cl)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 2,3-dichloro-4-p-tolylpyridine (711 mg, 3.0 mmol) in THF (5 mL) at room temperature under argon was added hydrazine (288 mg, 9.0 mmol). The reaction mixture was heated at 60° C. under argon for 5 h. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. Water (25 mL) was added to the residue while stirring. Solid precipitate was collected by filtration and further washed with water (15 mL×2). After drying in a vacuum oven under reduced pressure overnight, 692 mg of nearly pure title compound was obtained as an off-white solid. HPLC/MS: retention time=2.10 min, [M+H]+=234.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[NH:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([C:34]4[CH:35]=[CH:36][NH:32][N:33]=4)[CH:38]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc(-c2cc[nH]n2)c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(-c3cc[nH]n3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-pyrazol-3-yl)aniline (Apollo, 107 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:34](=[O:50])[N:35]([CH2:39][CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C)[CH2:36][CH2:37][CH3:38])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:34](=[O:50])[N:35]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:36][CH2:37][CH3:38])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(N)CC(C(=O)N(CCC)CCCO)=C3)cc1
Reaction time: 1 h

Procedure:
Butyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded butyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.59-7.63 (m, 2H), 7.50-7.51 (m, 1H), 7.34-7.38 (m 2H), 7.32-7.34 (m, 2H), 6.88 (s, 2H), 4.09-4.14 (m, 2H), 3.58-3.68 (m, 6H), 3.45-3.51 (m, 2H), 2.87 (s, 2H), 1.79-1.88 (m, 2H), 1.57-1.76 (m, 4H), 1.30-1.42 (m, 2H), 0.89-0.96 (m, 6H); m/z (APCI-pos) M+1=492.2.