Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH3:27])[C:4](=[O:28])[CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH3:27])[C:4](=[O:28])[CH:3]=[C:2]3[NH:1][C:29](=[O:31])[CH3:30])=[CH:17][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)cc(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 85 °C

Procedure:
The product of Example 4 (18 mg) was combined with pyridine (2 mL), acetic anhydride (0.2 mL), and DMAP (5 mg). The reaction was heated to 85° C. for 1 hr at which point LC/MS indicated significant imide formation. The reaction was concentrated and redissolved in 1,4-dioxane before adding aqueous 1 M NaOH (1 mL). After 15 hours at room temperature the reaction was diluted with EtOAc and washed with brine before drying (Na2SO4). The concentrated residue was purified by preparative TLC (silica gel) eluted with EtOAc affording the title compound. HPLC/MS: 471.9 (M+1), 473.9 (M+3); Rt=3.79 inn.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:23])[C:9]3[CH2:14][CH:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[CH3:15][CH:13]1[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]2[C:5]3[C:6]([N:8]([CH3:23])[C:9]=2[CH2:14]1)=[N:7][C:2]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][C:28]2[CH:38]=[CH:39][C:25]([F:24])=[CH:26][CH:27]=2)[CH2:32][C:33]1=[O:37])=[CH:3][CH:4]=3
Reactant: CC1Cc2c(c3ccc(Br)nc3n2C)CN1C(=O)OC(C)(C)C
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Product: CC1Cc2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)nc3n2C)CN1C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
tert-Butyl 2-bromo-7,9-dimethyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (2-((4 mg, 0.640 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (141 mg, 0.640 mmol) were reacted following the procedure for Example 2 (step e) to provide the title compound (245 mg, 73%) as a colorless oil: ESI MS m/z 522 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH2:10][CH2:9]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(CCBr)cc1
Reactant: COc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(CCN2CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
A mixture of 250 ml. butan-2-one, 15.47 g. (75 mmole) 1-(4-methoxybenzyl)-piperazine, 19.3 g. (75 mmole) ethyl 4-(2-bromoethyl)-benzoate and 20.7 g. (0.15 mole) powdered potassium carbonate is maintained at reflux temperature for 60 hours, then suction filtered while hot and the filtrate evaporated in a vacuum. After the addition of diethyl ether, the product crystallises, the yield being 17.5 g. (61% of theory) of the desired product; m.p. 75°-76° C. The hydrochloride is precipitated from the filtrate by means of hydrogen chloride-containing diethyl ether. After recrystallisation from aqueous ethanol, there are obtained 7.6 g. (23% of theory) of the desired product; m.p. 280°-281° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]2.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[C:23]([Cl:25])[CH:24]=1>N1C=CC=CC=1.ClCCl>[Cl:25][C:23]1[CH:22]=[C:21]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]3)(=[O:27])=[O:28])[CH:20]=[C:19]([Cl:18])[CH:24]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6 g tert-butyl 5-amino-2,3-dihydro-indole-1-carboxylate are dissolved in 50 ml of pyridine and 50 ml dichloromethane. To this is added dropwise a solution of 6.5 g 3,5-dichlorophenylsulphonyl chloride in 50 ml dichloromethane and the mixture is stirred for 1 hour at ambient temperature. Then it is diluted with dichloromethane and washed with 1 N hydrochloric acid and with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 30:70).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Cl)=[CH:10][N:9]=1.[CH2:16]([O:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[C:23]([NH2:30])[N:22]=1)[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:16]([O:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[CH2:14][C:11]2[CH:10]=[N:9][C:8]([Cl:7])=[CH:13][CH:12]=2)=[C:23]([NH2:30])[N:22]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOc1nc(N)c2[nH]cnc2n1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2ncn(Cc3ccc(Cl)nc3)c2n1
Temperature: 80 °C

Procedure:
Potassium carbonate (2.85 g, 20.6 mmol) and 2-chloro-5-chloromethylpyridine (3.33 g, 20.6 mmol) were added to the DMF solution (125 ml) of 2-butoxyadenine (2.60 g, 12.5 mmol) obtained in Reference Example 1. The resultant was stirred while heating at 80° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, water (100 ml) was added thereto, and the resultant was neutralized with 1N hydrochloric acid. The precipitated solid was collected by filtration. The resulting solid was dissolved in methylene chloride (100 ml), hexane (150 ml) was added under ice cooling, and the precipitated crystal was collected by filtration. Thus, 2-butoxy-9-(6-chloro-3-pyridylmethyl)adenine was obtained (yield: 3.12 g). Bromine (1.92 ml, 37.5 mmol) was added to an acetic acid suspension (186 ml) comprising sodium acetate (3.05 g, 37.2 mmol) and 2-butoxy-9-(6-chloro-3-pyridylmethyl)adenine (3.1 g, 9.31 mmol) at room temperature, and the resultant was allowed to react for 4 hours. The reaction solution was removed by distillation under reduced pressure, water (200 ml) was added to the residue, and the resultant was neutralized with 5N sodium hydroxide under ice cooling. The precipitated crystal was collected by filtration, and crude crystal was recrystalized with the aid of methanol. The resultant was dried under reduced pressure at 40° C. for 15 hours. Thus, 2.38 g of the title compound was obtained as a white powdery crystal (yield: 62%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18](=O)[C:17]3[C:16]([C:27]([O:29]C)=O)=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11]2)=[CH:6][CH:5]=1.O.[NH2:34][NH2:35]>>[CH3:1][O:2][CH:3]([O:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[NH:11][C:12]3[C:17]4[C:18](=[N:34][NH:35][C:27](=[O:29])[C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccc(C(OC)OC)cc1)N2
Solvent: O
Product: COC(OC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To methyl 2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg, 0.28 mmol) was added hydrazine monohydrate (20 mL) and the mixture was stirred under 40° C. for 3 h. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, 89 mg of solid of 8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one was obtained (yield: 78%). LC-MS (ESI) m/z: 414 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:19][O:20][C:21]1[CH:61]=[CH:60][C:24]([CH2:25][N:26]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[C:27]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]3[C:35]([NH:42][C:43]4[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=4)=[N:36][CH:37]=[C:38]([CH:41]=3)[CH:39]=[O:40])[N:28]=2)=[CH:23][CH:22]=1>C1COCC1>[CH3:59][O:58][C:55]1[CH:54]=[CH:53][C:52]([CH2:51][N:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:61][CH:60]=2)[C:27]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]3[CH:41]=[C:38]([CH:39]([OH:40])[C:6]4[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=4[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:37]=[N:36][C:35]=3[NH:42][C:43]3[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=3)[N:28]=2)=[CH:57][CH:56]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4cc(Br)ccc4S(=O)(=O)N(C)C)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
A solution of 4-bromo-N,N-dimethylbenzenesulfonamide (Aldrich; 152 mg, 0.575 mmol) in THF (1.0 mL) was cooled to −78° C. and treated dropwise with n-butyllithium (1.60 M solution in hexanes) (359 μL, 0.575 mmol). The resulting pale solution was allowed to slowly warm to 0° C. over 30 min to give a dark brown solution which was then added dropwise to a suspension of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (110.7 mg, 0.192 mmol) in THF (2.0 mL) cooled to −78° C. The mixture was stirred for 2 h, slowly allowing to warm to 0° C., and the resulting yellow suspension was quenched (water) and extracted into DCM from saturated aqueous NaHCO3. The extracts were dried (MgSO4), concentrated and purified by flash chromatography (0 to 10 to 20 to 30 to 40% EtOAc in DCM) to give recovered 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (54.6 mg, 49%, eluting off with 20% EtOAc/DCM) followed by 2-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-4-bromo-N,N-dimethylbenzenesulfonamide (30.0 mg, 0.036 mmol, 18.60% yield) (eluting off with 30% EtOAc/DCM) followed by 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-N,N-dimethylbenzenesulfonamide (38.3 mg, 0.050 mmol, 26.2% yield) (eluting off with 40% EtOAc/DCM).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[CH:11]=1.[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([N:16]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:4])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]1=[O:13])[CH3:15]
Reactant: Cc1cc2c(oc1=O)CCCC2=O
Reactant: CCN
Product: CCn1c2c(cc(C)c1=O)C(=O)CCC2

Procedure:
Prepared analogously to Example 5(b) from 3-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.[O:14]1[CH2:16][CH:15]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:16][CH:15]([OH:14])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26](=[O:28])[CH3:27])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(NC2CCNC2)cc1
Reactant: CC(=O)Nc1ccccc1OCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)Nc1ccccc1OCC(O)CN1CCC(Nc2ccc(Cl)cc2)C1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 39.6 %

Procedure:
A mixture of N-(4-chlorophenyl)-3-pyrrolidinamine (2xCF3COOH), (186 mg, 0.438 mmol), N-[2-(2-oxiranylmethoxy)phenyl]acetamide (91 mg, 0.438 mmol) and K2CO3 (200 mg) in ethanol (6 mL) was kept on stirring at 65° C. for 2.5 h. The volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and aq. NH4Cl solution. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0-3% MeOH in CHCl3) to give the titled product (70 mg).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].N1C=CN=C1.Cl>CN(C=O)C>[O:4]([CH2:3][CH2:2][CH2:1][OH:5])[Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,3-propanediol (10 mmol), tert-butyldimethylchlorosilane (11 mmol), and imidazole (22 mmol) dissolved in 5 mL of DMF was stirred at room temperature for 16 hours. The mixture was poured into 0.1 M HCl (100 mL) and extracted with ether (3×100 mL). The organic phases were washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The mixture was purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([O:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])[C:12]([CH2:28][C:29]2[CH:42]=[CH:41][C:32]([CH2:33][NH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][C:30]=2[O:43][CH3:44])=[C:11]([CH3:45])[N:10]=1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:9]1[N:14]=[C:13]([O:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])[C:12]([CH2:28][C:29]2[CH:42]=[CH:41][C:32]([CH2:33][N:34]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:1](=[O:3])[CH3:2])=[CH:31][C:30]=2[O:43][CH3:44])=[C:11]([CH3:45])[N:10]=1
Reactant: CCOC(=O)CNCc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (6 μL) was added to a solution of the product from step (i) (23 mg) and triethyl amine (9 μL) in THF (1 mL), and the mixture was stirred at RT for 3 h. The mixture was quenched with water, extracted with EtOAc, combined organic layer was washed with brine, dried and concentrated under reduced pressure. The sub-title compound (25 mg) was obtained as a colourless gum, which was used for next reaction without further purification; LC-MS: m/z=585.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[S:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]([C:26]3[O:27][C:28]4[C:33]([C:34](=[O:43])[C:35]=3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:25])[N:15]=2)=[CH:12][CH:13]=1)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([C:26]3[O:27][C:28]4[C:33]([C:34](=[O:43])[C:35]=3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:25])[N:15]=[C:14]([C:11]3[S:10][C:9]([CH2:8][NH2:7])=[CH:13][CH:12]=3)[C:22]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(CNC(=O)OC(C)(C)C)s2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(CN)s2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of Example 102 (0.070 g, 0.114 mmoles) in dichloromethane (3 ml), TFA (0.1 ml) was added under nitrogen atmosphere stirred at room temperature. After 3 h, the reaction mixture was concentrated, neutralised with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as yellow solid (0.030 g, 51% yield). MP: 275-278° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.06(s,1H), 8.05(dd, J=7.9,1.5 Hz, 1H), 7.85(m,1H), 7.66(d, J=8.3 Hz, 1H), 7.53(t, J=7.2 Hz, 1H), 7.28(m, 2H), 7.09(d, J=3.5 Hz, 1H), 7.05(dt, J=8.7,2.4 Hz, 1H), 6.92(br s,2H), 6.02(q, J=7.1 Hz, 1H),4.03(s,2H), 1.87(d, J=7.1 Hz, 3H). Mass: 513.27(M++1).
Reaction SMILES: [OH:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.ClCCl>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:12]=[CH:11][C:10]([C:2]([OH:1])([CH3:9])[CH2:3][CH2:4][OH:5])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)(CCO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.00 g (25.34 mmol) of the compound from Example 88A, dissolved in 150 ml of tetrahydrofuran, were added dropwise to 76.0 ml (76.0 mmol) of a 1N solution of diisobutylaluminum hydride in dichloromethane in 250 ml of tetrahydrofuran, and the reaction mixture was stirred at room temperature for 3 h. After addition of 1N hydrochloric acid, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated aqueous sodium chloride solution. Drying over sodium sulfate and filtration was followed by removal of the solvents in a rotary evaporator. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol gradient) to result in 5.55 g (91% purity, 85% of theory) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.O1CCCC1.[Pd]>[C:1]([NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nccc(C=Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1nccc(CCc2ccc(N)cc2)n1
Yield: 91.1 %

Procedure:
A mixture of 2-acetamido-4-[2-(4-nitrophenyl)vinyl]pyrimidine (8.52 g) in ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (2 g) under atmospheric pressure of hydrogen gas for 6 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-acetamido-4-[2-(4-aminophenyl)ethyl]pyrimidine (7.0 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][CH2:11][OH:12].[H-].[Na+].C(OCC)C>C1COCC1>[CH2:10]1[CH2:11][O:12][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=2[O:9]1
Reactant: Cc1nccc(Cl)c1OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nccc2c1OCCO2
Yield: 58.9 %

Procedure:
A mixture of 4-chloro-3-hydroxyethoxy-2-methylpyridine (1.03g, 0.0055 mol) and NaH (55% in oil, 599 mg, 0.0138 mol) in 600 ml THF was refluxed for 15 h. Excess NaH was destroyed with 3 ml of H2O. The solvent was evaporated and the residue partitioned between 100 ml 1M HCl and 100 ml CH2Cl2. The aqueous layer was collected, washed once more with 100 ml CH2Cl2 and then treated with Na2CO3 until the pH was ≈10. The aqueous layer was extracted with 150+100 ml CH2Cl2. The two latter organic layers were combined, dried over MgSO4, and evaporated leaving 720 mg enriched product. Chromatography (silica gel, diethyl ether) furnished 0.49 g (59%) pure product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]3[CH:16]=[C:15]4[C@:17]5([CH2:30][C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[CH2:29][CH2:28][C:23]6(OCC[O:24]6)[CH2:22][C@H:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:30][C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nnn3cc4c(cc23)CCC[C@@H]2CC3(CC[C@@]42Cc2ccccn2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1CCC2(Cc3ccccn3)c3cn4nnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
rac-(4aR,13bS)-9-(4-Fluorophenyl)-13 b-(pyridin-2-ylmethyl)-1,2,4,4a,5,6,7,13 b-octahydrospiro[benzo[3,4]cyclohepta[1,2-d][1,2,3]triazolo[1,5-a]pyridine-3,2′-[1,3]dioxolane] (156, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.230 g, 0.475 mmol) in acetone (3 mL) was treated with 6 N hydrochloric acid (0.060 mL, 0.322 mmol) then stirred at rt for about 3 h. Sat. aq. NaHCO3 (˜5 mL) and EtOAc (15 mL) were added to the mixture then the layers were separated. The organic layer was washed with brine (˜5 mL) then dried over MgSO4, filtered and concentrated in vacuo to yield rac (4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-4,4a,5,6,7,13b-hexahydro-1H-benzo[3,4]cyclohepta[1,2-d][1,2,3]triazolo[1,5-a]pyridin-3(2H)-one (157, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.142 g, 68%); LC/MS, method 3, Rt=2.30 min, MS m/z 441 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.36-8.27 (m, 1H), 8.12 (s, 1H), 8.11-8.03 (m, 2H), 7.48-7.30 (m, 3H), 7.08-6.98 (m, 1H), 6.64 (d, J=7.8 Hz, 1H), 3.85-3.73 (m, 1H), 3.55-3.42 (m, 2H), 2.75-2.64 (m, 1H), 2.42-2.23 (m, 3H), 2.20-2.02 (m, 5H), 1.79-1.68 (m, 1H), 1.49-1.36 (m, 1H), 1.29-1.21 (m, 1H).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][N:4]2[C:13]=1[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]1[CH:14]=[N:15][C:16]([C:17]([NH2:19])=O)=[C:5]21.P(Cl)(Cl)(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[C:17]([C:16]1[N:15]=[CH:14][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3=[N:1][CH2:2][CH2:3][N:4]3[C:5]=12)#[N:19]
Reactant: NC(=O)c1ncn2c1N1CCN=C1c1ccccc1-2
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncn2c1N1CCN=C1c1ccccc1-2
Temperature: 0 °C

Procedure:
A mixture of 2,3-dihydrodiimidazo[1,5-a:1',2'-c]quinazoline-5-carboxamide (1 g, 4 mmol) (prepared by standard methods from the corresponding carboxylic acid ethyl ester, Compound 3) and phosphorus pentachloride (0.9 g, 4.1 mmol) in phosphorus oxychloride (10 ml) was stirred at reflux for 3 h, and then evaporated to dryness. The residue was partitioned between 25 ml of water and 25 ml of dichloromethane. The organic layer was extracted with 4×25 ml of 10% acetic acid. The combined aqueous phases were adjusted to pH around 11 and cooled to 0° C. The precipitate which had formed was filtered off and dried, giving the title compound as yellow crystals, m.p. 227°-240° C. (decomposition). Yield 0.53 g (57%). (Compound 49).