Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].CS[C:24]1[NH:25][CH:26]=[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[N:34][CH:33]=2)[C:28](=[O:30])[N:29]=1>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:24]3[NH:25][CH:26]=[C:27]([CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[N:34][CH:33]=4)[C:28](=[O:30])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2ccnnc2)c[nH]1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1ccnnc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.317 mmol, 1.00 eq) and 2-methylsulfanyl-5-pyridazin-4-ylmethyl-1H-pyrimidin-4-one (0.341 mmol, 1.01 eq) were dissolved in dry ethanol (300 μL) and stirred at 150° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-7% in 15 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]ethylamino}-5-pyridazin-4-ylmethyl-1H-pyrimidin-4-one (0.135 mmol, yield: 43%, UPLC-MS/UV:[M+H]+=502.30; rt: 1.07 mins; purity: 95%). 1H NMR (300 MHz; CDCl3) δ/ppm 1.42 (s, 1H), 2.89 (t, J=7.33, 2H), 3.55-3.60 (m, 2H), 3.62 (s, 2H), 6.99 (dd, J=8.40, J=10.08, 2H), 7.01 (dd, J=9.07 J=3.02, 1H), 7.16-7.28 (m, 3H), 7.35-7.42 (m, 2H), 7.62-7.70 (m, 1H), 8.94 (dd, J=5.42, J=0.95, 1H), 9.09-9.12 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: BrCCCCBr
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)NC(=O)c2cc(OCCCCBr)ccc2O1
Reaction time: 5 h

Procedure:
A suspension of 96.5 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one and 76 g of potassium carbonate in 300 ml of 1,4-dibromobutane is stirred for 5 hours in a bath at 120°-130°. The reaction mixture is filtered, and the excess 1,4-dibromobutane is distilled off at about 1 Torr. The crystalline residue is triturated with ether, and filtered off under suction. There is thus obtained crude 2,3-dihydro-2,2-dimethyl-6-(4-bromobutoxy)-4H-1,3-benzoxazin-4-one, m.p. 139°-142°, which is sufficiently pure for the further reaction.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:11]([CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:15]1)#[N:12].[OH-].[Na+]>C(OCC)C.O1CCCC1.O>[NH2:12][CH2:11][CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:15]1
Reactant: N#CCC1CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: NCCC1CCc2ccccc2O1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
First, at room temperature and while stirring, 2.2 g (16.5 mmol) of aluminium chloride in 70 ml of absolute diethyl ether are added dropwise to a suspension of 3.8 g (100 mmol) of lithium aluminium hydride in 150 ml of absolute diethyl ether. Then 8.66 g (50 mmol) of 2-cyanomethylchroman in 70 ml of absolute tetrahydrofuran are added dropwise within a period of 20 minutes. The reaction mixture is stirred for a further 16 hours at room temperature and then carefully decomposed with 3.8 ml of water, 3.8 ml of sodium hydroxide solution (15% strength) and 11.4 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The ethereal phase is washed with water, dried over sodium sulphate and concentrated by evaporation. 8.75 g (98.8%) of 2-(2-aminoethyl)chroman are obtained in the form of a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]#[N:27])[CH:20]=2)[CH:5]=[CH:6][C:7]=1F.BrC1C=C(C(OCC)=O)OC=1C1C=CC=C([C:40]#[N:41])C=1>>[C:26]([C:21]1[CH:20]=[C:19]([C:10]2[CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:13][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:40]#[N:41])[CH:3]=2)[CH:24]=[C:23]([F:25])[CH:22]=1)#[N:27]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2ccc(F)c(Cl)c2)o1
Reactant: CCOC(=O)c1cc(Br)c(-c2cccc(C#N)c2)o1
Product: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2cccc(C#N)c2)o1

Procedure:
The synthesis of the title compound takes place in analogy to the synthesis of the compound from Example 15A starting with the compound from Example 8A. 190 mg (56% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([C:14]([OH:16])=O)=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)([N:19]1C=CN=C1)=O.ClC1C(Cl)=CC=CC=1N1CCN(CCCCN)CC1>O1CCCC1>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([C:14]([NH2:19])=[O:16])=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2[nH]c3c(c2c1)CCCC3
Agent: NCCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Solvent: C1CCOC1
Product: NC(=O)c1ccc2[nH]c3c(c2c1)CCCC3
Reaction time: 8 h
Yield: 163.4 %

Procedure:
A mixture of 1,2,3,4-tetrahyrocarbazole-6-carboxylic acid (100 mg, 0.46 mmol) and 1,1′-carbonyldiimidazole (78 mg, 0.48 mmol) in 5 mL of anhydrous tetrahydrofliran was stirred for 8 hours. A solution of 4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-1-aminobutane (140 mg, 0.46 mmol) in 1 mL of tetrahydrofuran was added and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with aqueous Na2CO3 solution, dried (Na2SO4) and concentrated in vacuo to afford the free base of the title compound, N-(1-{4-[4-2,3-dichlorophenyl)piperazin-1-yl]}butyl)-1,2,3,4-tetrahydrocarbazole-6carboxamide, (161 mg, 70%). The hydrochloride salt was prepared by treating the free base with a solution of hydrogen chloride in ethyl acetate (mp 236-238° C.).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][C:32]=1[O:33]CC1C=CC=CC=1)[CH2:12][N:13]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][C:16]=2[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:14]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:15]2[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[N:13]([CH2:12][C:11]3[CH:10]=[C:9]([OH:8])[C:32]([OH:33])=[CH:31][CH:30]=3)[N:14]=2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(-c2nn(Cc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c3c2CCNCC3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of 1-(3,4-bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-carboxylic acid tert-butyl ester (Example 154, 0.1 mmol) in CH2Cl2 (5 mL) was cooled to 0° C., and 1 M BBr3 in CH2Cl2 (0.5 mL) was added. The mixture was allowed to warm to RT and was stirred at RT for 1 h. The precipitate that had formed was collected by filtration, washed with water, and dried under vacuum to provide the title compound (25 mg). MS (ESI): exact mass calculated for C20H20ClN3O2, 369.12; found, m/z 370.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.42 (m, 4H), 7.39-7.37 (m, 2H), 6.63 (d, J=8.1 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 6.45 (dd, J=8.1, 2.1 Hz, 1H), 5.18 (s, 2H), 3.29-3.25 (m, 4H), 3.06-3.04 (m, 2H), 2.97-2.95 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:11][N:12](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:13][CH2:14][N:15](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:16][CH2:17][N:18](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:19][C:20]([N:23]=2)=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].C(O)(=O)CS>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]2[CH2:11][NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]([N:23]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2ccc(OCc3ccccc3)c(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3nc2CNCCNCCNC3)cc1
Reaction time: 8 h

Procedure:
24.2 g (0.0279 mol) of 12-benzyloxy-3,6,9-tris(2-nitrobenzenesulphonyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(14),11(15),12-triene are dissolved in 200 ml of DMF and then 22 g of LiOH and 21 ml of thioglycolic acid are introduced. The combined mixture is left at AT overnight. After evaporating the DMF, the residual oil is taken up in dichloromethane and the organic solution is then washed with water, dried and concentrated. A brown oil is obtained. w=15 g.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1)[CH:25]=[CH2:24]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.15 g, 0.37 mmol) in 5 ml of anhydrous DMF was added allyl tributyltin (0.26 ml, 0.86 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.007 g, 0.0056 mmol) was then added and the reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (100-200 M) using ethyl acetate/Hexane (60:40) as the eluent to provide the title compound (0.10 g, 75%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([OH:12])=O)=[CH:8][C:7]([CH3:13])=[N:6]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[F:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([F:48])=[C:26]([NH:25][C:10]([C:9]5[N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=[C:7]([CH3:13])[CH:8]=5)=[O:12])[CH:27]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: COCCn1nc(C)cc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 75.2 %

Procedure:
In the same manner as in Example 259 and using 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylic acid (150 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (230 mg, 77%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 80 °C
Yield: 96.3 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-2-[3-(phenylmethoxy)phenyl]acetamide (4.5 g, 0.012 mol) in THF (20 ml) on ice was added the borane-tetrahydrofuran complex (15 ml, 0.023 mol). The reaction was allowed to reflux at 80° C. for six hours. The reduction reaction was placed on ice, acidified using 4 N HCl, then stirred for twenty minutes. The reaction was then basified with an aqueous solution of potassium hydroxide. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (4.3 g, 99% yield): ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1)#[N:2].[CH3:10]N(C=O)C.C([O-])([O-])=O.[K+].[K+].CI>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(O)cn1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
2-Cyano-5-hydroxy pyridine (200 mg, 1.66 mmol), DMF (10 mL) and K2CO3 (253 mg, 1.83 mmol), and MeI (354 mg, 2.49 mmol) were combined at rt and the reaction mixture was stirred for 24 h at rt. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water, dried and concentrated to give 2-cyano-5-methoxy pyridine (175 mg, 78%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:13][OH:14])[CH2:8]2
Reactant: NO
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1C2CC3CC(C2)CC1C3
Yield: 90.9 %

Procedure:
To 30 g of 2-adamantanone (Aldrich Chem. Co.) in 100 mL of methanol was added 50 g of hydroxylamine hydrochloride and 92 g of sodium acetate trihydrate and the mixture was refluxed for 2 hours. The mixture was concentrated in vacuo, the residue was distributed between 250 of dichloromethane and 50 mL of water. The organic layer was separated, dried with magnesium sulfate and concentrated in vacuo to give 30 g of crude 2-adamantanone oxime. This was dissolved in 100 mL of chloroform and 135 g of PPE (polyphosphate ester, prepared by refluxing phosphorus pentoxide with diethyl ether in chloroform, as described by G. Schramm, H. Groetsch, and W. Pollmann, Angew. Chem., Internat. Ed., 1,1 (1962)) was added carefully. When the exothermic reaction ceased, the mixture was refluxed for 5 minutes. Then it was cool in ice, diluted with 500 mL of water and stirred overnight. The organic layer was separated, dried with magnesium sulfate and concentrated in vacuo to give 16.6 g of the crude lactam product. This was dissolved in 250 of chloroform and 11 mL of phosphorus oxychloride was added dropwise in 30 minutes. To this was then added a solution of 15 g of 4,6-dichloroanthranilic acid and 4 of triethylamine in 150 mL of chloroform in 25 minute at room temperature. Then the mixture was refluxed for 16 hours. Column chromatography using 50:1 to 25:1 chloroform:methanol on silica gel provided 16 g of 1,3-dichloro-7,8,9,10,11,12-hexahydro-6,10:8,12-dimethanoazonino[2,1-b]quinazolin-14(6H)-one as white coarse crystals. This was then reduced with zinc and hydrochloric acid to the 1,3-dichloro-6,7,8,9,10,11,12,14-octahydro-6,10:8,12-dimethanoazonino[2,1-b]quinazoline by the same procedure as described in Example 2 to give after treatment with 1 equivalent of HCl and recrystallization from absolute alcohol/ethyl acetate 1,3-dichloro-6,7,8,9,10,11,12,14-octahydro-6,10:8,12-dimethanoazonino[2,1-b]quinazoline monohydrochloride as white crystalline solid, with m.p. 310° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C

Procedure:
30 g (70.7 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate in 500 ml of dioxane are introduced into a three-necked flask. The reaction medium is degassed, 30 g of palladium on carbon (10%) are added and the mixture is hydrogenated at a pressure of 3 bar at 60° C. The reaction medium is filtered, evaporated off and the residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and methanol (99-1) mixture. 18 g (60%) of the expected product are recovered after evaporation of the solvents.
Reaction SMILES: [Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[Cl:12].[I:13]N1C(=O)CCC1=O>CC#N>[Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][C:9]([I:13])=[C:4]2[C:3]=1[Cl:12]
Reactant: Nc1nccc2c(Cl)c(Cl)oc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Nc1ncc(I)c2c(Cl)c(Cl)oc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A solution of 2,3-dichlorofuro[2,3-c]pyridin-7-amine (5.7 g, 28.2 mmol) in MeCN (200 mL) was treated with N-iodosuccinimide (9.57 g, 42.3 mmol), added portionwise over 5-10 min. The mixture was heated at 60° C. for 16 h. After cooling to RT, the reaction was quenched with 20% aqueous sodium thiosulfate and stirred for 10 min. EtOAc (200 mL) was added and the phases separated. The organic phase was washed with 20% aqueous sodium thiosulfate (50 mL), then water (2×100 mL) and finally with brine. After drying over Na2SO4, the organic extracts were filtered and concentrated in vacuo. The material was purified using flash chromatography eluting with 2% MeOH in DCM to afford 3.8 g (41%) of the title compound. 1H NMR (300 MHz, DMSO-d6): δ 6.75 (br. s, 2H); 8.02 (s, 1H).
Reaction SMILES: C([C:4]1[C:5]([CH3:13])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)(=O)C.[ClH:14].[N:15]([O-])=O.[Na+]>O>[ClH:14].[NH2:15][C:4]1[C:5]([CH3:13])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: CC(=O)c1c(C)nn2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1nn2ccccc2c1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7 g. 3-Acetyl-2-methylpyrazolo[1,5-a]pyridine (see J. Org. Chem., 42, 443/1977) are dissolved in 140 ml. 6N hydrochloric acid and mixed dropwise at 0° C. with a solution of 5.52 g. sodium nitrite in water. After 2 hours, the ice-bath used for the cooling is removed and the reaction mixture is left to stand overnight at ambient temperature and then adjusted to pH 9. The precipitated nitroso compound (6.4 g.) is filtered off with suction and dissolved in about 150 ml. 2N hydrochloric acid. The nitroso compound is reduced with zinc dust analogously to Example 1.2. The crude product is chromatographed on silica gel with ethyl acetate. The product-containing fractions are evaporated, the residue is dissolved in ethanol and the solution is mixed with ethanolic hydrogen chloride. The precipitate which is obtained after some time is filtered off with suction and dried. There are obtained 3.1 g. (45% of theory) of the title compound; m.p. >275° C.; TLC (silica gel, ethyl acetate/acetone/glacial acetic acid/water 50:25:12.5:12.5 v/v/v/v): Rf =0.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH3:11])[CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:25][C:24]=3[CH2:23]2)=[O:21])=[CH:4][CH:3]=1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(Cl)cc1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CNC[C@@H](CC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution 322 (28 mg, 0.056 mmol) in MeOH (2 mL) was added 4M HCl in dioxane (0.6 mL, 2.4 mmol) and the reaction stirred at RT 4 h. The reaction was diluted with DCM (25 mL) and satd. aq. NaHCO3 (25 mL), the phases separated and the aqueous phase extracted with 10% MeOH/DCM (25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified on a preparative SiO2 TLC plate (0.5 mm) developed with MeOH/DCM/NH4OH (9/90/1) to afford 6 mg (25%) of I-113 as a pale yellow residue: 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 0.6H), 8.02 (s, 0.4H), 7.15-7.30 (m, 4H), 4.80 (m, 1H), 4.52 (s, 1H), 4.34 (m, 1H), 4.09 (m, 1H), 3.74 (m, 1H), 3.59 (m, 1H), 3.47 (m, 1H), 2.79-2.92 (m, 3H), 2.51-2.73 (m, 3H), 2.42 (s, 1.2H), 2.39 (s, 2.8H), 1.87 (br s, 2H), 1.22 (m, 6H); LRMS (M+H) (APCI pos) m/e=402.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]([NH2:13])=O>O>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:8](=[O:10])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1cccnc1C(=O)O
Solvent: O
Product: O=c1[nH]cnc2cccnc12

Procedure:
A mixture of 6.5 g of 3-amino-pyridine-2-carboxylic acid in 9 g of formamide was heated in an oil bath while stirring. The temperature was increased from 130° C. to 180° C. over a two hour period, then the mixture was allowed to cool. The mixture was then diluted with water. The solids were collected and washed with fresh water, then dried. Yield 4.6 g. M.P. 346°-347° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH:12]=[CH:11][N:10](C(=O)C(C)(C)C)[CH:9]=[C:8]1[CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])([CH3:4])([CH3:3])[CH3:2].[S]>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1C1=CN(C(=O)C(C)(C)C)C=CC1COC(C)(C)C
Agent: [S]
Solvent: Cc1ccccc1
Product: CN1CCCC1c1cnccc1COC(C)(C)C
Yield: 73.3 %

Procedure:
A solution of 1-[4-tert-butoxymethyl-3-(1-methylpyrrolidin-2-yl)-4H-pyridin-1-yl]-2,2-dimethyl-propan-1-one (0.194 g 0.5 mmol), sulfur (0.02 g, 0.5 mmol) and toluene (5 mL) was refluxed for 1 day. After filtration of the mixture through a pad of Celite and evaporation of the solvent under reduced pressure, the crude material was purified by radial PLC (hexanes) to afford 0.091 g (54%) of 4-tert-butoxymethyl-3-(1-methylpyrrolidin-2-yl)-pyridine as a yellow oil. IR (thin film, neat, NaCl) 2970, 2778, 1594, 1362, 1193, 1088 cm−1. 1H NMR (CDCl3, 400 MHz) δ 8.72 (s, 1 H), 8.45 (d, 1 H, J=6.4 Hz), 7.40 (d, 1 H, J=6.4 Hz), 4.52 (s, 2 H), 3.32-3.20 (m, 3 H), 2.32-2.22 (m, 2 H), 2.18 (s, 3 H), 1.96-1.66 (m, 4 H), 1.29 (s, 9 H); 13C NMR (CDCl3, 100 MHz) δ 148.3, 147.7, 146.2, 135.3, 121.4, 73.4, 65.2, 59.6, 56.5, 40.2, 33.7, 27.20, 22.4; HRMS Calcd for C15H24N2O: 249.1967 [M+H]30. Found: 249.1964 [M+H]+. [α]d2δ-108.2 (c 3.4, CH2Cl2).