Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.C(I)I.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22](=[CH2:26])[CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C:22]1([CH2:1][CH2:26]1)[CH2:21][CH2:20]2
Reactant: CC[Zn]CC
Reactant: C=C1CCc2cc(Br)ccc21
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c(c1)CCC21CC1
Yield: 94.9 %

Procedure:
The title compound was synthesized in analogy to example S87 using diethyl zinc (3.25 ml, 1M solution in hexane, 3.25 mmol), trifluoroacetic acid (251 μl, 3.25 mmol), CH2I2 (262 μl, 3.25 mmol) and 5-bromo-1-methyleneindan (340 mg, 1.63 mmol). The isolated residue was purified by flash column chromatography (100% pentane) to give 5′-bromo-2′,3′dihydro-spiro[cyclopropane1,1′-[1H]indene](345 mg, 95%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.40-7.29 (m, 3H), 3.02 (apt t, J=7.5 Hz, 2H), 2.11 (apt t, J=7.5 Hz, 2H), 0.96-0.84 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[CH:10]=2)[O:3]1.Br[C:30]1[CH:51]=[CH:50][C:33]2[NH:34][C:35]([C@@H:37]3[CH2:42][C@@H:41]4[C@@H:39]([CH2:40]4)[N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:36][C:32]=2[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:28])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:30]2[CH:51]=[CH:50][C:33]4[N:34]=[C:35]([C@@H:37]5[CH2:42][C@@H:41]6[C@@H:39]([CH2:40]6)[N:38]5[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[NH:36][C:32]=4[CH:31]=2)[CH:13]=[CH:12]3)[O:5]1
Reactant: CC1(C)OB(c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(Br)ccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3ccc4cc(B5OC(C)(C)C(C)(C)O5)ccc4c3)cc2[nH]1
Temperature: 100 °C
Yield: 50 %

Procedure:
Pd(Ph3P)4 (0.382 g, 0.330 mmol) was added to a degassed solution of 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (2.51 g, 6.61 mmol), (1R,3S,5R)-tert-butyl 3-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (2.5 g, 6.6 mmol) and sodium carbonate (2.78 g, 33.0 mmol) in DME (52.9 mL) and water (13.2 mL) at 80° C. The reaction was backfilled with nitrogen, sealed and heated at 100° C. overnight. The volatiles were removed under vacuum and the residue was taken in EtOAc, washed with water, and the water layer was extracted with EtOAc. The combined organic layers were filtered through a pad of diatomaceous earth (CELITE®) and dried over Na2SO4, concentrated and purified on a BIOTAGE® (dry loaded on silica gel, charged to a 90 g silica gel cartridge and eluted with a gradient of 0 to 70% ethyl acetate in hexanes, then flushed with 10% MeOH/DCM) to yield (1R,3S,5R)-tert-butyl 3-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.8 g, 3.3 mmol, 49% yield) as yellowish solid. LC-MS retention time 1.905 min; m/z 552.47 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[C:14]([CH2:16][C:17]([NH2:19])=[S:18])#[N:15].C(N(C(O)C)CC)C>C(O)C>[C:14]([C:16](=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])[C:17]([NH2:19])=[S:18])#[N:15]
Reactant: N#CCC(N)=S
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: CCN(CC)C(C)O
Solvent: CCO
Product: N#CC(=Cc1c(O)ccc2ccccc12)C(N)=S
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 2-hydroxy-1-naphthaldehyde (172 mg, 1 mmol), 2-cyanothioacetamide (110 mg, 1.1 mmol), N,N-diethylaminoethanol (23 mg, 0.2 mmol) and 15 ml ethanol is stirred for 30 min at reflux under nitrogen. Then the mixture is chilled, the precipitate filtered, washed with ice-cooled ethanol and dried in a vacuum-oven. Thus an almost pure title compound is obtained in 85% yield (1080 mg). Recrystallization from ethanol furnishes very pure samples.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[NH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH2:34][CH2:33]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: c1ccc2c(c1)NCCN2
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (100 mg, 0.35 mmol, 1.0 equiv; Example 31, Step 1) in thionyl chloride (3.28 g, 2 ml, 27.6 mmol, 230 equiv; [CAS RN 7719-09-7]) was heated to 100° C. for 1 h. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (452 mg, 595 μL, 3.5 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydro-quinoxaline (56 mg, 0.42 mmol, 1.2 equiv; [CAS RN 3476-89-9]) and the reaction mixture was stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 17.3 mg (12%) of the title compound. MS (ISP): 400.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:20]=[CH:19][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: COC(=O)COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)c2ccc(OCC(=O)O)cc2)cc1
Reaction time: 3 h

Procedure:
9.0 g of the methyl ester (Example 1) are dissolved in 120 ml of 1,2-dimethoxyethane/water (4:1, v:v), and 15 ml of 2N NaOH are added. The mixture is stirred for three hours, and the pH is adjusted to 3 with 3N HCl. The organic solvent is evaporated off in vacuo, and the precipitated product is filtered off, washed with water and dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]([CH:13]([OH:27])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:27][CH:13]([C:11]#[CH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CC(OC(=O)C1C(C)(C)C1(C)C)c1cccc(Oc2ccccc2)c1
Reaction time: 16 h

Procedure:
2,2,3,3-Tetramethylcyclopropanoyl chloride (3.05 g) was added with stirring to a solution of α-ethynyl-3-phenoxybenzylalcohol (4.8 g) and triethylamine (2.16 g) in dry toluene (70 ml) at 10°C. The solution was allowed to attain room temperature and stirred for 16 hours. The mixture was filtered and the solvent removed from the filtrate under reduced pressure. The residue was washed with 5% sulphuric acid, followed by saturated sodium bicarbonate solution and finally purified by chromatography on silica gel using toluene as eluent to give the desired product as an oil nD2μ 1.5455.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH:14]=[CH:13][C:12](=O)[NH:11][C:10]=12)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.C(OCC)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:12]1[CH:13]=[CH:14][N:9]2[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]2[N:11]=1
Reactant: CCOC(=O)c1cnn2ccc(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(Cl)nc12
Temperature: 90 °C
Yield: 73 %

Procedure:
To a suspension of 5-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (prepared according to Gavrin, L. K. et al, J. Org. Chem. 2007, 72, 1043-1046) (3.00 g, 14.5 mmol, 1 equiv) in phosphorus oxychloride (30 mL) was added diisopropylethylamine (2.00 mL, 11.6 mmol, 0.8 equiv). The mixture was heated to 90° C. for 4.5 hours. After cooling, the mixture was carefully quenched with ice-water and extracted with dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to give a solid. Trituration (diethyl ether) afforded 2.38 g (73%) of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate as a solid. LCMS (ESI) m+H=226.2 (mono chlorinated isotope pattern); 1H NMR (400 MHz, CDCl3) δ: 8.63 (d, 1H), 8.56 (s, 1H), 6.99 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C(N(C(C)C)CC)(C)C.I.[NH2:26][C:27]1[C:28]([C:35]([NH:37][C:38](=[NH:41])SC)=[O:36])=[N:29][C:30]([Cl:34])=[C:31]([NH2:33])[N:32]=1>C(O)C>[NH2:26][C:27]1[C:28]([C:35]([N:37]=[C:38]([NH2:41])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:36])=[N:29][C:30]([Cl:34])=[C:31]([NH2:33])[N:32]=1
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCCCCCCCCC(=O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of 12-aminododecanoic acid (1) (0.096 g, 0.45 mmol) and diisopropylethylamine (0.39 mL, 2.23 mmol) in absolute ethanol (5 mL) was stirred at 70° C. for 30 min. 1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (191 mg, 0.49 mmol) was added in one portion and heating at 70° C. was continued for a further 16 hours. After this time, the reaction was cooled to room and the resulting yellow precipitate collected by filtration and washed with ethanol (2×2 mL). Further purification by Biotage silica gel column chromatography using a gradient of 3% to 20% of 10% concentrated aqueous ammonium hydroxide in methanol to dichloromethane afforded acid 2 (96 mg, 50%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 4H), 2.18 (t, 2H), 3.15 (t, 2H), 6.92 (m, 3H). m/z (ESI) 428 [C18H30ClN7O3+H]+. mp 194-196° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:18]=[C:17]([CH2:19][CH:20]([NH2:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:16][N:15]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:29]=1[C:30](Cl)=[O:31]>>[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:18]=[C:17]([CH2:19][CH:20]([NH:26][C:30](=[O:31])[C:29]2[C:28]([Cl:27])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:37])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:16][N:15]=1)=[O:8])([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOC(=O)C(N)Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Product: CCOC(=O)C(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from 2-[5-(2-amino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester hydrocloride and 2,6-dichlorobenzoylchloride in the manner described in example 3B. MS (CI) m/z 525.9 (M+1), 425.9 (M−99).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CO.C(OCC)C.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([NH:26][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Reactant: CCCCN
Solvent: CO
Solvent: CCOCC
Product: CCCCNc1ccc2cccc([N+](=O)[O-])c2n1
Temperature: 78 °C
Yield: 90 %

Procedure:
2-chloro-8-nitroquinoline (0.20 g; 0.96 mmol) is suspended in 9.5 ml of 1-butylamine and the medium is heated under reflux (78° C.) for 15 hours. The yellow solution obtained is subsequently concentrated under vacuum. The crude reaction product is taken up in a minimum volume of CH3OH and poured over 3 ml of diethyl ether. After centrifugation, butyl ammonium chloride crystals are removed and the supernatant is concentrated under reduced pressure to yield N-butyl-8-nitro-2-quinoline amine in the form of a yellow oil (0.21 g; 0.86 mmol, yield=90%). NMR-1H (250 MHz, CDCl3) δ, ppm: 7.83 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.77 (d, 3J (H, H)=9.0 Hz, 1H); 7.69 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 7.14 (m, 1H), 6.67 (d, 3J (H, H)=9.0 Hz, 1H); 5.07 (s large, 1H); 3.47 (m, 2H); 1.60 (m, 2H); 1.39 (m, 2H); 0.93 (t, 3J (H, H)=7.5 Hz, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 157.8 (Cq); 145.6 (Cq); 140.2 (Cq); 136.7 (CH); 131.5 (CH); 124.7 (CH); 124.1 (CH); 119.7 (CH); 113.3 (Cq); 41.3 (CH2); 31.5 (CH2); 20.2 (CH2); 13.8 (CH3). MS (CID, NH3): m/z=246 (MH+). Analysis (%) for C13H15N3O2: calculated C, 63.66. H, 6.16. N, 17.13. found C, 63.33. H, 6.21. N, 16.64.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1>>[NH:25]1[C:24]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])=[N:28][N:27]=[N:26]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cccc(Br)n1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(Nc1nnn[nH]1)c1cccc(Br)n1
Yield: 56.5 %

Procedure:
0.89 g of 6-bromo-2-pyridinecarboxylic acid, 0.71 g of N,N-carbonyldiimidazole and 0.41 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.67 g of N-(5-tetrazolyl)-6-bromo-2-pyridinecarboxamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCN(C)C
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2 (PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 5% MeOH in CH2Cl2 (1L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 153.5 mg (55%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH:14](O)=O.C=O.[OH-].[Na+]>O.C(OCC)C>[CH3:14][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: CC1CC(C)(C)NC2CCCCC12
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1CC(C)(C)N(C)C2CCCCC12

Procedure:
1,2,2,4-tetramethyl decahydroquinoline was prepared. 36.3 grams (0.2 mole) of 2,2,4-trimethyl decahydroquinoline of about 58% cis structure was placed in a reactor vessel equipped for agitation. Formic acid, 20.2 grams (0.44 mole) was added dropwise to the reactor vessel followed by the slow addition of 17.4 grams of 38% by weight formaldehyde in water solution. After addition, the mix was refluxed at for 4 hours. A 5N sodium hydroxide solution was then added until the mix was basic. Diethyl ether was added and the mix separated out and the ether fraction obtained. The fraction was concentrated and then distilled using a 3 inch Vigreaux column to yield 5.4 grams of a product boiling at 70° C. at 0.6 mm Hg. The NMR spectra of the product was consistent with the desired product, 1,2,2,4-tetramethyl decahydroquinoline. The theoretical carbon, hydrogen, nitrogen analysis for the formula C13H25N is 79.92% carbon, 12.90% hydrogen, and 7.17% nitrogen while measured values were 77.23% carbon, 13.13% hydrogen, and 6.56% nitrogen.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.O.Cl.Cl.[CH:19]1([CH2:29][CH2:30]N2CCN(C3C=CC=CC=3OC)CC2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][O:20]1>>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:30][CH2:29][CH:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][O:20]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: O
Product: Clc1cccc(N2CCN(CCC3OCCc4ccccc43)CC2)c1

Procedure:
Following the general procedure of EXAMPLE 1 and making non-critical variations but using 1-(3-chlorophenyl)piperazine dihydrochloride (XI, 0.5169 g (1.92 mmol) in place of 1-(2-chlorophenyl)piperazine dihydrochloride (XI), the title compound is obtained, mp 176.75-179°; MS (m/z) 356; IR (mineral oil) 2269, 2295, 2166, 2130, 2200 and 1449 cm-1.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:11]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCOCCOCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCCOCCO
Temperature: 100 °C
Reaction time: 12 h
Yield: 84.4 %

Procedure:
To a solution in which 2-(2-(2-chloroethoxy)ethoxy)ethanol (3.48 g, 20.63 mmol) of Chemical Formula 7 was dissolved in DMF (15 mL), sodium azide (4.02 g, 61.89 mmol) was added at room temperature, and the mixture was heated to 100° C. and stirred for 12 hours. After the reaction, DMF was removed by vacuum distillation, and the residue was partitioned to distilled water (40 mL) and ethyl acetate (150 mL). The organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, and vacuum distilled, and the residue obtained was column chromatographed on silica gel (hexane/ethyl acetate (2:1)) to give 2-(2-(2-azidoethoxy)ethoxy)ethanol (3.05 g, 84%). 1H NMR (500 MHz, CDCl3) δ 3.72-3.74 (m, 2H), 3.65-3.69 (m, 6H), 3.60-3.62 (m, 2H), 3.39 (t, 2H, J=5.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (230 mg, 0.74 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (220 mg, 0.74 mmol) according to the general procedure M. Obtained as a light yellow solid (260 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (13 mg, 10%). MS (ISP) 511.5 [(M+H)+]; mp 230–231° C.
Reaction SMILES: [CH2:1]([N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.II.[I:22](O)(=O)(=O)=O>C(O)(=O)C.O>[I:22][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:4][CH:5]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C1CCCN1CCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCN1CCc1ccc(I)cc1
Temperature: 60 °C

Procedure:
To a stirring solution of HJC-1-53 (500 mg, 2.6 mmol), water (1 mL), 95% sulfuric acid (285 mg, 2.9 mmol) and acetic acid (8 mL) was added iodine (335 mg, 1.3 mmol) and periodic acid (H5IO6, 150 mg, 0.7 mmol) at rt. The reaction mixture was warmed to 60° C. for 3 h. After cooling down to rt, the solution was extracted with EtOAc (80 mL) and H2O (20 mL), and washed with 10% NaHSO3 (20 mL), followed by 10% NaHCO3 (40 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc=1/2) to obtain HJC-1-60 (130 mg, 16%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.60 (d, 1H, J=7.8 Hz), 7.26-7.30 (m, 1H), 7.19-7.21 (m, 1H), 6.96 (d, 1H, J=9.0 Hz), 3.48-3.53 (m, 2H), 3.23-3.26 (m, 2H), 2.83 (t, 1H, J=7.8 Hz), 2.78 (t, 1H, J=7.8 Hz), 2.32-2.36 (m, 2H), 1.91-1.97 (m, 2H).