Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][CH:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[CH2:15][CH3:16]
Reactant: CCCNCCC
Reactant: COC1=CC=C2CC(=O)CCC2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCN(CCC)C1CCc2cc(OC)ccc2C1

Procedure:
20 g of 6-methoxytetrahydronaphthalen-2-one, 20 ml of dipropylamine and 200 mg of para-toluenesulphonic acid are introduced into 300 ml of benzene under a nitrogen atmosphere. The mixture, which has become black, is then heated under reflux for 12 hours, the water of condensation being removed by azeotropic distillation. The solution, which contains the compound (IV), is then concentrated to a volume of about 100 ml. For the hydrogenation, 150 ml of ethanol and 300 mg of PtO2 are added thereto and hydrogenation is carried out, under a pressure of about 0.3 MPa, until the absorption has stopped.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[CH:7]=1.O=S(Cl)[Cl:17]>>[Cl:17][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn(-c2ccc(I)cc2)cn1
Product: ClCc1cn(-c2ccc(I)cc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 4-hydroxymethyl 1-(4-iodophenyl)imidazole I-1 (0.810 g, 2.70 mmol) was dissolved in SOCl2 (6 mL). The solution was stirred at room temperature for 15 min. It was then concentrated in vacuo. The residue was partitioned between EtOAc and 5% aq. NaHCO3. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give 4-chloromethyl 1-(4-iodophenyl)imidazole 1-3 as a solid (0.780 g). MS 318.9 and 320.9 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH2:13][CH:14]1[CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:12][CH2:13][CH:14]3[CH2:17][CH2:16][O:15]3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Clc1ccc2nnc(Cl)n2n1
Reactant: OCC1CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nnc2ccc(OCC3CCO3)nn12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
a mixture of 756 mg of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine, 0.352 cm3 of 2-hydroxymethyloxetane and 552 mg of potassium carbonate in 8 cm3 of N,N-dimethylformamide is heated at 100° C. for 6 h and then stirred at 20° C. overnight. The reaction medium is concentrated to dryness under vacuum. The residue obtained is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a dichloromethane/methanol gradient of 100/0 to 97/03. 701 mg of 3-chloro-6-(oxetan-2-ylmethoxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a beige solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8])(=[NH:3])[NH2:2].Br[CH:16]1[C:21](=O)[CH2:20][CH2:19][O:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]1[NH:2][C:16]2[CH2:17][O:18][CH2:19][CH2:20][C:21]=2[N:3]=1
Reactant: COC(=O)c1ccc(C)c(C(=N)N)c1
Reactant: O=C1CCOCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-c2nc3c([nH]2)COCC3)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A mixture of methyl 3-carbamimidoyl-4-methylbenzoate (compound 1.9, 400 mg, 1.98 mmol, 1.00 equiv, 95%), 3-bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 750 mg, 2.09 mmol, 1.00 equiv), and potassium carbonate (580 mg, 4.20 mmol, 2.00 equiv) in CH3CN (15 mL) was stirred overnight at 80° C. under nitrogen. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and washed with 2×10 mL of H2O. The organic phase was dried over (Na2SO4) and concentrated under reduced pressure. The residue was purified using silica gel column chromatography and purified using ethyl acetate/petroleum ether (1/3) to yield 0.21 g (37%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.CC([O-])(C)C.[K+].CS(O[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)[CH2:28][CH3:29])(=O)=O>C1COCC1.CCOC(C)=O>[C:36]([C:32]1[CH:31]=[C:30]([CH:27]([N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:28][CH3:29])[CH:35]=[CH:34][CH:33]=1)#[N:37]
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: CCC(OS(C)(=O)=O)c1cccc(C#N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(c1cccc(C#N)c1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
To a suspension of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.030 g, 0.143 mmol) in THF (5 mL) was added KOtBu (1M in THF) (0.157 mL, 0.157 mmol). After stirring at rt for a couple of min, a solution of 1-(3-cyanophenyl)propyl methanesulfonate (0.0512 g, 0.214 mmol) in THF (1 mL) was added, and the mixture was heated at 80° C. in a sealed tube. The reaction was monitored by LCMS. After ˜30 min, additional 1-(3-cyanophenyl)propyl methanesulfonate (0.0342 g, 0.143 mmol) in THF (1 mL) was added, and the mixture was heated at 80° C. for another 30 min. Upon cooling, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using 0-25% EtOAc-hexane gradient. The material was further purified by preparative HPLC (Phenomenex Luna column; gradient: 10-100% MeCN-water with 0.1% TFA). The fractions with product were combined and concentrated down to the aqueous phase, which was then partitioned between EtOAc (25 mL) and saturated aq. NaHCO3 solution (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give 1-(1-(3-cyanophenyl)propyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.014 g, 26% yield): MS (ESI): m/z 354 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[CH2:25][C@@H:24]2[C:26]([NH:28][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:33][N:32]=2)[CH3:30])=[O:27])=[CH:19][CH:18]=1.O>ClCCl>[F:42][C:39]([F:40])([F:41])[CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:29]([NH:28][C:26]([C@H:24]2[CH2:25][C@@H:23]2[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:22][CH:21]=2)=[O:27])[CH3:30])=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1)c1ccc(OCC(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCC(=O)OC(C)(C)C)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A mixture of tert-butyl 2-bromoacetate (0.063 ml, 0.434 mmol), potassium carbonate (109 mg, 0.789 mmol) and (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (150 mg, 0.394 mmol) in dichloromethane (4 ml) was refluxed with stirring for 3 hours. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from tetrahydrofuran/hexane. To give 137 mg (70% yield) of title compound as a white crystal:
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[N:7][C:8](Cl)=[C:9]([CH:12]=1)[C:10]#[N:11]>C(O)C>[Br:4][C:5]1[CH:12]=[C:9]2[C:10]([NH2:11])=[N:3][NH:2][C:8]2=[N:7][CH:6]=1
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2ncc(Br)cc12

Procedure:
Hydrazine hydrate (19 ml, 391 mmol) was added to a stirred solution of 5-bromo-2-chloronicotinonitrile (34 g, 156 mmol) in ethanol (300 ml). The reaction mixture was stirred at reflux for 4 hours then the solvent was removed in vacuo. Water was added and the resulting solids were filtered, washed with water, and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: C1COCCN1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc2ccc(N3CCOCC3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and morpholine according to general procedure 1 providing the amino compound (235 mg, 85%) as a yellow solid: Rf=0.79 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=9.9 Hz, 1H), 7.53 (s, 1H), 6.81 (d, J=9.9 Hz, 1H), 3.86 (t, J=5.0 Hz, 4H), 3.55 (t, J=4.8 Hz, 4H); ES-MS: (M+H)=283, 285 m/z.
Reaction SMILES: Br[CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH:4]=[CH2:5].[Mg].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:21][C:22]([CH3:37])([CH3:36])[CH2:23][CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:19]=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:21][C:22]([CH3:36])([CH3:37])[CH2:23][CH2:24][O:25][Si:26]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:31])[CH3:32])[CH:33]([CH3:34])[CH3:35])[C@@H:19]([OH:20])[CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH:4]=[CH2:5])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: C=CC(CBr)C(C)C
Reactant: CC(C)[Si](OCCC(C)(C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: [Mg]
Product: C=CC(C[C@H](O)[C@H](CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C)C(C)C

Procedure:
The title compound is prepared in a manner analogous to that described in Example 35f) starting from 23.9 g of 1-bromo-2(R,S)-isopropyl-3-butene (preparation according to D. Mesnard et al., C.R. Acad. Sci. Paris, t. 277, Series C-567), 3.3 g of magnesium powder and 11.25 g of 2(S)-tert-butoxycarbonylamino-6-triisopropylsilyloxy-4,4-dimethyl-hexanal (Example 1g). The crude product is purified by FC over 900 g of silica gel (mobile phase E) to give the title compound as a diastereomer mixture: Rf (E)=0.31.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](O[C:10](=[O:11])[C:2]=12)=[O:8].[NH2:12][NH2:13]>C(O)(=O)C>[N:1]1[C:2]2[C:10](=[O:11])[NH:12][NH:13][C:7](=[O:8])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: O=C1OC(=O)c2ncccc21
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2ncccc12
Temperature: 125 °C
Reaction time: 0.05 h

Procedure:
To 25 mL of acetic acid at 100° C. was added 2,3-pyridinedicarboxylic anhydride (5.00 g, 34 mmol). Once the solution was homogeneous, it was removed from the oil bath and anhydrous hydrazine (2.0 ml, 64 mmol) was added dropwise over 5 minutes. The reaction was returned to reflux. After 3 min, the solution crystallized and became a solid mass. The reaction was heated in a 125° C. bath for 10 minutes then cooled to room temperature. The solid was transferred to a Büchner funnel and washed with 2×10 mL of acetic acid. The solid was dried under high vacuum to afford 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione 77. 1H-NMR (400 MHz, DMSO): δ 9.10 dd, J=4.7, 2.0 Hz, 1H), 8.50 (dd, J=7.8, 1.6 Hz, 1H), 7.86 (dd, J=8.2, 4.7 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[C:24]4[O:23][CH2:22][O:21][C:20]=4[C:19]([C:25]#[C:26][CH2:27][O:28][CH3:29])=[CH:18][C:17]=3[Cl:30])=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:30][C:17]1[CH:18]=[C:19]([C:25]#[C:26][CH2:27][O:28][CH3:29])[C:20]2[O:21][CH2:22][O:23][C:24]=2[C:16]=1[NH:15][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[C:6]([O:31][CH3:32])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCl)c(OC)cc23)c2c1OCO2
Reactant: CN1CCNCC1
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCN4CCN(C)CC4)c(OC)cc23)c2c1OCO2
Yield: 17 %

Procedure:
7-(2-Chloroethoxy)-N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-6-methoxyquinazolin-4-amine (0.2 g, 0.4 mmol) was dissolved in 1-methylpiperazine (4 ml) and heated at 50 C for 12 hours. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography on alumina eluting with a mixture of 0-10%, methanol in dichloromethane to give the product as a white solid (0.037 g, 17%). NMR Spectrum: (CDCl3) 2.28 (s, 3H), 2.50 (s(broad), 4H), 2.63 (s(broad), 4H), 2.94 (t, 2H), 3.44 (s, 3H), 4.01 (s, 3H), 4.33 (t, 2H), 4.36 (s, 2H), 6.08 (s, 2H), 6.78 (s, 1H), 7.04 (s, 1H), 7.05 (s, 1H), 7.25 (s, 1H), 8.63 (s, 1H). Mass Spectrum: M+H+ 540 and M+H−]538.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[C:15]([CH3:20])=[C:16]([CH2:18]O)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[CH2:21]([SH:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[C:15]([CH3:20])=[C:16]([CH2:18][S:29][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:2])[CH3:3]
Reactant: Cc1c(CO)oc2cccc(OCCCNC(C)C)c12
Reactant: SCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CSCCc2ccccc2)oc2cccc(OCCCNC(C)C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To a solution of [4-(3-isopropylamino-propoxy)-3-methyl-benzofuran-2-yl]-methanol (14 mg, 0.05 mmol) and phenethyl mercaptan (10.3 mg, 0.075 mmol) in anhydrous CH2Cl2 (0.9 ml) was added TFA (0.2 ml). The Mixture was stirred at room temperature for 2.5 hours. The solvent was removed in vacuo. The residue was purified over preparative TLC (CH2Cl2/MeOH=100/1) to give desired compound (15 mg, 74%). FAB-MS: m/z 398 (MH+); 1H-NMR (CDCl3): δ 1.11 (6H, d, J=6.2 Hz), 2.05 (2H, m), 2.34 (3H, s), 2.61-2.96 (7H, m), 3.80 (2H, s), 4.11 (2H, m), 6.56 (1H, m), 6.95-7.28 (7H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN2CCOC2=O)c1
Temperature: 25 °C

Procedure:
{3-[4-Amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.15 g, 0.38 mmol), 4-chlorobenzoyl chloride (0.15 g, 0.86 mmol), and triethylamine (0.27 mL, 1.9 mmol) were combined in CH2Cl2 (10 mL) and stirred at room temperature until no starting material was seen by analytical tlc. The mixture was concentrated to give the title compound, which was used directly in the hydrolysis step.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:24].[C:31]1([C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:37]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][N:9]1[C:10]2[C:16]3[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:24]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccc([N+](=O)[O-])cc43)c2=O)c(OC)c1
Product: O=c1c2sc3ccc([N+](=O)[O-])cc3c2n(Cc2ccccc2-c2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-8-nitro-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-phenylbenzyl bromide and subsequently deprotected to provide the title compound as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.53 (s, 2H); 7.20-7.57 (m, 9H); 8.29 (dd, J1=9 Hz, J2=2 Hz, 1H); 8.36 (d, J=2 Hz, 1H); 8.40 (d, J=9 Hz, 1H); Ret. time=3.14 min., m/z=444.0.
Reaction SMILES: NC1N=C2C(NC=N2)=C([Cl:11])N=1.C(=O)([O-])[O-].[K+].[K+].NC1N=C2C(N=CN2[CH:28]2[C:30]([C:35]([O:37][CH3:38])=[O:36])([C:31]([O:33][CH3:34])=[O:32])[C:29]2([Cl:40])[Cl:39])=C(Cl)N=1>CN(C)C=O>[Cl:11][C:29]([Cl:39])([Cl:40])[CH:28]=[C:30]([C:31]([O:33][CH3:34])=[O:32])[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)C1(C(=O)OC)C(n2cnc3c(Cl)nc(N)nc32)C1(Cl)Cl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CC(Cl)(Cl)Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
In a 0.3-liter four-necked flask, 7.06 g (41.6 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Fine Chemicals Co., Ltd.) and 12.4 g (89.7 mmol) of potassium carbonate were added to 188 ml of N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. Next, 16.0 g (61.2 mmol) of dimethyl 2,2,2-trichloroethylidenemalonate, which was prepared by the process described in U.S. Pat. No. 3,495,012, was added to the resulting mixture, and the mixture was stirred for four hours at room temperature. Thereafter, the reaction mixture was filtered, and the filtrate was poured into water. The precipitated crystals were collected by filtration, washed with 100 ml of water, and then dried under reduced pressure, to give 12.14 g (34.7 mmol) of white crystals of 2-amino-6-chloro-9-(3,3-dicarbomethoxy-2,2-dichlorocyclopropyl)purine. The yield was 83.4%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[N+:31]([O-])=O)[CH2:12][CH2:13][NH:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[C:21]([Br:23])[C:20]([O:24][CH3:25])=[C:19]([Br:26])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C.Cl>[NH2:31][C:30]1[CH:29]=[CH:28][C:11]([CH2:12][CH2:13][NH:14][C:15](=[O:27])[CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[C:20]([O:24][CH3:25])=[C:19]([Br:26])[CH:18]=2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br

Procedure:
A solution of N-(3-Benzyloxy-4-nitrophenethyl)-3,5-dibromo-4-methoxy-phenylacetamide (3.49 g, 0.006 mol) and tin (II) chloride dihydrate (16.10 g, 0.071 mol) in a mixture of ethanol (300 mL) and 1.2 N HCl (150 mL) was refluxed for 3h, cooled and concentrated. Tin salts were dissolved in 1N NaOH solution. The reaction mixture was extracted with methylene chloride 3 times. The extracts were dried over Na2SO4 and concentrated. A residue was crystallized from ethyl acetate-hexanes mixture. Yield 1.57 g (47.4%).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:14][C:15]=2[I:17])[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[Mg]Br>>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[CH:14][C:15]=2[I:17])[C:9]([OH:10])([C:26]2[CH:25]=[CH:24][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[C:7]1=[O:8])[CH3:23]
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(C(F)(F)F)ccc(I)c21
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(C(F)(F)F)ccc(I)c21
Yield: 53 %

Procedure:
The title compound (103 mg, 53%) was prepared from 1-(2-diethylaminoethyl)-7-iodo-4-trifluoromethylisatin (152 mg, 0.345 mmol) and 2-naphthylmagnesium bromide by the procedure similar to that described in Example 1.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][C@@H:19]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[O:21]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
To a solution material from Example 97 (4.7 g, 9.10 mmol) in anhydrous DMF (30 mL) is added piperidine (15 mL, 152 mmol). The resulting solution is stirred at room temp for 45 rain and the solvent is removed in vacuo. The resulting residue was redissolved in 1,4-dioxane (50 mL), the solvent was removed in vacuo again and the resulting solid was dried under high vacuum for 18 h to give the title compound as a white solid in quantitative yield that contains 1 equivalent of 1-((9H-fluoren-9-yl)methyl)piperidine as a side product. LC/MS (Condition A): ret. T=2.30 rain, (M+H)+ 295.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[Na+].[F:9][C@H:10]1[CH2:29][C@@:28]2([CH3:30])[C@@H:21]([CH2:22][CH2:23][C@:24]2([OH:31])[C:25](=[O:27])[CH3:26])[C@H:20]2[C@H:11]1[C@:12]1([CH3:33])[C:17]([CH:18]=[CH:19]2)=[CH:16][C:15](=[O:32])[CH:14]=[CH:13]1>CS(C)=O>[F:9][C@H:10]1[CH2:29][C@@:28]2([CH3:30])[C@@H:21]([CH2:22][CH2:23][C@:24]2([OH:31])[C:25](=[O:27])[CH3:26])[C@H:20]2[C@H:11]1[C@:12]1([CH3:33])[C:17]([CH:18]=[CH:19]2)=[CH:16][C:15](=[O:32])[C@@H:14]2[CH2:2][C@H:13]12
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Reaction time: 4.5 h

Procedure:
One gram of trimethylsulfoxonium iodide in 30 ml. of dimethyl sulfoxide is agitated under nitrogen for 30 minutes with 200 mg. of pulverized sodium hydroxide. Then, 1.6 g. of 11β-fluoro-17-hydroxy-1,4,6-pregnatriene-3,20-dione is added to the reaction mixture. After 4.5 hours, the reaction mixture is stirred into acetic ice/water. The precipitate is vacuum-filtered, taken up in methylene chloride, and dried over sodium sulfate. After chromatographing the crude product on silica gel with acetone/hexane, 1.4 g. of 11β-fluoro-17-hydroxy-1α,2α -methylene-4,6-pregnadiene-3,20-dione is obtained. UV: ε282 = 16,900.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][CH2:8]1.O.NN>C(O)C>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:11][CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2ccccc2-c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN1CCN(c2ccccc2-c2ccccc2)CC1

Procedure:
Batch size: 20.8 g (47.3 mol) 2-[4-(4-biphenyl-2-yl-piper-azin-1-yl)-butyl]-isoindolin-1,3-dione and 4.6 ml (94.6 mmol) hydrazine-hydrate in 185 ml ethanol.