Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1(C)[NH:6][CH:5]=[C:4]([Cl:7])[S:3]1.[CH3:9][C:10]1([CH3:18])[C:12]([CH3:14])([CH3:13])[CH:11]1[C:15](Cl)=[O:16].[CH2:19](N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1.CCOC(C)=O>[Cl:7][C:4]1[S:3][C:2]([NH:1][C:15]([CH:11]2[C:10]([CH3:18])([CH3:9])[C:12]2([CH3:14])[CH3:13])=[O:16])=[N:6][C:5]=1[CH3:19]
Reactant: CC1(N)NC=C(Cl)S1
Reactant: CCN(CC)CC
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)C2C(C)(C)C2(C)C)sc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-amino-5-chloro-2-methyl-thiazole (Matsuo, Masaaki; Ogino, Takashi; Igari, Norihiro; Seno, Hachiro; Shimomura, Kyoichi., EP 412404) (150 mg, 0.81 mmol), 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (143 mg, 0.89 mmol), 4-dimethylaminopyridine (50.0 mg, 0.41 mmol) and triethylamine (226 μL, 1.62 mmol) in 15 mL of THF heated at reflux for 48 hours. The mixture was cooled to ambient temperature, diluted with EtOAc and washed with brine. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography afforded the title compound: MS (LC/MS) m/z 273 (M+H)+.
Reaction SMILES: [F-].[Cs+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[O:20])=[CH:14][CH:13]=1>COCCOC.CO>[CH:27]1([C:25]2[NH:24][N:23]=[C:22]([NH:21][C:19](=[O:20])[CH2:18][C:15]3[CH:16]=[CH:17][C:12]([C:5]4[CH:6]=[CH:7][S:3][CH:4]=4)=[CH:13][CH:14]=3)[CH:26]=2)[CH2:29][CH2:28]1.[CH3:4][C:5]([CH3:6])=[O:20]
Reactant: O=C(Cc1ccc(Br)cc1)Nc1cc(C2CC2)[nH]n1
Reactant: OB(O)c1cccs1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CC(C)=O
Product: O=C(Cc1ccc(-c2ccsc2)cc1)Nc1cc(C2CC2)[nH]n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 533.2 %

Procedure:
330 mg (2.17 mmol) of CsF, 81 mg (0.63 mmol) of thienylboronic acid and 36 mg (0.031 mmol) of tetrakis triphenylphosphine palladium (Pd(PPh3)4 were added to 100 mg (0.31 mmol) of 2-(4-bromophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)acetamide) in 25 mL of DME and 2 mL of MeOH. The mixture was shaken 48 hrs at 80° C. under nitrogen. The reaction mixture is evaporated, redissolved in ethyl acetate and then washed with a saturated solution of NaHCO3. The organic layer was, after treatment with anhydrous sodium sulfate, evaporated under reduced pressure and the title compound was obtained by crystallization from acetone (48 mg, 48% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[N:4]=[C:5]([S:37][CH3:38])[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([O:28][Si](C(C)(C)C)(C)C)[C:21]=1[F:36])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C.O>C1COCC1>[CH3:1][O:2][C:3](=[O:39])[N:4]=[C:5]([S:37][CH3:38])[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([OH:28])[C:21]=1[F:36])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(O)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
To a solution of 0.76 g of {2-[3-(t-butyldimethylsilanyloxy)-5-ethyl-2-fluorophenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 30 ml of THF there was added 1.6 ml of TBAF (1.0 M, THF solution) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours, and then 200 ml of ethyl acetate and 100 ml of water were added. The organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, the desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (0.41 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:40]3[CH2:41][CH2:42][NH:37][C:38](=[O:43])[CH2:39]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:35])[CH3:36])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1CNCCN1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12i) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 607.4 [(M+H)+]
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([C:29](=O)[CH2:30][O:31][CH3:32])[C:25](OC)=[O:26])=[CH:19][CH:18]=1)#[N:10].O1CCOCC1>CO>[CH3:32][O:31][CH2:30][C:29]1[N:4]=[C:2]([CH3:3])[NH:5][C:25](=[O:26])[C:24]=1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][CH:19]=1
Reactant: CC(=N)N
Reactant: COCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of acetamidine hydrochloride (3.4 g) in methanol (30 mL) was added sodium methoxide (28% methanol solution, 10.3 g) at 0° C., a solution of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-4-methoxy-3-oxobutanoate in methanol (60 mL)-1,4-dioxane (20 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and water (50 mL) and 50% aqueous acetic acid solution were added to the residue and adjusted to pH 5. The obtained crystallized product was collected by filtration and washed with water to give the title compound as colorless crystals (5.27 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=NO.Cl.C=[O:16].O>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:16]
Reactant: Cc1cccc([N+](=O)[O-])c1C=NO
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc([N+](=O)[O-])c1C=O

Procedure:
At 65° C., 14 g of 2-methyl-6-nitrobenzaldoxime (80 mmol) are stirred in a mixture of 55 ml of 5% strength hydrochloric acid, 37 g of 37% strength formaldehyde solution, 50 ml of water and 100 ml of tetrahydrofuran for 24 hours. The phases are then separated and the dark phase is extracted with methylene chloride/water. The organic phase is dried with sodium sulfate and concentrated. This gives 10.1 g of crude product, which is purified by filtration through silica gel using the mobile phase toluene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].C[Li].C([Li])(C)(C)C.CN(C)[CH:32]=[O:33]>O1CCCC1>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH:32]=[O:33])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Reactant: CN(C)C=O
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (3.25 g, Example 23a) in anhydrous tetrahydrofuran (150 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of methyllithium (1.4M in diethyl ether, 6.1 ml) was added over 2 min. The mixture was stirred at −78° C. for 10 min, then a solution tert-butyllithium (1.7M in pentane, 10.0 ml) was added dropwise. The mixture was stirred at −78° C. for a further 10 min, then dimethylformamide (1.0 ml) was added. The resulting solution was stirred at −78° C. for 30 min., quenched with saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the subtitle compound as a solid (2.76 g).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)SC)#[N:2].[CH3:18][NH2:19]>CO>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)#[N:2]
Reactant: CSC(=NCc1ccc(CCO)cc1)NC#N
Reactant: CN
Solvent: CO
Product: CNC(=NCc1ccc(CCO)cc1)NC#N

Procedure:
A solution of 0.42 g (0.00168 mol) of N-cyano-N'-[4-(2-hydroxyethyl)benzyl]-S-methylisothiourea in 50 ml of methanol and 10 g of methylamine was stirred at room temperature overnight. Evaporation of the solvent gave the title compound.
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:15].CCN(C(C)C)C(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][CH:8]2[CH2:11][N:10]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:9]2)=[CH:4][C:3]=1[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(OCC2CNC2)cc(C)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCC2CN(S(C)(=O)=O)C2)cc(C)c1Br
Temperature: 0 °C
Yield: 64 %

Procedure:
3-(4-Bromo-3,5-dimethyl-phenoxymethyl)-azetidine (400 mg, 1.48 mmol) and DIPEA (0.48 g, 3.7 mmol) are dissolved in 20 mL of dichloromethane and stirred at 0° C. Methanesulfonylchloride (0.12 mL, 1.48 mmol) is added and the reaction mixture is stirred at 0° C. for 2 h. The reaction mixture is washed with water, the organich phase is separated, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by flash chromatography 0-50% ethyl acetate in cyclohexane) to give the title compound (Yield: 330 mg).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[P].FF>>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: FF
Agent: [P]
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Yield: 73 %

Procedure:
Then, the first distillation of Example 1 was repeated, thereby to obtain 114.3 kg of trifluoromethanesulfonic acid anhydride which is colorless and transparent. By chemical analysis, this first distillate was found to have a purity of at least 99 wt % and contain up to 0.5 wt % of trifluoromethanesulfonic acid ester, 0.5 wt % of trifluoromethanesulfonic acid, up to 5 wt ppm of phosphorus, and 510 wt ppm of free fluorine. The actual amount of trifluoromethanesulfonic acid anhydride produced by the reaction was 34.3 kg, and the yield was 73%, based on the amount of trifluoromethanesulfonic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:36])[CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:36])[CH:16]=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:13]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 4-nitrobenzaldehyde (15.1 g, 0.1 mol) in CH2Cl2 (200 mL) was added dropwise (triphenylphosphanylidene)acetic acid ethyl ester (34.8 g, 0.1 mol) in CH2Cl2 (100 mL) at 0° C. After the addition was completed, the resulting mixture was stirred for 2 h. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3-(4-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6% yield). 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J=8.8 Hz, 2H), 7.71 (d, J=16.0 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 6.55 (d, J=16.0 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[BrH:10].N([O-])=O.[Na+]>O>[Br:10][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc(Br)c1Cl
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
32.7 g 2,3-Dichloroaniline (0.20 mole) is added to a mixture of 168.5 g of 48% aqueous HBr (1.0 mole, 5.0 equivalents) and 40 ml water at 30-40° C. The mixture is stirred for 15 minutes at 30-40° C. and then heated to 45° C. Then 2.9 g Cu(I)Br (0.02 mole, 0.10 equivalent) is added and the mixture is stirred for 15 minutes at 45° C. After this, an aqueous solution of NaNO2 (40% solution in water, 35.6 g, 0.21 mole, 1.0 equivalents) is added via subsurface feeding over a period of 2 hours at 45° C. The reaction mixture is stirred for 30 minutes at 45° C. After this, the reaction mixture is heated to 60-65° C. The organic phase containing the reaction product is separated from the aqueous phase and is cooled to ambient temperature, leading to solidification of the reaction product. The remaining liquid is discarded and the crude product is washed twice with 10 ml water and dried under vacuum. 40.0 g (80% of theory) of 1-bromo-2,3-dichlorobenzene is obtained in the form of a light brown solid (purity: 90%).
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][C:8]([CH2:19][NH:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23])=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[OH:29]>>[C:27]([O:25][CH2:24][C:21]([NH:20][CH2:19][C:8]1[CH:7]=[C:6]2[C:15](=[C:14]3[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:16]=[CH:17][C:18]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=1)([CH3:26])[CH2:22][OH:23])(=[O:31])[CH:28]([CH3:30])[OH:29]
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CC(O)C(=O)O
Product: CC(O)C(=O)OCC(C)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Yield: 44.1 %

Procedure:
A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol free base (ID) (3.45 g, 10 mmol) and lactic acid (Fisher Scientific Co., 711 Forbes Ave., Pittsburgh, PA, 15219, 85% liquid, 1.04 g, 10 mmol) in CH3ON (500 mL) was brought to reflux and filtered through a glass fritted funnel. The solvent was removed by rotary evaporation to give a crude white solid. This was crystallized (CH3OH/Et2O) 3× to give 1.84 g (42.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol lactate mp 163°-164°, (C, H, N).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9]3([C:10]([F:13])([F:12])[F:11])[NH:21][CH2:18][CH2:19][NH:20]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)NCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.02 g; 3.61 mmol), ethylene diamine (0.74 mL; 11.04 mmol) and para-toluenesulphonic acid monohydrate (0.12 g; 0.603 mmol) were suspended in toluene (80 mL), then heated to reflux with a Dean-Stark trap for 3 hrs. After 3 hrs, ethylene diamine (0.74 mL; 11.04 mmol) was added to the reaction mixture and the reaction mixture was allowed to reflux with the Dean-Stark trap for 18 hrs. The reaction was cooled to room temperature and concentrated in vacuo to a crude brown residue. The crude brown residue was dissolved in ethyl acetate (60 mL), washed with water (3×50 mL) and brine (50 mL), then dried over Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated in vacuo to a crude brown oil, which was purified by column chromatography (SiO2, 50% ethyl acetate/hexanes) to yield the title compound as a light orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([CH3:16])[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:4]2[N:3]=1.Cl.[CH3:19][C:20]1([CH3:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([CH3:16])[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([N:23]3[CH2:24][CH2:25][C:20]([CH3:26])([CH3:19])[CH2:21][CH2:22]3)[N:4]2[N:3]=1
Reactant: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Reactant: CC1(C)CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Temperature: 60 °C

Procedure:
To a solution of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (1.33 g, 4.18 mmol, 1 equiv) in DMF (14 mL) was added 4,4-dimethylpiperidine hydrochloride (0.75 g, 5.01 mmol, 1.2 equiv) and DIPEA (1.75 mL, 10.02 mmol, 2.4 equiv). The reaction was then heated in an oil bath at 60° C. Upon completion, the reaction was removed from heating, diluted with water, and extracted with EtOAc (×2). The combined EtOAc extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-100% EtOAc/hexane) to provide methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate as an off white solid (1.50 g, 91%). 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 3.80 (s, 2H), 3.77 (s, 3H), 3.41 (br. s., 4H), 2.51 (s, H), 1.54 (t, J=5.6 Hz, 4H), 1.09 (s, 6H); LCMS (ESI, M+1): 395.25.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5](O)[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:3]([CH2:1][CH3:2])[N:4]=1
Reactant: CCc1nc(O)c2sccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nc(Cl)c2sccc2n1

Procedure:
2-Ethyl-4-hydroxythieno[3,2-d]pyrimidine (0.6725 g, 0.00373M) was refluxed with phosphorus oxychloride (20 ml) for 2 hours. The reaction mixture was cooled, concentrated under vacuum, the residue dissolved in methylene chloride, poured over ice and water and basified with ammonia. The layers were separated and the aqueous layer extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under vacuum to obtain the product, 0.65 g, as a tan solid, m.p. 46°-48° C. the structure of which was confirmed by NMR.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: COC(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
3-(tert-Butoxycarbonylamino)piperidine (7.07 g, 35.3 mmol) was dissolved in N,N-dimethylformamide (120 mL). To this solution, potassium carbonate (9.80 g, 70.9 mmol) and methyl 2-fluorobenzoate (5.0 mL, 39.2 mmol) were added and the mixture was stirred at 130° C. for 8 hours. Subsequently, the mixture was allowed to cool, diluted with ethyl acetate, and washed sequentially with water and brine. The washed product was dried over sodium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=10:1->5:1) gave 2.34 g (20%) of the desired compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10]Br.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.CCOCC>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1ccc(Br)c(CBr)c1
Reactant: c1ccc2c(c1)CCN2
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Br)c(CN2CCc3ccccc32)c1

Procedure:
A mixture of 4-bromo-3-bromomethyl-benzonitrile (2.66 g, 9.7 mmol), indoline (1.14 mL, 10.2 mmol) and triethylamine (1.60 mL, 11.5 mmol) was heated at reflux for 18 h in dry tetrahydrofuran (50 mL). The flask was cooled and ether (100 mL) was added. Evaporation gave crude 4-bromo-3-(2,3-dihydro-indol-1-ylmethyl)-benzonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20](Br)=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]1[C:37]([Sn](CCCC)(CCCC)CCCC)=[C:36]([CH3:51])[N:35]=[N:34]1>[Cu]I.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.O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20]([C:37]4[N:33]([CH3:32])[N:34]=[N:35][C:36]=4[CH3:51])=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)nnn1C
Reactant: Cc1cc(C)c(CN2CCc3c(Cl)cc(Br)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
To a mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253 g, 500 mg, 0.96 mmol), and 1,4-dimethyl-5-(tributylstannanyl)-1H-1,2,3-triazole (CAS: 1047637-17-1, 754 mg, 1.95 mmol) in a microwave tube was added 1,4-dioxane (10 mL), copper (I) iodide (28 mg, 0.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.14 mmol). The solution was degassed using a stream of argon gas and degassing was continued for 10 minutes. The microwave vial was sealed and the mixture was heated at 125° C. for 2 hours under microwave irradiation. TLC (petroleum ether/ethyl acetate=1:1, Rf: 0.5) showed about 50% of 253g remained. However, further heating did not prove fruitful. The mixture was diluted with methyl tert-butyl ether (100 mL), washed with water (3×100 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=1:1 to yield -{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (229a, 108 mg, 21% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.76 (s, 1H), 7.44 (d, J=1.35 Hz, 2H), 7.28-7.34 (m, 3H), 6.75 (s, 1H), 5.38 (s, 2H), 4.71 (s, 2H), 3.77 (s, 3H), 3.30-3.34 (m, 2H), 2.82 (s, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.08 (s, 3H) MS: 446.1 [M+1].