Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>C(O)C>[NH2:12][C:11]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[N:22]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of ethyl ethoxymethylenecyanoacetate (3 g, 17.7 mmol) and 4-chlorophenylhydrazine hydrochloride (3.33 g, 18.6 mmol) in ethanol (60 mL) was refluxed for 2 days, following the procedure described in Schmidt, P. et al. Helv.Chim.Acta, 1959, 349. The reaction mixture was then allowed to cool to room temperature, whereupon a precipitate was formed. Cold CHCl3 was added, the precipitate was filtered and washed with more CHCl3. The filtrate and the washings were evaporated to dryness, precipitated with ether, filtered and dried to give ethyl 5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate (2.25 g, 48%) as a white solid: mp 150°-156° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 7.77 (s, 1H, pyrazole), 7.48 (s, 4H, arom), 4.30 (q, J=7, 2H, OCH2), 1.36 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H12ClN3O2 : C 54.25; H 4.55; N 15.81. Found: C 54.77; H 4.49; N 15.65.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=1.[CH2:13](O)[CH2:14][OH:15].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[O:15][CH2:14][CH2:13][O:11]2)[CH:5]=1
Reactant: OCCO
Reactant: COC(=O)c1cccc(C=O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C2OCCO2)c1
Yield: 100.5 %

Procedure:
A solution of 3-formyl-benzoic acid methyl ester (9.48 g, 57.8 mmol), ethylene glycol (8.97 g, 144.5 mmol, 2.5 eq.) and conc. sulfuric acid (0.18 g, 1.8 mmol) in toluene was heated under Dean-Stark reflux for 3 hrs. After cooling, satd. NaHCO3 (100 ml) was added. The aqueous phase was extracted with EtOAc, the combined organic phases were dried over Na2SO4 and evaporated to afford the title compound (12.1 g, 101% yield) as a yellow liquid. MS: m/e=164 (M+).
Reaction SMILES: CS[CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].O[O:13][S:14]([O-:16])=O.[K+].OS([O-])(=O)=O.[K+].[CH3:24]O>O>[CH3:24][S:14]([CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])(=[O:16])=[O:13]
Reactant: CSCCNC(=O)C(F)(F)F
Reactant: CO
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A solution of N-(2-methylthioethyl)trifluoroacetamide (19.0 g, 109.7 mmol) in methanol (200 ml) was cooled to 0° C. using an ice bath. A suspension of Oxone™ (2KHSO5.KHSO4.K2SO4) (74.19 g, 120.67 mmol) in water (100 ml) was added portionwise over 10 minutes, and the reaction was stirred at room temperature for 24 hours. The methanol was removed in vacuo, water (600 ml) was added and the mixture was extracted with dichloromethane (3×300 ml). The combined extracts were dried (MgSO4), and concentrated in vacuo to give the title compound as a white solid (12.42 g, 56.7 mmol, 52%); δH CDCl3 7.33 (1H,br s), 3.93 (2H,q), 3.31 (2H,t), 3.02 (3H,s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:15][CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:16]([OH:18])=O)[S:9][C:8]=3[C:7]=2[CH:19]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[NH:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C=O)C.C(#N)C>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[N:29]([CH3:30])[C:16]([C:10]1[S:9][C:8]2[C:7]3[CH:19]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=1)=[O:18]
Reactant: N#Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CCO2
Reactant: CNc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-cyano-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (300 mg) in dichloromethane (10 mL) was added DMF (1 drop) and oxalyl chloride (0.165 mL) and the reaction stirred at room temperature for 30 min. The solvent was then reduced in vacuo and the residue redissolved in acetonitrile (10 mL). To this solution was added 2-chloro-N-methylaniline (0.165 mL) and potassium carbonate (308 mg) and the reaction stirred at room temperature for 16 h. The mixture was partitioned between water (40 mL) and ethyl acetate (30 mL). The organic layer was dried (Na2SO4), reduced in vacuo and purified on silica to give 120. NMR: (CDCl3): 3.08 (t, 2H, CH2, J=5.00 Hz), 3.41 (s, 3H, CH3), 4.29 (t, 2H, CH2, J=5.02 Hz), 6.92 (s, H, ArH), 7.03 (d, H, ArH, J=8.43 Hz), 7.38-7.47 (m, 4H, 4×ArH), 7.57 (m, H, ArH), 7.72 (d, H, ArH, J=1.65 Hz). MS: (ESI+) MH+ 395
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>>[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1
Yield: 68.5 %

Procedure:
2-Bromo-4-nitroquinoline (50 mg, 0.2 mmol) and tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66 mg, 0.2 mmol) were reacted using General Procedure (A) to afford tert-butyl methyl(4-(4-nitroquinolin-2-yl)phenyl)carbamate as a yellow oil (52 mg, 68%). 1H NMR (400 MHz, CDCl3): δ 8.43-8.40 (m, 2H), 8.28 (m, 1H), 8.19 (m, 2H), 7.87 (m, 1H), 7.73 (m, 1H), 7.46 (m, 2H), 3.35 (s, 3H), 1.59 (s, 3H), 1.50 (s, 9H); MS (ESI): 380 (M+H+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[C:19]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:18])([F:17])[F:1])=[CH:10][CH:11]=1)#[CH:19]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a stirred suspension of the product of Example 36, Step A, (0.21 g, 1 mmol) and K2CO3 (0.166 g, 1.1 mmol) in anhydrous MeOH (5 mL) was added a solution of dimethyl 1-diazo-2-oxopropylphosphonate (0.212 g, 1.1 mmol) in anhydrous MeOH (1 ml) and the mixture was stirred overnight at room temperature. The solvent was evaporated to dryness and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4, and filtered. The filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the product (0.21 g, 85.4%), as creamy paste, which was used as such in next step. 1H-NMR (CDCl3) 3.11 (s, 1H); 7.25-7.31 (m, 3H); 7.44-7.55 (m, 4H); 7.73 (d, 1H, J=7.69 Hz).
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[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[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[CH:10]=[C:9]([CH2:11][N:20]([CH3:19])[CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:8][C:6]=2[N:7]=1
Reactant: CNC1CCN(C)CC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (0.3 g, 1.0 mmol) in 1,2-dichloroethane (3.6 mL) was added N,1-dimethylpiperidin-4-amine (1.4 mmol), and AcOH (1.0 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (1.1 mmol) was added then the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford pure N-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N,1-dimethylpiperidin-4-amine (0.2 g). MS (Q1) 410 (M)+
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[C:48]([CH3:50])[N:49]=[C:23]23)=[CH:17][CH:16]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[C:48]([CH3:50])[N:49]=[C:23]23)=[CH:17][CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(CC)nc2)c2nc(C)nn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(Cc2ccc(CC)nc2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.9 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[(6-ethylpyridin-3-yl)methyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.22 g, 46%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:18][CH2:17]1)[CH3:2].C(=O)(O)[O-].[Na+].[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[N:55][N:54]=[N:53]2)=[CH:47][C:43]=1[C:44](Cl)=[O:45]>C(OCC)(=O)C.CCCCCC.CC(C)=O.C(OCC)(=O)C>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[N:55][N:54]=[N:53]2)=[CH:47][C:43]=1[C:44]([N:26]1[CH2:27][CH2:28][C:24]([CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][CH:16]([NH:15][C:7]3[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:17][CH2:18]2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25]1)=[O:45]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(Cn2cnnn2)cc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(Cn5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (1.5 mmol) and sodium bicarbonate (0.93 g, 11.07 mmol) in acetone/water (1/1, 40 mL). Cool in an ice bath. Add a solution of 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl chloride (0.38 g, 1.49 mmol) in acetone (25 mL). After 18 hours, dilute the reaction mixture with ethyl acetate and extract twice with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel to give the title compound
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1.[BH4-].[Na+]>O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CNCc2ccc(OC)cc2)cc1
Temperature: 5 °C

Procedure:
p-Anisaldehyde (411 mmol), 4-methoxybenzylamine (411 mmol) and toluene (500 mL) were combined in a round bottomed flask fitted with a condenser and a Dean-Stark trap. The reaction was refluxed for 1 h during which water was removed from the reaction mixture. The reaction was cooled and concentrated. The residue was dissolved in MeOH (120 mL). The mixture was cooled to 5° C. and NaBH4 (205 mmol) was added in portions over 45 min. The reaction was slowly heated to reflux. After 2 h at reflux, the reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc. The organic layer was washed (3×H2O and brine), dried (Na2SO4) and concentrated to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:14][N:15]1[C:19]([NH2:20])=[N:18][N:17]=[C:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(O)C(F)(F)F.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:20][C:19]2=[N:18][N:17]=[C:16]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[N:14]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: O=C1Nc2c(Cl)ccc(Cl)c2C1=O
Solvent: O
Solvent: OCC(F)(F)F
Product: Oc1ccc(Cc2nnc3nc4[nH]c5c(Cl)ccc(Cl)c5c4nn23)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
In a pressure tube, 0.60 mmol of 4,7-dichloro-1H-indole-2,3-dione (130 mg) and 0.65 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (133.5 mg) in a mixture of trifluoroethanol (8 mL) and water (4 mL) was stirred at 125° C. overnight (16 hr). The mixture was cooled to room temperature, allowed to crystallize for 2 hours. The precipitated product was collected by filtration, washed with MeOH+water 1:1, then with chilled MeOH. Dried on high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[C:38](I)=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Si:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([C:38]1[C:29]([Cl:28])=[N:30][C:31]3[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:10]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Clc1nc2ccccc2cc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 90 °C

Procedure:
A deoxygenated mixture of 1-(tert-butoxycarbonyl)-5-{[tert-butyl(dimethyl)silyl[oxy}-1H-indol-2-ylboronic acid 1-6 (4.10 g, 10.5 mmol, 1 equiv), 2-chloro-3-iodo-quinoline (1-2, 3.64 g, 12.6 mmol, 1.20 equiv), potassium phosphate (6.67 g, 31.4 mmol, 3.00 equiv), and tetrakis(triphenylphosphine)palladium (0.605 g, 0.524 mmol, 0.050 equiv) in dioxane (100 mL) was heated at 90° C. for 20 h. The reaction mixture was cooled, then partitioned between a mixture of water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (20% dichloromethane in hexanes, grading to 90% dichloromethane in hexanes) to give tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (1-7) as a tan-colored foam. 1H NMR (400 MHz, CDCl3) δ8.16 (s, 1H), 8.15 (d, 1H, J=9.0 Hz), 8.07 (d, 1H, J=8.2 Hz), 7.86 (d, 1H, J=7.8 Hz), 7.77 (br t, 1H, J=8.4 Hz), 7.60 (br t, 1H, J=8.1 Hz), 7.03 (d, 1H, J=2.4 Hz), 6.92 (dd, 1H, J=9.0, 2.4 Hz), 6.55 (s, 1H), 1.26 (s, 9H), 1.02 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[P:15]([O:22]CC)([O:19]CC)[O:16]CC.BrCC.Cl>O>[CH:2]([P:15](=[O:16])([OH:22])[OH:19])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCBr
Product: O=P(O)(O)C(c1ccccc1)c1ccccc1
Yield: 81 %

Procedure:
Benzhydrylphosphonic acid was prepared as follows. 308.93 g (1.25 moles) of bromodiphenylmethane (Aldrich Chemical Company) and 240.93 g (1.45 moles) of triethyl phosphite (Aldrich Chemical Company) were combined under nitrogen, heated carefully and maintained at 160° C. with removal of bromoethane by-product by distillation over a period of 4 hours. 750 ml of concentrated hydrochloric acid (~12 molar) and 250 ml of distilled water was added to the crude product and the mixture was refluxed under nitrogen for two days (approximately 40 hours). The frothy mixure was allowed to cool and then filtered. The resulting solid was then washed with water, to remove the remaining hydrochloric acid, and then with petrol (b.p. 60°-80° C.), to remove hydrocarbon by products, for example 1,1,2,2-tetraphenylethane. The solid was then dried in a vacuum oven at 120° C. 250.06 g (81% yield) was obtained.
Reaction SMILES: O[C:2]1([Cl:12])[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][CH:3]1[CH2:4][CH2:5][NH2:6].CN(C)/[CH:15]=[N:16]/[N:17]=[CH:18]/N(C)C.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>C1(C)C=CC=CC=1>[OH:30][CH:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:12])[CH2:5][N:6]1[CH:18]=[N:17][N:16]=[CH:15]1
Reactant: NCCC1C=CC(Cl)=CC1(O)Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)/C=N/N=C/N(C)C
Solvent: Cc1ccccc1
Product: OC(Cn1cnnc1)c1ccc(Cl)cc1Cl
Yield: 200.2 %

Procedure:
A mixture of 1.5 g (0.007 m) of 2-hydroxy-2,4-dichlorophenethyl amine, 1.5 g (0.01 m) of N,N-dimethylformamide azine, 0.5 g of toluene p-sulfonic acid in 50 ml of toluene is heated under reflux overnight. Solvent is evaporated under reduced pressure. The residue is taken up in methylene chloride and the free base is purified by converting it to its hydrochloride salt and back neutralized with ammonium hydroxide solution to give 1.5 g of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1
Reactant: COc1ccc(C)c(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 2-methyl-5-(methyloxy)phenol (Intermediate 12, 2 g) and 2-chloro-5-nitropyridine (2.1 g, 13.2 mmol) in DMF (50 mL) was added potassium carbonate (2.76 g, 20 mmol) and the reaction mixture was stirred at 100° C. overnight. The mixture was evaporated under vacuum and water (100 mL) was added. It was extracted with ethyl acetate (3 times 100 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by column chromatography on silica gel (mobile phase: EtOAc/PE=1/50-1/20) to give the title compound (1.5 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([N:8]1[CH2:9][CH2:10][N:5]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH2:27][CH2:28][C:29]5[N:30]([C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=5)[N:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCN4CCNCC4)cc3)CC1)CC2
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
A solution of acetyl chloride (0.027 mL, 0.38 mmol) in DCM (0.5 mL) was added dropwise to 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.31 mmol) and triethylamine (0.088 mL, 0.63 mmol) in DCM (1 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 5 minutes then allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and then the organic layer was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of is water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (80 mg, 49%) as a gum.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=1.O>C(N)(CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CC(=O)NC(C)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: O
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 45.5 mg (0.15 mmol) N-(1-(4-iodophenyl)propan-2-yl)acetamide (I52.1) and 27.3 mg (0.20 mmol) 1-chloro-4-ethynylbenzene in 750 μl sec-butylamine are added 14.3 (0.02 mmol) bis(triphenyphosphine)dichloropalladium (in 400 μl sec-butylamine) followed by 1.0 mL water. The reaction mixture is stirred at r.t. overnight. The solvent is removed in vacuo and the residue is purified by HPLC (ACN/H2O/TFA).