Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[C:4](Br)[CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:2]3[CH:15]=[CH:16][C:5]([CH3:6])=[CH:4][CH:3]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[C:4]([C:11]3[CH:10]=[CH:9][C:8]([CH3:7])=[CH:17][CH:12]=3)[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Brc1ccc2ccc3c(Br)cc(Br)c4ccc1c2c34
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)cc(-c5ccc(C)cc5)c5ccc2c3c45)cc1
Temperature: 130 °C
Reaction time: 9 h
Yield: 167.2 %

Procedure:
Next, a mixed solution of 2.0 g of 1,3,6-tribromopyrene, 2.5 g of 4-methylphenylboronic acid, 5.8 g of tripotassium phosphate, 0.88 g of tetrabutylammonium bromide, 61 mg of palladium acetate and 137 ml of deaerated dimethylformamide was heated with stirring under a nitrogen gas flow at 130° C. for 9 hours. After cooling to room temperature, 800 ml of water was injected, followed by extraction with 200 ml of dichloromethane. The organic layer was washed twice with 100 ml of water, dried over magnesium sulfate and then evaporated. The resultant concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 1.8 g of 1,3,6-tri(4-methylphenyl)pyrene as a pale yellow powder.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([C:13]([CH:15]2[CH2:17][CH2:16]2)=O)[C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([N:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1)[CH3:19]>C(O)(C)(C)C>[CH:1]1([C:7]2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:13]([CH:15]3[CH2:17][CH2:16]3)[N:25]=[C:24]3[N:20]([CH2:18][CH3:19])[N:21]=[CH:22][C:23]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1nccc1N
Reactant: COC(=O)C(=CC1CCCCC1)C(=O)C1CC1
Solvent: CC(C)(C)O
Product: CCn1ncc2c(C3CCCCC3)c(C(=O)OC)c(C3CC3)nc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 3-cyclohexyl-2-(cyclopropylcarbonyl)acrylate (6.01 g) and 1-ethyl-1H-pyrazol-5-amine (2.97 mg) in tert-BuOH (60 ml) was refluxed for 22 hours. The solvent was evaporated off, and the residue was dissolved in dioxane (60 ml). To the mixture was added 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (5.77 g). The mixture was stirred for 6 h at room temperature. The mixture was filtered off, and the filtrate was evaporated. The residue was dissolved in EtOAc (20 ml), and to the solution was added silicagel, followed by hexanes (100 ml). The mixture was filtered, and filter cake was washed with EtOAc-hexanes (1-5). The filtrate was evaporated off. Silicagel column chromatography (EtOAc-hexanes, a linear gradient of EtOAc from 0 to 15%) afforded methyl 4-cyclohexyl-6-cyclopropyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate as a colorless oil, which was crystallized upon standing (4.36 g).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CO>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1)[CH3:26]
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)CCCCOc1ccc(NC=C2C(=O)Nc3ccccc32)cc1
Temperature: 50 °C

Procedure:
A 25 mL pressure tube is charged with 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one (75 mg, 0.173 mmol), diethylamine (2 mL) and the reaction mixture is heated at 50° C. for 3 h. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The organic layer is washed with saturated aqueous NaHCO3 solution, brine, and dried over anhydrous Na2SO4. The organic layer is collected by filtration and concentrated to give a yellow solid. The solid is broken up in MeOH and collected by filtration to give the named compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 10.12 g of 4′-chloropropiophenone, 0.1 ml of hydrobromic acid (48% aqueous solution) and 60 ml of acetic acid was added 3.1 ml of bromine at 0° C. under a nitrogen atmosphere, and stirred at room temperature for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure, to obtain 14.34 g of 2-bromo-4′-chloropropiophenone.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][CH:25]=2)[C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[C:20]([F:19])([F:39])[F:40])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccc(OC(F)F)cc1)c1ccccc1C(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: FC(F)Oc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Yield: 111.6 %

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (1.12 g, 4.7 mmol) and 2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydrol (173) (3.0 g, 9.4 mmol) using the procedure described for compound (3). After basic aqueous workup, the crude product was partially purified by flash column chromatography [SiO2; ethyl acetate-iso-hexane (10:90-+15:85)] to afford an amber gum (2.83 g) which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:5]1)[CH2:2][CH3:3].C(N1C(C2SC=CC=2)=CC=N1)CC.[I:27]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:27][C:7]1[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCCn1ccc(-c2cccs2)n1
Agent: CCCn1nccc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: CN(C)C=O
Product: CCCn1cc(I)c(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a mixture of 1-propyl-3-(2-thienyl)-1H-pyrazole and 1-propyl-5-(2-thienyl)-1H-pyrazole (80:20, 5.0 mmol) in 18 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (5.2 mmol) in small portions. The reaction mixture was stirred overnight at room temperature. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with ethyl acetate. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 180 mg 4-iodo-1-propyl-3-(2-thienyl)-1H-pyrazole (11% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[O:9][CH:10]=1)=[O:5])C>C(O)C>[C:12]([NH:11][C:8]1[O:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1coc(NC(C)=O)n1
Solvent: CCO
Product: CC(=O)Nc1nc(C(=O)O)co1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.3 g (6.60 mmol) 2-Acetylamino-oxazole-4-carboxylic acid ethyl ester is added to 33 mL ethanol. 0.55 g (13.2 mmol) LiOH monohydrate is added and the mixture is stirred for 12 h at rt. The mixture is concentrated in vacuo, acidified by means of aq. HCl solution and the precipitate is collected and washed with cold water to yield the desired product.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:41][CH2:42][C:43]=5[C:44]5[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=5)[CH2:35][CH2:34][N:33]([CH:36]([CH2:39][F:40])[CH2:37][F:38])[CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15]C)=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.O[Li].O.Cl>O1CCCC1.CO>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:41][CH2:42][C:43]=5[C:44]5[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=5)[CH2:35][CH2:34][N:33]([CH:36]([CH2:37][F:38])[CH2:39][F:40])[CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([OH:15])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(CF)CF)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(CF)CF)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265I (320 mg) in tetrahydrofuran (4 mL) and methanol (2 mL) was added LiOH H2O (120 mg) and the solution was stirred overnight. The reaction was cooled, carefully neutralized with 1N aqueous HCl and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][CH2:10][Cl:11].CN(C=O)C.[OH:17][C:18]1[N:22]([CH3:23])[N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=1>O>[Cl:11][CH2:10][CH2:9][CH2:8][O:17][C:18]1[N:22]([CH3:23])[N:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=1
Reactant: COC(=O)c1cc(O)n(C)n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCCCl)n(C)n1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Cesium carbonate (2.08 g, 6.4 mmol) and 1-bromo-3-chloropropane (1.6 ml) were added to a DMF solution (5 ml) of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (0.83 g, 5.3 mmol) and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phase was washed with water and dried over magnesium sulfate. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:1→4:1). The purified product was concentrated to dryness under reduced pressure to obtain methyl 5-(3-chloropropoxy)-1-methyl-1H-pyrazole-3-carboxylate (1.17 g) as white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:42]1[CH:43]=[C:44]([NH:48][S:49]([N:52]([CH3:54])[CH3:53])(=[O:51])=[O:50])[CH:45]=[N:46][CH:47]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.ClCCl.CCOCC>[CH3:53][N:52]([CH3:54])[S:49]([NH:48][C:44]1[CH:45]=[N:46][CH:47]=[C:42]([C:2]2[CH:11]=[C:10]3[C:5](=[CH:4][CH:3]=2)[N:6]=[CH:7][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[N:9]3)[CH:43]=1)(=[O:50])=[O:51]
Reactant: CN(C)S(=O)(=O)Nc1cncc(Br)c1
Reactant: Cn1cc(-c2cnc3ccc(Br)cc3n2)cn1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN(C)S(=O)(=O)Nc1cncc(-c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
Temperature: 25 °C
Reaction time: 16.75 h
Yield: 56.5 %

Procedure:
In an oven dried high pressure vessel under a nitrogen atmosphere, 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline (150 mg, 0.519 mmol), bis(pinacolato)diboron (158 mg, 0.623 mmol), potassium acetate (153 mg, 1.556 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18.98 mg, 0.026 mmol) in anhydrous 1,4-dioxane (2 mL) was stirred at 100° C. in an oil bath for 1 hr. The reaction mixture was cooled to room temperature. N′-(5-bromo-3-pyridinyl)-N,N-dimethylsulfamide (145 mg, 0.519 mmol) followed by sodium bicarbonate (131 mg, 1.556 mmol) in water (0.67 mL) were added to the reaction mixture and the vessel was sealed again. The reaction was stirred at 100° C. for 16.75 hours then cooled to room temperature. The reaction was filtered through Celite and the pad was washed with ethyl acetate. The bi-phasic mixture was separated in a separatory funnel. The organic layer was washed with brine (20 mL), dried over magnesium sulfate, and concentrated in vacuo to give a brown solid. Trituration of the brown solid in dichloromethane (3 drops) and ether (8 mL) provided the title compound (120 mg, 57%) as a light brown solid. MS(ES)+ m/e 410.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.CC[N:25]=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.N>ClCCl.CO>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:25])=[O:11])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: Cc1cc(Nc2ncccc2C(=O)O)n(-c2ccccc2)n1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncccc2C(N)=O)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.6 %

Procedure:
To a solution of 2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]nicotinic acid (40 mg, 0.14 mmol), EDCI (52 mg, 0.27 mmol), HOAT (37 mg, 0.27 mmol), and triethylamine (0.06 mL, 0.41 mmol) in dichloromethane (4 mL) was added ammonia (7 N) in methanol (0.2 mL). The reaction mixture was stirred at rt for 16 h. The organic layer was washed with water, dried over MgSO4, and subsequently concentrated under reduced pressure. The product was purified on a silica gel preparative plate (1000 microns) with EtOAc/hexane (2:1, v/v) to obtain the product as a white solid (22 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 2.2 (s, 3H), 6.63 (s, 1H), 6.89 (m, 1H), 7.38 (m, 1H), 7.50 (m, 4H), 7.71 (s, 1H), 8.15 (d, 1H), 8.24 (s, 1H), 8.33 (d, 1H), 11.56 (s, 1H); ES-MS m/z 294.1 (MH+); HPLC RT (min) 2.02.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cncc(Br)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ncc(Br)cc1O
Temperature: 0 °C
Reaction time: 20 h
Yield: 91.3 %

Procedure:
5-Bromo-3-hydroxylpyridine (2 g, 0.011 mol) was dissolved in concentrated sulfuric acid (6 mL), fuming nitric acid (0.52 mL, 0.011 mol) was added under ice-cooling, and the mixture was stirred for 20 hours. The reaction mixture was gently poured into ice water and the mixture was stirred. The precipitated solid was filtered and washed with water to give the object product as a pale-yellow solid (2.2 g, yield 90%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Li]CCCC.C([O:17][C:18]([C:20]1[N:21]=[N:22][S:23][C:24]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)C>C1COCC1.C1CCCCC1>[N:4]1([CH2:3][CH2:2][NH:1][C:18]([C:20]2[N:21]=[N:22][S:23][C:24]=2[NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:17])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C(NCCN1CCOCC1)c1nnsc1Nc1ccccc1
Yield: 60 %

Procedure:
To a solution of N-aminoethylmorpholine (228 mg, 10 mmole) in 2 mL anhydrous THF at −40° C. was added 0.8 mL of 2 M n-BuLi solution in cyclohexane. Some white solid was precipitated instantly. The suspension was stirred for about a half an hour. When the bath temperature reached −10° C., a solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester (60 mg, 0.24 mmole) in anhydrous THF was added to the mixture. After it was stirred at room temperature for an hour, the reaction was quenched with saturated NH4Cl solution. The solution was extracted with EtOAc and residue obtained after the removal of EtOAc was purified by preparative TLC (silica gel, CH2Cl2:MeOH=15:1). The title compound was isolated as a white powder in 60% yield (48 mg). 1H NMR (ppm, in CDCl3): 10.91 (br. s, 1H), 7.77 (br. s, 1H), 7.00-7.60 (m, 5H), 3.70 (m, 4H), 2.60 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: C[C@H]1c2ccccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the titles-configurated compound in moderate yield.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[N:8][C:9]=2[N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:4]([CH2:28][CH3:29])[N:3]=1.C(=O)(O)[O-].[Na+].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.O>C1(C)C=CC=CC=1.CCO.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>[CH2:28]([N:4]1[C:5]2=[N:6][C:7]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[N:8][C:9]([N:11]3[CH2:12][CH:13]4[O:18][CH:16]([CH2:15][CH2:14]4)[CH2:17]3)=[C:10]2[C:2]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[N:3]1)[CH3:29]
Reactant: OB(O)c1cccnc1
Reactant: CCn1nc(Br)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1nc(-c2cccnc2)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Yield: 104.1 %

Procedure:
To a solution of 3-bromo-1-ethyl-6-(4-nitrophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg)(0.21 mmol) in toluene/EtOH (1:1) (2.0 mL) was added Pd(PPh3)4 (12 mg) (10 mol %), aqueous sodium bicarbonate solution (2.0 M) (0.135 mL) and 3-pyridine boronic acid (32 mg) (0.26 mmol). The reaction was heated in the microwave for 20 minutes at 140 C. The reaction was cooled and added water and then extracted three times with EtOAc. Organics were dried (MgSO4) and filtered off through a pad of Magnesol and concentrated in vacuo. to give a yellow oil 100 mg. MS m/z=458 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:13](N(C(OC)=O)C2C=CC=CC=2)[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7][CH2:6]1)=[O:4]>CO.C[O-].[Na+]>[CH3:1][O:2][C:3]([C:5]1[CH2:6][CH2:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=1)=[O:4]
Reactant: COC(=O)C1CCc2ccsc2C1N(C(=O)OC)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=Cc2sccc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-methoxycarbonyl-N-phenyl-7-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylic acid methyl ester (100 mg, 0.290 mmol) was dissolved in methanol (3 ml), to which sodium methoxide (28% methanol solution, 1 ml) was added and stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with diethyl ether. After washing the liquid extract with an aqueous solution of sodium chloride and drying over sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 46.7 mg (yield 48%) of 4,5-dihydrobenzo[b]thiophene-6-carboxylic acid methyl ester as white crystalline solids. 1H-NMR spectra (chemical shift, ppm: in CDCl3): 2.68 (2H, m), 2.84 (2H, m), 3.79 (3H, s), 6.90 (1H, d, J=4.9 Hz), 7.31 (1H, d, J=4.9 Hz), 7.53 (1H, s).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[N:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.Br>C(Cl)Cl>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[N:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)nc1
Agent: Br
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Br)nc1
Reaction time: 66 h
Yield: 116.2 %

Procedure:
A solution of bromine (4 g, 25 mmol) in DCM (10 mL) was added drop wise over 5 min to a cooled (0° C.) solution of 1-(6-bromo-pyridin-3-yl)-ethanone (5 g, 25 mmol) and HBr (48%, 0.2 mL). The cooling bath was removed 40 min later and stirring was continued at RT for 66 h. The solid that formed was filtered, washed with DCM and dried at room temperature to give the impure title intermediate (8.1 g) as a yellow solid. 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.96 (m, 1H), 8.28-8.25 (m, 1H), 7.82-7.79 (m, 1H), 4.7 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH-:23].[Na+]>C(OCC)C.CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:23]
Reactant: CNc1ccc(F)c(C#N)c1
Reactant: [OH-]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: CO
Product: CNc1ccc(F)c(C=O)c1
Reaction time: 19.5 h
Yield: 92.5 %

Procedure:
To a solution of 2-fluoro-5-methylaminobenzonitrile (307 mg, 2.04 mmol) in dry diethyl ether (10 ml) stirred at room temperature under nitrogen, was added dropwise by syringe diisobutylaluminium hydride (2.8 ml, 1.0 M in toluene, 2.8 mmol, 1.4 eq) and stirring continued for 19.5 h. The solution was chilled in an ice-bath and methanol (1.0 ml) was added dropwise and the mixture stirred for 1 h before 1.0 M HCl (9 ml) was added and stirring continued for a further 1 h. The reaction mixture was basified with NaOH (0.4 g) then partitioned between ether (50 ml) and water (50 ml) and the aqueous layer re-extracted with ether (50 ml). The combined ether extract was washed with brine (50 ml), dried over MgSO4 and evaporated to give an orange oil (289 mg), which was subjected to column chromatography (silica gel, 30×190 mm) eluting with 100% dichloromethane, affording 2-fluoro-5-methylaminobenzaldehyde (viii) as a yellow crystalline solid (162 mg, 52%), mp 36-38° C.
Reaction SMILES: [CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].CCOCC.[C:16]1([P:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH:1]1([P:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: c1ccc2[cH-]ccc2c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=CC(P(c2ccccc2)c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 83.5 %

Procedure:
In the drybox lithium indenide (8.00 g, 65.52 mmol) dissolved in 50 mL of THF was added within 15 minutes to a 180 mL ether solution of diphenylchlorophosphine (14.46 g, 65.52 mmol) (diphenylchlorophosphine was distilled before use (97° C. @ 0.4 torr)). After stirring overnight, LiCl was separated by filtration giving a yellow solution. Solvent was removed under vacuum leaving an off-white solid. This solid was triturated with 40 mL of hexane. Hexane was removed by decanting and the solid was dried under reduced pressure to give 16.43 g of off-white solid. Yield 84 percent.