Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[S:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=O)C.N>CO>[C@@H:9]1([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[S:16])[NH:14][C:12]2=[O:13])[O:10][C@H:6]([CH2:5][OH:4])[CH:7]=[CH:8]1
Reactant: CC(=O)OC[C@@H]1C=C[C@H](n2cc(C)c(=S)[nH]c2=O)O1
Agent: N
Solvent: CO
Product: Cc1cn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]c1=S
Reaction time: 12 h

Procedure:
To 100 mg of the compound synthesized in Example 9, 10 mL of methanol are added, which had been saturated at 0° C. with ammonia. The reaction mixture is kept for 12 hours at room temperature and then evaporated to dryness. Crystals, melting at 117° C.-118° C., are obtained from methanol/ether.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1
Yield: 63.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.300 g), KOH (0.300 g), water (5 mL) and THF (10.0 mL) to afford 0.150 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[I:12]Cl>CO>[I:12][C:5]1[CH:4]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=[CH:7][C:6]=1[NH2:9]
Reactant: ClI
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Preparation B5, Step 1: To a solution of 4-(trifluoromethyl)benzenamine (10.0 g, 0.0617 mol) in dry methanol (200 ml) was added iodine monochloride (10.49 g, 0.148 mol) in dry MDC (40 ml) at RT slowly. Reaction mixture was stirred at RT over night. The reaction mixture was concentrated, water was added and extracted with ethyl acetate (2×100 ml). The organic layer was washed with water, brine (2×50 ml), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 6% ethyl acetate in pet-ether to get 2-iodo-4-(trifluoromethyl)benzenamine (12.5 g, 70%) as pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ 4.42 (bs, 2H), 6.75 (d, 1H), 7.38 (d, 1H), 7.87 (s, 1H).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C@H:14]([NH2:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[NH:18][CH:17]=1>CO>[CH3:13][C@H:14]([NH:27][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[NH:18][CH:17]=1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: COc1ccc2[nH]cc(C[C@H](C)N)c2c1
Solvent: CO
Product: COc1ccc2[nH]cc(C[C@H](C)NC[C@H](O)c3ccc4nnnn4c3)c2c1
Yield: 54.4 %

Procedure:
A solution of 350 mg of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 429 mg of (S)-1-methyl-2-(5-methoxy-1H-indol-3-yl)ethyl amine (R. A. Glennon et al., Biol. Psychiatry, 18, 493 (1983) in 8 ml of methanol was heated at reflux under nitrogen for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue (765 mg) was purified twice by preparative TLC on silica gel (95:5:0.5 CH2Cl2 :MeOH:NH4OH) to give 419 mg of (R)-α-[[(1(S)-methyl-2-(5-methoxy-1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH2:7].[N+:8]([C:11]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:12]=1[O:13][CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])([O-:10])=[O:9]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:20]=[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:22]=[CH:23][C:11]=1[N+:8]([O-:10])=[O:9])[CH2:18][CH3:19]
Reactant: NCC1OCCO1
Reactant: CCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCC1OCCO1
Temperature: -15 °C

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]butanoyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]butyramide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([CH:28]=C)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1.I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1)[CH:28]=[O:32]
Reactant: C=Cc1c(F)c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c1OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
N-[1-(5-Chloro-4-fluoro-2-methoxy-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (240 mg, 0.56 mmol) was dissolved in THF (10 mL) and 0.16 M osmium tetraoxide in water (700 μL) was added. Sodium metaperiodate (360 mg, 1.7 mmol) and water (1 mL, 60 mmol) were added. The reaction was stirred at 60° C. for 2 hours. Reagents were doubled. 0.16 M osmium tetraoxide in water (700 μL) was added. Sodium metaperiodate (360 mg, 1.7 mmol) and water (1 mL) were added and the mixture was warmed to 60° C. for another 2 hours. The mixture was evaporated and the solids were extracted with dichloromethane. The extracts were purified on silica gel using 0-60% EtOAc in hexanes to give the desired compound (50 mg, 20%). LCMS calculated for C20H22ClFN5O3 (M+H)+: m/z=434.1. found: 434.1.
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][C:6]=1[OH:13]>CN(C=O)C.O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][C:6]=1[OH:13]
Reactant: [C-]#N
Reactant: Oc1cc(CBr)ccc1Br
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)c(O)c1
Temperature: 60 °C

Procedure:
A suspension of KCN (16.0 g, 238.3 mmol) in DMF (100 mL) was heated at 60° C. for 30 min. The slurry was cooled to room temperature and treated with a solution of 2-bromo-5-bromomethylphenol 72 (4.16 g, 15.7 mmol) in DMF (50 mL). The resultant mixture stirred at room temperature for 23 h, and then was diluted with water and extracted with ethyl acetate (5×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to afford impure (4-bromo-3-hydroxy-phenyl)acetonitrile 73. To a solution of KOH (26.5 mg) in MEOH (1.5 mL) was added (4-bromo-3-hydroxy-phenyl)-acetonitrile 73 (100.0 mg), the resulting mixture was stirred at room temperature for 10 min then conentrated in vacuo. DMSO (3 mL) and methanesulfonic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester, (prepared from 2-(1-methyl-pyrrolidin-2-yl)-ethanol, methane sulfonyl chloride in presence of triethylamine) were added. The reaction mixture was stirred at room temperature overnight. DCM (80 mL) was added and the organics washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was dried with MgSO4. The residue was purified by silica gel column chromatography (eluent: DCM/MeOH, 4/1) to give 74. MS (EI) m/z (M+H+) 324.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[N:18]2[CH:19]=[C:20]([O:23][C@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@@H:27]([NH2:34])[CH2:26][CH2:25]3)[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1)(C)C.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:53][C:54](=O)[NH:55][C:56]1[N:57]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:58]=[C:59]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH:60]=1>O1CCOCC1>[C:61]([C:59]1[CH:60]=[C:56]([NH:55][C:54]([NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]4[N:18]([C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[CH2:8][CH2:7][CH2:6][OH:5])=[N:15][N:16]=4)[CH:19]=3)[CH2:25][CH2:26]2)=[O:53])[N:57]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:58]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5CCCO)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of Intermediate 84g (140 mg, 0.25 mmol) in 1,4-dioxane (3.00 mL) was added DIPEA (86.0 μL, 0.50 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 100 mg, 0.25 mmol). The reaction was heated to 60° C. overnight then further (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (50.0 mg, 0.12 mmol) was added and heating at 60° C. continued overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (70.0 mg, 34%). LCMS (Method 1): Rt 3.46, m/z 820.4 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[H][H]>[Pd].CO>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc(N)c(N)c1

Procedure:
Methyl 6-amino-5-nitronicotinate (9.0 g, 46 mmol) and a small amount of Pd/C cat. were added to methanol (200 ml) and the mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. Following filtration through celite, the methanol was evaporated under reduced pressure to give the title compound, 7.0 g (92%).
Reaction SMILES: C1CO[C:3]2([C:6]([Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])=[C:5]([CH3:20])[C:4]2=[O:21])[O:2]1.O1CCCC1.S(=O)(=O)(O)O.O>O>[CH3:20][C:5]1[C:4](=[O:21])[C:3](=[O:2])[C:6]=1[Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=C(C)C(=O)C12OCCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)c(=O)c1=O
Temperature: 22 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
2,2-Ethylenedioxy-4-methyl-3-(tri-n-butylstannyl)cyclobut-3-ene-1-one (450 mg) was added to a stirred mixture of tetrahydrofuran (4 mL) and sulfuric acid-H2O (3 mL of 1:1). The mixture was stirred at 22° C. for 2.5 hrs and then was diluted with H2O. The mixture was extracted with n-heptane (2X). The combined extracts were sequentially washed with H2O (2X) and saturated NaCl, dried (Na2SO4), and concentrated to leave the title compound (145 mg, 36% yield) as a yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[CH:16]=2)[N:11]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:9])[CH:19]=[CH:18]2
Reactant: Cc1ccc2nc(Cl)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2cc(CBr)ccc2n1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
N-Bromosuccinimide (12.9 g, 72.5 mmol) and benzoyl peroxide (0.33 g, 1.30 mmol) are added to a solution of 2-chloro-6-methyl-quinoline (12.0 g, 67.5 mmol) in carbon tetrachloride (300 mL). The mixture is heated at reflux for 6 hours. At this time, the resulting mixture is cooled to room temperature, filtered, washed with CH2Cl2 and concentrated in vacuo. The crude residue is recrystallized from 50% EtOAc/hexanes to yield the title compound (8.80 g, 34.3 mmol) as a beige crystalline solid. 1H NMR (CDCl3, 300 MHz) δ8.08 (d, 1H), 8.02 (d, 1H), 7.83 (s, 1H), 7.77 (dd, 1H), 7.40 (d, 1H), 4.65 (s, 2H). MS (EI): m/z 256, 258 (M+), Cl pattern.
Reaction SMILES: [CH:1]1[N:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[NH:5][C:6]2=O.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:6]1[C:7]2[C:2](=[CH:1][N:10]=[CH:9][CH:8]=2)[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2c2cnccc12
Solvent: CC#N
Product: Clc1nc2ccccc2c2cnccc12

Procedure:
Benzo[c][2,6]naphthyridin-5(6H)-one (1.0 eq, 813 mg, 4.15 mmol) was stirred in phosphorus oxychloride (5.0 eq, 2 ml, 21.84 mmol) and acetonitrile (10 ml). The mixture was stirred at reflux for 5 hours. The mixture was poured on ice, and the resulting solid filtered and dried. 5-chlorobenzo[c][2,6]naphthyridine was isolated as a grey solid (459 mg, 52% yield). LCMS (ES): 95% pure, m/z 215 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:9]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH3:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:39]=[CH:38][S:37][CH:36]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)=[CH:3][CH:4]=2)[CH:9]([N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])[CH3:10])=[CH:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reactant: CC(C(Cc1ccc(Cl)cc1)c1ccc(Br)cc1)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C(Cc1ccc(Cl)cc1)c1ccc(-c2ccsc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
113 mg of N-{(1RS, 2RS)-2-(4-bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl}phthalimide prepared in the same manner as in Example 114, was dissolved in 3 ml of toluene, and 99 mg of tributyl(3-thienyl)tin and 14 mg of tetrakis(triphenylphosphine)palladium (0) were added thereto. The mixture was refluxed under heating for 3 hours in a light-shielding nitrogen atmosphere. The reaction solution was left to cool to room temperature. Then, 2 ml of a 5% potassium fluoride aqueous solution was added thereto, and the mixture was stirred for 30 minutes. Insoluble matters were separated by filtration. Then, ethyl acetate and water were added to the filtrate for liquid separation. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=100/1→30/1) to obtain 83 mg of N-[(1RS, 2RS)-3-(4-chlorophenyl)-1-methyl-2-{4-(3-thienyl)phenyl}propyl]phthalimide
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C#N)CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Ammonium chloride (7.0 g) and iron powder (36.6 g) were added to a mixed solvent of water (180 ml) and ethanol (540 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(4-tert-butoxycarbonylpiperazin-1-yl)benzonitrile (62.1 g) was added in parts over 40 min and the mixture was stirred at a refluxing temperature for 1 h. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution, and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (50.7 g), melting point: 145° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[CH2:8][C:6]=2[N:7]=1.[CH2:22]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)=[O:27])[CH2:23][CH3:24]>>[CH:12]1([CH2:11][N:9]2[CH2:10][C:5]3[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])=[N:3][C:2]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][C:26]([NH:25][CH2:22][CH2:23][CH3:24])=[O:27])=[CH:34][CH:33]=4)=[N:7][C:6]=3[CH2:8]2)[CH2:14][CH2:13]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Reactant: CCCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC2CC2)C3)cc1

Procedure:
Method as described for example 47 using intermediate 8 and 1-propyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials. Purified by prep. LCMS (low pH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[CH3:12])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:8]=2)[N:7]=1
Reactant: CC(C(=O)NNc1ccc(Cl)nn1)c1ccc2ncccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12

Procedure:
A solution of N′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide (4300 mg, 13119 μmol) in TFA (40 mL) was heated to 120° C. with microwaves for 40 min. LCMS suggests very good conversion. Solvents removed under reduced pressure and residue partitioned between 9:1 CHCl3/IPA (75 mL) and 1M NaOH (100 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×25 mL). Combined organics dried over MgSO4, concentrated, and oily residue dissolved in ACN/MeOH (2 mL). Resulting solid after 2 h was isolated by filtration and washed with ACN (5 mL). 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline isolated as a white solid. MS (EST pos. ion) m/z: 310 (MH+). Calc'd exact mass for C16H12ClN5: 309.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.[I:10]N1C(=O)CCC1=O>C(O)(=O)C>[I:10][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([NH2:9])=[N:6][CH:7]=1
Reactant: COc1ccnc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: COc1nc(N)ncc1I
Temperature: 80 °C

Procedure:
To a solution of 4-methoxy-pyrimidin-2-ylamine (405 mg) in acetic acid (10 mL) was added N-iodosuccinimide (950 mg) and the mixture was heated at 80° C. for 4 h. After cooling to room temperature, the reaction was quenched with 5% aqueous sodium thiosulphate solution (20 mL) and the solvent removed in vacuo. The product was then extracted into dicholoromethane (3×20 mL) and the combined organics were washed with brine (40 mL), dried (MgSO4) and reduced in vacuo to give 5-iodo-4-methoxy-pyrimidin-2-ylamine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1OC(=O)c2c(OCc3ccccc3)cccc21
Reaction time: 72 h
Yield: 68.7 %

Procedure:
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (0.51 g, 3.09 mmol) in anhydrous N,N-dimethylformamide (7 ml) under nitrogen was added sodium hydride (130 mg, 3.25 mmol). Immediate evolution of gas and bright yellow color was observed. The mixture was stirred for 5 minutes after which benzyl bromide (1.8 ml, 15.45 mmol) was added. The reaction was stirred for 72 hours. Saturated sodium bicarbonate (2 ml) was added and the mixture stirred for 2 minutes, diluted in ethyl acetate (35 ml) and washed with saturated sodium bicarbonate (5 ml), 1N hydrochloric acid (5 ml), and brine (2×5 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. To the crude material was added hexane and the formed precipitate was filtered off, washed further with hexane and dried in vacuo to give 0.54 g (69%) of 4-(benzyloxy)-isobenzofuran-1,3-dione as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N+:5]([O-])=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12
Reactant: [O-][n+]1c(OC2CCCC2)cc(Cl)c2c1CCC2
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: Clc1cc(OC2CCCC2)nc2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of crude 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.49 mmol) in methylene chloride (5 mL) was added phosphorous trichloride (0.100 g, 0.74 mmol). The mixture stirred at rt for 2 h. After this time, the mixture was quenched with a saturated solution of NaHCO3 and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.029 g, 25% over two steps) as a clear oil. MW=237.73. 1H NMR (CDCl3, 300 MHz) δ 6.45 (s, 1H), 5.34-5.26 (m, 1H), 3.01-2.84 (m, 4H), 2.11 (quip; J=7.5 Hz, 2H), 2.00-1.57 (m, 8H); APCI MS m/z 238 [M+H]+.