Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[C:21]=2[CH:20]=[CH:19][N:18]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([S:27]([N:8]3[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]3)(=[O:29])=[O:28])[C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
In 30 ml of chloroform were added 1.42 g of 1-isobutylpiperazine and 2.76 g of potassium carbonate, and to the mixture was added dropwise 50 ml of a chloroform solution containing 2.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred at a temperature of 15° C. to 25° C. for two hours, and then the reaction solution was washed with 20 ml of a 1N aqueous sodium hydroxide solution and extracted twice with a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline extracted three time with 30 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, the residue obtained was subjected to a silica gel column chromatography (silica gel; 100 g; solvent: 2% methanol-chloroform) to give 2.60 g of 1-(5-isoquinolinesulfonyl)-4-isobutylpiperazine, i.e., Compound (47) in a yield of 78%.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C>C1COCC1>[Si:30]([O:29][CH2:28][CH2:27][CH:21]1[N:14]2[C:15]3[C:11]([CH:12]=[CH:13]2)=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:17][C:16]=3[CH2:18][NH:19][CH2:20]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCC1CNCc2cc(CCc3ccccc3)c(C(F)(F)F)c3ccn1c23
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 100 mg, 0.26 mmol), 2-bromoethoxy t-butyl(dimethyl)silane (63 mg, 0.26 mmol) and diisopropylethylamine (0.09 mL, 0.53 mmol) in THF was heated at 80° C. for 5 h. The solvent was evaporated to yield 2-(2-((tert-butyldimethylsilyl)oxy)ethyl-6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (107 mg, MS m/z 503 (MH+)).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O.O>C1(C)C=CC=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[N:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=Cc1ccccn1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1N=Cc1ccccn1

Procedure:
27.6 g of o-nitroaniline and 21.4 g of 2-pyridine aldehyde are heated in 200 ml of toluene for 10 hours, and the water formed is collected by means of a water separator. 500 ml of diethyl ether are then added to the solution, and the crystals which precipitate are filtered off with suction.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.CC(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(Cl)c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Acetone (320 ml), 75 g (450 mmol) of ethyl bromoacetate, and 40.0 g (310 mmol) of 3-chlorophenol were mixed together, then 69.8 g (505 mmol) of potassium carbonate was added. The mixture was mechanically stirred and heated to reflux for 4 h, and after cooling to room temperature, was poured into 350 mL of ethyl acetate. To this was then cautiously added 400 mL of 1 M HCl, taking care to avoid excess foaming. The layers were separated and the aqueous layer was extracted with portions of ethyl acetate (3×200 mL). The combined organic layers were dried over MgSO4, filtered, concentrated, and the resulting solid was recrystallized from hexane to afford 58 g (87%) of 10 as a white solid, m.p.=39-40° C. 1 H NMR δ 7.20-7.08 (m, 1 H), 6.95-6.82 (m, 2 H), 6.75-6.70 (m, 1 H), 4.53 (s, 2 H), 4.21 (q, J=7.2 Hz, 2 H), 1.23 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:26][OH:27].O>C(O)(C)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:26][OH:27])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1COC(=O)c1c(Cl)cccc1-2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: NC(=NO)c1ncn2c1COC(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.3 %

Procedure:
A mixture of 7-chloro-5,6-dihydro-6-oxo-4H-imidazo [1,5-a][4,1]benzoxazepine-3-carbonitrile (16.86 g, 0.06 mole), potassium carbonate (13.5 g, 0.9 mole) and hydroxylamine hydrochloride (4.6 g, 0.06 mole) in isopropanol (843 ml) containing water (13.5 ml) was stirred at room temperature for 4 days. The reaction mixture was then concentrated to a volume of 256 ml by distillation, cooled to room temperature and water (256 ml) added. The resulting mixture was cooled at 0° C. for 1 hour and the solid collected, washed with water and dried in vacuo at 50° C. to give the product (12 g, 63%), m.p. 252°-254° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:8]([CH3:23])[CH:7]=[CH:6][N:5]=1.[H][H]>COCCOCCOC.O.C(O)(=O)C>[CH3:23][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11](=[O:12])[NH:10][C:9]=12
Reactant: [H][H]
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: COCCOCCOC
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A 500 ml 4NRB flask with stirrer, temperature controller thermocouple, addition funnel and condenser with an oil bubbler to exclude air was inserted with nitrogen and charged with 15.00 g of 60% sodium hydride in a mineral oil slurry and 120 ml of diglyme. The mixture was heated to 130° C. and treated dropwise with a solution of 41.7 g (0.138 mol) of N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide, from example 4, in 70 ml of diglyme at 80 ° C. The reaction mixture was heated at 130° C. until hydrogen evolution ceased. The mixture was cooled to ambient temperature and water (6.75 g) was added dropwise cautiously. When hydrogen evolution ceased, an additional 100 ml of water was added. Acetic acid (20 ml) was added to reduce the pH of the mixture from 11-13 to about 7. An additional 100 ml of water was added and the reaction mixture stirred under ambient conditions for 30 minutes while the product crystallized. The solid product was collected by filtration and the filter cake rinsed with 100 ml of water followed by 50 ml of cyclohexane to remove any residual mineral oil from the mineral oil-sodium hydride slurry. The wet cake was dried in a vacuum oven at 50° C. for 18 hours to obtain 35.58 g of nevirapine.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].ClCCl.[C:44](=O)(O)[O-:45].[Na+].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:13][C:12]1[C:2]([N:1]=[C:44]=[O:45])=[C:3]([CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:17]3=[N:18][CH:19]=2)[CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: O=C([O-])O
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N=C=O)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a scintillation vial was combined 125 mg (0.224 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide, 2.0 mL dichloromethane, and 2.0 mL of a saturated aqueous solution of sodium bicarbonate. The vial was cooled to 0° C. in an ice bath and, under vigorous stirring, 601 μL (1.12 mmol) of a 20% phosgene in toluene solution was added. The reaction was stirred in the ice bath for 30 minutes and then stirred at room temperature for another 30 minutes. The layers were separated and organic layer was dried over sodium sulfate and concentrated to afford 3-fluoro-2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a brown foam.
Reaction SMILES: Cl[CH2:2]Cl.[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)C1)[CH2:11]2.[H][H]>O>[CH2:6]1[CH:7]2[CH:8]([CH2:13][CH2:4][CH2:11][CH2:2]2)[CH2:9][CH2:10][CH2:12]1
Reactant: ClCCl
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: [H][H]
Solvent: O
Product: C1CCC2CCCCC2C1

Procedure:
EXAMPLE 5 is the comparative example of EXAMPLE 4.65 g of endo-THDCPD crystals from the same source of EXAMPLE 4 are placed in a 250 ml of glass bottle, followed by adding 40 g of dichloromethane thereto to dissolve these crystals, purging with dry nitrogen and stirring in the ice bath. Subsequently, 10 g of AlCl3 is added to the dichloromethane solution of endo-THDCPD, followed by stirring for 2 hours in the ice bath, and continuously stirring for 16 hours at room temperature. The resulting mixture is washed with 100 ml of saturated KCl solution, followed by adding it to a separatory funnel, shaking to allow to separate into two layers and leaving the upper layer in the separatory funnel. The above saturated KCl solution washing procedure is repeated for three times. Subsequently, the mixture washed with the saturated KCl solution is washed with 100 ml of deionized water, followed by adding it to a separatory funnel, shaking to allow to separate into two layers and leaving the lower layer in the separatory funnel. The above deionized water washing procedure is repeated for three times. Subsequently, the lower layer is distilled to remove dichloromethane and water. The bottoms is collected, and determined by chemical analysis. The chemical analysis shows that the bottoms is composed of 85.7 wt % of exo-THDCPD, 0.5 wt % of endo-THDCPD, 1.2 wt % of Decalin, 5.8 wt % of adamantane, 1.3 wt % of exo-THMDCPD, and the other two-stage hydrotreated and saturated C11+ derivatives, namely CPD and/or MCPD diners. The bottoms has a volumetric heating value of 39.17 MJ/L, a density of 0.9339 at 15° C., and a viscosity of 3.52 cSt at 20° C. and more than 26.7 cSt at −20° C. In this example, the isomerization reaction is violent because isomerization reaction time is too long so that portions of exo-THDCPD is further isomerized to adamantane which will increase the viscosity of the high energy fuel. Under such a violent reaction conditions, a small amount of THDCPD will be ring opened by hydrogen to give decalin (the side product) with relatively less volumetric heating value as well as density. Therefore, the isomerization reaction of this example is not suitable for preparing the high energy fuels because the freezing point of the isomerization product is too high.
Reaction SMILES: I.[NH:2]=[C:3]1[NH:7][CH2:6][CH2:5][NH:4]1.[H-].[Li+].[CH2:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N:19]=[C:20]=[O:21])[CH3:11]>CN(C)C=O>[CH2:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20]([N:2]=[C:3]1[NH:7][CH2:6][CH2:5][NH:4]1)=[O:21])[CH3:11]
Reactant: CCc1cccc(C)c1N=C=O
Reactant: N=C1NCCN1
Agent: I
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NC(=O)N=C1NCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a manner similar to that previously described, 15.55 grams (0.073 mole) of 2-iminoimidazoline hydroiodide is added dropwise to a dry cooled suspension of 596 milligrams (0.075 mole) of lithium hydride in 30 milliliters of dimethylformamide under an atmosphere of nitrogen. After completion of the addition, the mixture is allowed to warm to room temperature to complete the reaction. Thereafter the mixture is again cooled, a solution of 8.1 grams (0.05 mole) of 2-ethyl-6-methylphenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over a two hour period and thereafter the resulting mixture is stirred overnight while the temperature is allowed to rise to ambient temperatures to obtain a N-(2-ethyl-6-methylphenyl-N'-(2-imidazolidinylidene)urea product. The base product is recovered by procedures similar to that previously described and after recrystallization from methanol-water, a purified base product, m.p. 185°-187° C. is obtained.
Reaction SMILES: [Cl:1]/[C:2](/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[CH:3]\[CH2:4]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6](/[C:2](/[Cl:1])=[CH:3]/[CH2:4][Cl:15])=[CH:7][CH:8]=1
Reactant: OC/C=C(\Cl)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: ClC/C=C(\Cl)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (Z)-3-chloro-3-(4-chloro-phenyl)-prop-2-en-1-ol (101 mg) in toluene (3 ml) was added thionyl chloride (0.11 ml) and one drop of dimethylformamide. After 1 h, the solution was concentrated in vacuo to afford 120 mg of the desired allylic chloride (100%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:28]1C[CH2:31][CH2:30][CH2:29]1.C(Cl)(=O)C=C>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:29](=[O:28])[CH:30]=[CH2:31])[CH2:13][CH2:14]1
Reactant: C1CCOC1
Reactant: OCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reaction time: 4 h

Procedure:
First, 4.77 g of 2,3-difluoro-1-[trans-4-(5-hydroxypentyl)cyclohexyl]benzene, 1.9 g of triethylamine, and 60 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 1.7 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling, and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=1/1) and recrystallized from hexane to obtain 3 g of 2,3-difluoro-1-[trans-4-(5-propenoyloxypentyl)cyclohexyl]benzene (Y: 52.9%). The compound thus obtained had a purity of 99.8% by GC, 99.2% by HPLC, and 1 spot by TLC. Furthermore, the compound had an m.p. of 29.6° C. to 30.7° C.
Reaction SMILES: COP([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])NN=1)(=O)OC.[N+:18]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH:27]=O)[CH:22]=1)([O-:20])=[O:19].C(N(CC)CC)C.C1C[O:39]CC1>O>[N+:18]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH:27]=[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7](=[O:39])[O:17]2)[CH:22]=1)([O-:20])=[O:19]
Reactant: COP(=O)(OC)c1n[nH]c(=O)c2ccccc12
Reactant: C1CCOC1
Reactant: O=Cc1cc([N+](=O)[O-])ccn1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OC(=Cc2cc([N+](=O)[O-])ccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled solution of (4-oxo-3,4-dihydro-phthalazin-1-yl)-phosphonic acid dimethyl ester (0.202 g, 0.837 mmol) in THF (4 mL) at 10° C. was added 4-nitro-pyridine-2-carbaldehyde (0.837 mmol) under a nitrogen atmosphere. Triethylamine (0.174 mL, 1.25 mmol) was added dropwise over 10 minutes and then allowed to stir at room temperature for 18 hours. The yellow suspension was poured in water (9 mL), and the then filtered, the solid was washed with water (2×2 mL), hexane (2×2 mL) and then diethyl ether (2×2 mL) and then dried in vacuo to afford a 0.73 g of the desired products. Two peaks in LC-MS analysis, (0.13 g, 18% two steps) and required no further purification, m/z (LC-MS, ESP), RT=4.26 mins (M+H) 269, & RT=4.52 mins (M+H) 269.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:25])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCO)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.269 min, m/z=432.2; 1H NMR (CDCl3) 1.50 (d, 3H), 2.05-2.35 (m, 5H), 2.90 (m, 1H), 3.51 (m, 1H), 3.70 (m, 1H), 3.97 (s, 3H), 5.63 (m, 1H), 6.85 (d, 1H), 6.92 (m, 2H), 7.17-7.35 (m, 6H), 7.81 (d, 1H), 8.32 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:7]([Br:14])=[N:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19](N2C3C=CC=C(C(O)=O)C=3C=N2)=[CH:18][CH:17]=1>>[Br:14][C:7]1[C:6]2[C:5]([C:3]([OH:2])=[O:4])=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:8]=1
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: COC(=O)c1cccc2[nH]nc(Br)c12
Product: O=C(O)c1cccc2c1c(Br)nn2-c1ccc(F)cc1

Procedure:
3-Bromo-1H-indazole-4-carboxylic acid methyl ester was then subjected to the reaction conditions described in Example 2, for the synthesis of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid, to yield 3-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid. Using the methods described in Example 2, 3-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid was used to provide the following compounds:
Reaction SMILES: CC([CH:5]1[C@@H:10]([NH2:11])[CH2:9][CH2:8][CH2:7][N:6]1[C:12]([O-:14])=[O:13])(C)C.[O:15]1[CH2:19][CH2:18][CH:17]([CH:20]=O)[CH2:16]1>[Pd].C(O)C>[O:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:11][C@H:10]2[CH2:9][CH2:8][CH2:7][N:6]([C:12]([O:14][C:17]([CH3:20])([CH3:18])[CH3:16])=[O:13])[CH2:5]2)[CH2:16]1
Reactant: O=CC1CCOC1
Reactant: CC(C)(C)C1[C@@H](N)CCCN1C(=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H](NCC2CCOC2)C1
Reaction time: 8 h

Procedure:
To 5% palladium on carbon (0.05 g) under nitrogen was added a solution of 1,1-dimethylethyl-(3S)-3-aminopiperidine-1-carboxylate (0.50 g, 2.5 mmol) and tetrahydrofuran-3-carboxaldehyde (50% w/w in water) (0.50 g, 2.5 mmol) in ethanol (20 mL). The reaction mixture was hydrogenated overnight at 60 psi in a Parr hydrogenator. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to give 1,1-dimethylethyl (3S)-3-[(tetrahydrofuran-3-ylmethyl)amino]piperidine-1-carboxylate as a colourless, slightly cloudy oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccnc(F)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine was reacted with 2-fluoropyridine-4-boronic acid in General Procedure A. Purification on silica yielded 2-(2-fluoro-pyridin-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:20]3[NH:19][CH2:18][CH:17]4[CH2:23][CH2:24][CH2:25][C:15]=2[C:16]=34)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([C:26](=[O:28])[CH3:27])[CH2:18][CH:17]4[CH2:23][CH2:24][CH2:25][C:15]=2[C:16]=34)=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c4c2CCCC4CN3)CC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c4c2CCCC4CN3C(C)=O)CC1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A mixed solution of 3-(1-acetyl-4-piperidinyl)-1-(1,2,2a,3,4,5-hexahydrobenz[cd]indol-6-yl)-1-propanone (free base, 0.15 g, 0.44 mmol) and acetic anhydride (0.066 ml, 0.69 mmol) in ethyl acetate (20 ml) was heated at 70-75° C. with stirring for 1 hour. The solvent was then distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=20:1) to provide the title compound (0.155 g) as colorless crystals melting at 130-132° C.
Reaction SMILES: [O:1]([C:8]([N:10]=[C:11]=[O:12])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([O:22][CH3:23])[C:17]([O:20][CH3:21])=[CH:18][CH:19]=1>O1CCOCC1>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:9])=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C=NC(=O)Oc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)NC(=O)Oc2ccccc2)cc1OC

Procedure:
To a solution of phenoxycarbonylisocyanate (7.0 g., 0.043 mole) in 50 ml. of dioxane is added 4-aminoveratrole (6.57 g., 0.043 mole) under a nitrogen atmosphere while maintaining a temperature of 20°-25°. Following the addition of the 4-aminoveratrole, a second 50 ml. portion of dioxane is added and the solution refluxed for a period of one hour. Concentration of the reaction mixture under reduced pressure provides an oily solid residue. Titration of this residual material with about 40 ml. of cold carbon tetrachloride followed by crystallization from acetonitrile provides analytically pure 1-(3,4-dimethoxyphenyl)-3-phenoxycarbonylurea, m.p. 139.5°-142°.