Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[C:22]2[CH:23]=[C:24]3[CH:33]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][CH2:31][N:25]3[C:26]=2[CH:27]=[C:28]([F:30])[CH:29]=1.[CH2:39]([O:41]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:40]>CN(C=O)C>[C:39]([C:21]1[C:22]2[CH:23]=[C:24]3[CH:33]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][CH2:31][N:25]3[C:26]=2[CH:27]=[C:28]([F:30])[CH:29]=1)(=[O:41])[CH3:40]
Reactant: COC(=O)CC1CCn2c1cc1c(Br)cc(F)cc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)CC1CCn2c1cc1c(C(C)=O)cc(F)cc12
Temperature: 90 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
A mixture of tris(dibenzyllideneacetone)dipalladium (281 mg, 0.3 mmol) and triphenyl arsine (367 mg, 1.2 mmol) in DMF (4 mL) was sonicated for 10 minutes and then degassed. A solution of (+/−)-methyl (8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 7, Step 8, 200 mg, 0.6 mmol) in 3 mL of DMF and 1-ethoxyvinyltri-n-butyltin (650 mg, 1.8 mmol) were added and the mixture was degassed. The reaction mixture was stirred at 90° C. for 12 hours and 1N HCl (4 mL) was added. The mixture was stirred at 90° C. for 12 hours and extracted with EtOAc. The combined organic layers were washed with 1N HCl, brine and water, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc in hexanes to provide the title compound (70% pure) as a pale yellow oil used as such.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][OH:15])[N:10]=2)=[CH:5][CH:4]=1)#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.OP(O)(O)=O.O>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH:14]=[O:15])[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2nc(CO)no2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2nc(C=O)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A mixture of 5-(4-cyanophenyl)-3-hydroxymethyl-1,2,4-oxadiazole (4.08 g), N,N'-dicyclohexylcarbodiimide (20.92 g) and o-phosphoric acid (9.94 g) in dimethyl sulfoxide (80 ml) was stirred at ambient temperature. After 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ether to give 5-(4-cyanophenyl)-3-formyl-1,2,4-oxadiazole (2.17 g).
Reaction SMILES: O1CCCC1.B(F)(F)F.CCOCC.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[CH2:24]([SH:27])[CH2:25][SH:26]>O.C(Cl)Cl>[S:26]1[CH2:25][CH2:24][S:27][CH:20]1[C:19]1[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=1
Reactant: SCCS
Reactant: O=Cc1ccc(O)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C2SCCS2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 108.6 %

Procedure:
In a tetrahydrofuran (THF) (3 mL) solvent, boron trifluoride diethyl etherate (0.03 mL, 0.25 mmol) was added to a mixed solution including 4-hydroxybenzaldehyde (300 mg, 2.16 mmol) and 1,2-ethanedithiol (0.21 mL, 2.46 mmol), and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was distributed between methylene chloride and water, and an organic layer was dried by using MgSO4, filtered, and evaporated under reduced pressure to obtain Compound 81 (465 mg, 95.3%).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH2:21][CH2:22][C:23]#[N:24])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2]>CO.N.[Ni]>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH:12]=[CH:13][CH:5]=[CH:6]2)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: N#CCCc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(CCCn2cccc2)c1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
The nitrile (3.46 g) is dissolved in 70 ml of methanol saturated with ammonia, the solution is after-saturated for 30 minutes under an ammonia pressure of 5 bars and, after adding 1 g of Raney Ni, is hydrogenated for 12 hours at 70°-80° C. and under an initial hydrogen pressure of 100 bars. The catalyst is then filtered off and washed with methanol and the filtrate is evaporated. After taking up the residue in a little water, the solution is acidified and extracted by shaking with ethyl acetate and the acid aqueous phase is again evaporated, dried and extracted with ethanol, the ethanol extract is concentrated to 30 ml and ether is added: 3-sulphamoyl-4-phenoxy-5-[γ-aminopropyl]-benzoic acid hydrochloride crystallises out; melting point 259°-262° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:31]([C:22]3[CH:23]=[CH:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=3)=[O:32])[CH2:2][CH2:3]2)[N:14]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccc5ccccc5c4)CC3)cccc2n1
Yield: 88 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 2-naphthoyl chloride (70.5 mg; 0.37 mmol) via Method AA to yield 139 mg. (88% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.97 (m, 4H), 7.58 (m, 2H), 7.50 (dd, J=8.4, 1.6 Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.2 (br s, 2H), 6.76 (d, J=8.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.59 (br s, 1H), 4.04 (d, J=6.0 Hz, 2H), 3.72 (br s, 1H), 3.15 (br s, 1H), 2.91 (br s, 1H), 2.24 (m, 1H), 1.9 (br s, 1H), 1.75 (br s, 1H), 1.35 (m, 2H). MS m/z (ESI) 428 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[S:25][CH:24]=[CH:23][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][SiH2:15][C:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)C>[N:37]1[CH:38]=[CH:39][C:34]([C:2]2[C:3]3[S:25][CH:24]=[CH:23][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][SiH2:15][C:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=3)[N:7]=2)=[CH:35][CH:36]=1
Reactant: CC(C)(C)C(C)(C)[SiH2]Oc1cccc(-c2nc(Br)c3sccc3n2)c1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)C(C)(C)[SiH2]Oc1cccc(-c2nc(-c3ccncc3)c3sccc3n2)c1
Temperature: 130 °C
Yield: 93.4 %

Procedure:
A mixture of 4-bromo-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine, (72 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine (52 mg), sodium carbonate (57 mg), PdCl2(PPh3)2 (0.1 eq), toluene (2 mL), ethanol (1 mL) and water (0.5 mL) was heated to 130° C. for 5 minutes under microwave irradiation. The reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The residue was purified using flash chromatography to yield 4-pyridin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine (67 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN(C)S(=O)(=O)O[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[CH2:27][CH2:28][C:29]#[N:30].O>CCCCCC.C1COCC1>[CH3:26][O:25][C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][C:21]=1[O:23][CH3:24])[CH:28]([C:29]#[N:30])[CH2:27]2
Reactant: COc1cc(CCC#N)c(OS(=O)(=O)N(C)C)cc1OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC)C(C#N)C2
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 110.8 %

Procedure:
Under nitrogen, mix together 5.4 ml (0.0382 mol) of redistilled diisopropylamine and 60 ml of THF. Cool the mixture to −50° C. and pour in dropwise 15.3 ml (0.0382 mol) of a 2.5N solution of butyllithium in hexane. Allow the temperature to rise again to −5° C. and stir for 10 minutes. Cool the solution to −60° C. and pour in dropwise a solution of 3 g (0.00954 mol) of 2-(2-cyanoethyl)-4,5-dimethoxyphenyl dimethylsulphamate in 35 ml of THF. Allow the temperature slowly to rise again to −24° C. while monitoring by HPLC disappearance of the reactant. Add the reaction mixture to a mixture of water and ice and extract with ethyl acetate. Wash the organic phases in succession with 1N sodium hydroxide solution, aqueous 1N HCl solution, water and saturated aqueous NaCl solution and then dry them over MgSO4, filter, and evaporate off the solvents. 2 g of residue are obtained which is purified by flash chromatography on 70 g of silica (eluant=dichloromethane) to yield 0.9 g of title product in the form of a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14](OC)=[O:15])[CH:12]=3)[O:7][CH2:6][CH:5]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[O:15])[CH:12]=3)[O:7][CH2:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)C(C1CC1)=CCO2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)C(C1CC1)=CCO2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Methyl 4-cyclopropyl-2H-chromene-6-carboxylate (101 mg, 0.44 mmol) was dissolved in dichloromethane (4.40 mL), and cooled to −78° C. DIBAL-H (877 μL, 0.88 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at −78° C. and warmed to room temperature. It was then quenched with methanol at room temperature and diluted with dichloromethane. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was used directly in the next step. The crude alcohol was dissolved in dichloromethane (4.00 mL) and Dess-Martin periodinane (372 mg, 0.88 mmol) was added in one portion at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum on silica gel. The crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc/Hexanes to afford the desired product as a colorless oil.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]Br)=[O:8])=[CH:5][CH:4]=[C:3]([Cl:11])[CH:2]=1.[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH2:15]>C(O)C>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH:15][CH2:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([Cl:11])=[CH:2][CH:1]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCO
Product: Cc1cccc(C)c1NCC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
46.7 g (0.2 mole) of ω-bromo-4-chloroacetophenone in 40 ml of ethanol were added to 48.4 g (0.4 mole) of 2,6-dimethylaniline in 40 ml of ethanol and the mixture was warmed to 50° C. for 20 minutes. Thereafter, it was cooled to 0° C. and the crystals which had formed were filtered off and rinsed with a little ethanol. 30 g (55% of theory) of 2,6-dimethyl-N-(4-chlorobenzoylmethyl)-aniline of melting point 82° C. were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[O:14][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7-Nitro-1,2,3,4-tetrahydronaphthalen-1-ol (1.0 g, 5.2 mmol) was dissolved in a mixture of DCM (10 mL) and pyridine (10 mL). Then, the reaction mixture was cooled to 0° C. and methane sulphonyl chloride (0.44 mL, 5.7 mmol) was added dropwise, and the reaction mixture was stirred at 60° C. for 2 hours. Next, the reaction mixture was cooled to room temperature and then diluted with ethyl acetate, and washed with 1N HCl, saturated NaHCO3, and brine. The organic solution was dried (Na2SO4) and concentrated to give methanesulfonic acid 7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl ester. Yield 1.34 g (95%). LCMS (ESI): calc. C11H13NO5S=271; obs. low ionization.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[CH2:20]([NH2:26])[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:26][CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][O:25]3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCC1CCCO1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: Clc1nc(SCc2ccccc2)nc2nc(NCC3CCCO3)sc12

Procedure:
Prepared according to the method of Example 220 using the product of Example 219 and tetrahydrofurfurylamine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]([O:11][CH2:12][C:13]2[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][CH2:10][CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[O:11][CH2:12][C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC(OCc1ccccc1OC)c1cccc(Cl)c1
Reactant: NCc1ccccc1
Product: COc1ccccc1COC(CCNCc1ccccc1)c1ccccc1

Procedure:
A secondary N-benzylamine can likewise be debenzylated to produce the desired primary amine. To prepare such a secondary benzlamine, 3-chloro-1-(o-anisyloxy)propylbenzene or other 1-substituted phenyl-3-chloropropylbenzene, utilized as an intermediate in an earlier procedure, can be reacted with benzylamine to yield N-benzyl 3-phenyl-3-(o-anisyloxy)propylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])([O-:12])=[O:11].N1C=CC=CC=1>C(Cl)Cl>[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:4][C:3]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:2]=1[CH3:1])(=[O:21])=[O:20])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Cc1ccc(C)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C)c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
2,5-dimethyl-aniline (2.4 g, 20 mmol) and 2-nitrobenzenesulfonyl chloride (4.4 g, 20 mmol) are dissolved in CH2Cl2 and treated with pyridine (1.8 mL, 22 mmol). The reaction mixture is stirred at room temperature until TLC shows no starting material. The reaction mixture is quenched with dilute HCl, and the organic layer washed with saturated brine. Drying over MgSO4, filtration, and concentration provides a solid that is recrystallized from hot EtOAc/hexanes to provide 2-nitro-N-(2,5-dimethyl-phenyl)-benzenesulfonamide.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].BrBr.[Cl:7][C:8]1[NH:9][C:10]([CH3:15])=[CH:11][C:12]=1[C:13]#[N:14].O>CO>[Cl:7][C:8]1[NH:9][C:10]([CH3:15])=[C:11]([S:1][C:2]#[N:3])[C:12]=1[C:13]#[N:14]
Reactant: N#C[S-]
Reactant: Cc1cc(C#N)c(Cl)[nH]1
Agent: BrBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(Cl)c(C#N)c1SC#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium thiocyanate (7.5 g) in 50 ml of methanol was cooled to −76° C. Bromine in 30 ml of cold methanol was added dropwise over 12 min. A slurry of 2-chloro-3-cyano-5-methylpyrrole in 30 ml of cold methanol was added at once. After stirring 30 min at −78° C., the mixture was poured into H2O and stirred overnight, then filtered, washed with water and hexane, and air dried to afford 6.57 g of an off-white solid, m.p. 171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[I:17]Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClI
Reactant: Clc1cnc2[nH]ccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (1, 15.00 g, 98.31 mmol) in 300 mL of dichloromethane under nitrogen, pyridine (7.951 mL, 98.31 mmol) and iodine monochloride (110 mL, 1.0 M in dichloromethane, 110 mmol) were added slowly over 20 minutes. The reaction was stirred at room temperature for 2 hours, then quenched with 100 mL of 1 M aqueous sodium thiosulfate pentahydrate. The layers were separated, solids collected from the aqueous layer by filtration and combined with the organic layer. The aqueous layer was extracted with ethyl acetate, organic layers were combined and washed with brine, then concentrated under vacuum. The resulting solid was washed with 20% ethyl acetate in hexane to provide the desired compound. 5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine is prepared similarly from 5-fluoro-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][N:29]=1)[C:17]([NH:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)=[O:18]>>[CH3:26][C:22]1[CH:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][N:29]=[C:28]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:27]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: Cc1cccc(NC(=O)c2ccnc(Br)c2)c1
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C)c3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-m-tolyl-isonicotinamide were converted to the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[CH:11][N:12]=[N:13][C:14]([NH2:15])=[C:9]3[CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.[OH-].[Na+].O>ClCCl>[Br:16][C:8]1[C:9]2[C:10](=[CH:11][N:12]=[N:13][C:14]=2[NH2:15])[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1
Reactant: BrBr
Reactant: Nc1nncc2c1ccn2C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Nc1nncc2c1c(Br)cn2C1CCCC1
Reaction time: 1 h
Yield: 34 %

Procedure:
A mixture of 1-cyclopentyl-1H-pyrrolo[2,3-d]pyridazin-4-amine (0.595 mg, approx. 60% pure, 1.76 mmol) in dichloromethane (100 mL) was treated with a solution of dichloromethane (5 mL) containing bromine (0.5 g, 2.95 mmol) over the course of 1.25 hours. The mixture was stirred an additional one hour then another portion of dichloromethane (3 mL) containing bromine (0.3 g) was added. The mixture was stirred for 2.5 hours then treated with 5 mL 5N aqueous sodium hydroxide and 25 mL water. The layers were separated and the organic layer was concentrated under reduced pressure to give a residue which was purified by reverse phase preparative HPLC to give 3-bromo-1-cyclopentyl-1H-pyrrolo[2,3-d]pyridazin-4-amine (168 mg, 35%); 1H NMR (DMSO-d6, 400 MHz) δ 8.94 (s, 1H), 7.79 (s, 1H), 6.11 (bs, 2H), 4.94 (m, 1H), 2.12 (m, 2H), 1.83 (m, 4H), 1.67 (m, 2H); 5%–100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 11.25 min.; LC/MS: MH+ 282.8.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17]C)=[O:16])=[CH:5][C:4]=2[NH:3]1.CO.C1COCC1.[Li+].[OH-]>O>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 618 mg, 2.38 mmol) was suspended in 10 ml of a mixture of MeOH, THF, and water (1:1:1, v:v:v). LiOH (2.0 eq, 114 mg, 4.76 mmol) was added and the mixture was stirred at room temperature for 2 hours. An additional amount of LiOH (114 mg) was added and the mixture was stirred for an hour. LiOH (50 mg) was added and the mixture stirred for an additional 2 hours. Water was added and the solution filtered through a pad of celite. The pad of celite was thoroughly washed with aqueous 1 N NaOH. The solution was acidified with 6 N aqueous HCl to induce precipitation of the expected material. Filtration and drying afforded 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylic acid as a yellow solid (562 mg, 96% yield). LCMS (ES): 95% pure, m/z 246 [M+1]+; 1H NMR (DMSO-d6, 400 MHz) δ 7.61 (d, J=5.2, 1H), 7.73 (dd, J=1.6, J=8.0, 1H), 7.88 (d, J=5.6, 1H), 7.92 (d, J=8.4, 1H), 8.02 (d, J=1.6, 1H), 11.92 (s, 1H), 13.21 (br. s, 1H) ppm.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:15]1=[O:16]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[NH:14][C:15](=[O:16])[CH2:17][CH2:18]3)=[O:8])[CH:3]=1
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C(Cl)c1cccnc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(C(=O)c3cccnc3)ccc2N1

Procedure:
A mixture of 1.42 g of nicotinoyl chloride (a compound of Formula A2), 6 g of aluminum trichloride and 1 g of 3,4-dihydrocarbostyril were reacted in the same manner as in Preparation 1. The product was isolated similarly giving 6-(3-pyridylcarbonyl)-3,4-dihydrocarbostyril, m.p. 195°-202° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[Cl:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[Cl:55])(=[O:64])=[O:63])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(S(=O)(=O)c2ccccc2Cl)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 22 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-chlorobenzenesulfonyl chloride as starting materials in 22% yield. LCMS for C30H30Cl2N7O3S (M+H)+: m/z=638.2.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[C:9]=2[C:8](=[O:22])[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH3:24]I>>[CH3:24][N:7]1[C:8](=[O:22])[C:9]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:11]=[N:12][C:13]=2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1=[O:23]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2CCCCCC(C)=O
Reactant: CI
Product: CCCCn1c(=O)n(C)c(=O)c2c1ncn2CCCCCC(C)=O
Reaction time: 46 h
Yield: 80.1 %

Procedure:
The reaction is performed according to example 15 from 3-(n-butyl)-7-(6'-oxoheptyl)-xanthine and methyl iodide, but at a temperature of the mixture of 50° C. under stirring for 46 hours. Prior to the distillation at a bath temperature of 140° C. and 0.02 mmHg the product is purified by column chromatography at silica gel 60 (Merck) with methylene chloride/acetone (80:2) as eluent. 1-Methyl-3-(n-butyl)-7-(6'-oxoheptyl)-xanthine was obtained as a viscous oil (nD20 1.5280; yield 80.1%, referred to reacted 3-(n-butyl)-7-(6'-oxoheptyl)-xanthine.