Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][OH:19])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[N:8][C:7]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[N:15][C:6]1=2.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl.O>[CH3:46][C:36]1[CH:41]=[CH:40][C:39]([S:42]([O:19][CH2:18][C@H:2]([OH:1])[CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH:9]=[N:8][C:7]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[N:15][C:6]2=3)(=[O:44])=[O:43])=[CH:38][CH:37]=1
Reactant: COc1ccc2ncc(=O)n(CC[C@@H](O)CO)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(=O)n(CC[C@@H](O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.1 %

Procedure:
In dichloromethane (80 ml) was dissolved 4-[(3R)-3,4-dihydroxybutyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (4.38 g, 16.51 mmol) and triethylamine (2.76 ml, 19.81 mmol), dimethylamino pyridine (403 mg, 3.30 mmol) and p-toluene sulfonyl chloride (3.46 g, 18.16 mmol) were added thereto under cooling on ice and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added to the reaction solution, which was extracted with dichloromethane. After drying the extract over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 4.30 g (62%) of the title compound in the form of an orange oily product.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24](O)([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].FC(F)(F)C(O)=O>ClCCl>[N:28]([C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:15]2[C:13]3[N:14]=[C:9]([NH:8][C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=4)[N:10]=[CH:11][C:12]=3[N:17]=[N:16]2)=[CH:19][CH:20]=1)([CH3:26])[CH3:25])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)O)cc4)c3n2)cn1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)N=[N+]=[N-])cc4)c3n2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-{4-[5-(1-ethyl-1H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-propan-2-ol (237 mg, 0.65 mmol) and sodium azide (186 mg, 2.86 mmol) in dichloromethane (2.5 ml) is added dropwise under external cooling a solution of trifluoroacetic acid (822 μl, 10.7 mmol) in dichloromethane (2.5 ml). The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between dichloromethane and diluted aqueous ammonia. The organic phase is dried over sodium sulfate and evaporated to afford {3-[4-(1-azido-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-(1-ethyl-1H-pyrazol-4-yl)-amine as yellow-green powder; HPLC/MS 2.01 min (A), [M+H] 390.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH3:17]>>[CH2:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9](=[O:18])[CH2:6][C:2]#[N:1])[CH3:17]
Reactant: CCc1ccccc1C(=O)OC
Reactant: Nc1cc[nH]n1
Product: CCc1ccccc1C(=O)CC#N
Yield: 92 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 2-ethyl-benzoic acid methyl ester (2.9 g, 17.6 mmol, 1.0 eq). The crude product was extracted with DCM as a yellow oil and used in the following step without further purification (2.8 g, yield: 92%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][N:7]([CH3:11])[N:6]=1)=[O:4].C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][N:7]([CH3:11])[N:6]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1nn(C)cc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1nn(C)cc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 91.1 %

Procedure:
A solution of 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (160 mg, 1.03 mmol) in N,N-dimethylformamide (1.0 mL) at 25° C. was treated with triethylamine (0.35 mL, 2.6 mmol) and triphenylmethylchloride (316 mg, 1.13 mmol). Additional N,N-dimethylformamide (2.0 mL) was added to the reaction to aid stirring. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and then was washed with a IN aqueous hydrochloric acid solution (1×10 mL), a saturated aqueous sodium bicarbonate solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-methyl-4-(trityl-amino)-1H-pyrazole-3-carboxylic acid methyl ester (373 mg, 91.1%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) δ7.25 (m, 16H), 3.74 (s, 3H), 3.53 (s, 3H).
Reaction SMILES: OCC[N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[CH3:10].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14]>>[C:11]([O:17][CH2:18][CH2:19][C:7]1[CH:6]=[C:5]([CH3:10])[NH:4][C:8]=1[CH3:9])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14]
Reactant: Cc1ccc(C)n1CCO
Reactant: CCOC(=O)CC(C)=O
Product: CC(=O)CC(=O)OCCc1cc(C)[nH]c1C
Temperature: 145 °C
Yield: 60.5 %

Procedure:
A mixture of 28 g (0.20 mol) of 1-(2-hydroxyethyl)-2,5-dimethylpyrrole and 31.2 g (0.24 mol) of ethyl acetoacetate was heated at 145° C. for six hours. Residual ethanol was removed in vacuo and kugelrohr distillation of the residue gave 27 g (61%) of a pale green oil. NMR: (CDCl3) δ 2.1 (9H, s), 3.3 (2H, s), 4.0 (4H, m) 5.6 (2H, s).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:50]([NH:49][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[CH:47]=[CH:46][C:45]=1[F:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)Nc1nc(N)ccc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To 2 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.56 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.42 g of 2-amino-6-(t-butylamino)-5-fluoropyridine. The solution was concentrated under reduced pressure to obtain yellow solid residue. To this residue were added 0.6 g of anhydrous potassium carbonate and 1.5 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 20 minutes and allowed to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, supplemented with 2 ml of ethanol, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 0.48 g of the title compound as a pale yellow powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.[Ti:12](Cl)(Cl)(Cl)[Cl:13]>CCCCCCC>[Cl-:13].[Cl-:13].[Cl-:13].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][Ti+3:12])[CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: Oc1cccc2cccnc12
Solvent: CCCCCCC
Product: [Cl-]
Product: [Ti+3]Oc1cccc2cccnc12
Temperature: 32.5 °C
Reaction time: 0.5 h
Yield: 286.6 %

Procedure:
8-Quinolinol (1.45 g, 0.010 mol) is added to a three-neck flask with heptane (30 mL), and the mixture is stirred under nitrogen at 25 to 40° C. for 0.5 h. It becomes a pale yellow suspension. Titanium tetrachloride (10 mL of 1.0 M solution in heptane, 0.010 mol) is added dropwise to the suspension. After stirring at 25° C. for 2 h, solvents are removed under vacuum. The product is washed with heptane (30 mL), and the washings are decanted. The residue is dried under vacuum for 1 h, and is then recrystallized from a mixture of hydrocarbon solvents to give purple crystals of 8-quinolinoxytitanium trichloride (2.85 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+].CI.[CH3:29]COCC>CN(C=O)C.O>[CH3:29][N:10]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([CH3:1])[CH:3]=2)[CH:8]=[C:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOCC
Reactant: CCOC(=O)c1cc(COc2cccc(C)c2)c(C(=O)OCC)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cc(COc2cccc(C)c2)c(C(=O)OCC)n1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Diethyl 4-(3-methylphenoxy)methylpyrrole-2,5-dicarboxylate (107 g, 0.41 mol) is dissolved in dry DMF (200 ml) and added dropwise over 10 minutes to an ice-cooled suspension of hexanes-washed sodium hydride (0.41 mol) in dry DMF (400 ml). The resulting mixture was then stirred for one hour, then recooled in an ice bath and treated dropwise over 15 minutes with methyl iodide (30 ml, 0.49 mol). Stirring is continued for an additional thirty minutes, then the mixture is slowly poured into a separatory funnel containing ether (500 ml) and water (one liter). The ether layer was washed with water and saturated brine, then dried over sodium sulfate and the solvent removed in vacuo to give diethyl 1-methyl-4-(3-methylphenoxy)methylpyrrole-2,5-dicarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[F:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[F:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(F)c2[nH]1
Product: CCOC(=O)c1cc2ccc(Cl)c(F)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=399.4 (M+H+), was prepared in accordance with the general method of example 12b) from 6-chloro-7-fluoro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][C@@H:12]1[CH2:14][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][C@H:25]([CH2:28]CN)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CC#[N:33]>>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:33][CH2:14][C@H:12]([OH:13])[CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:15])[CH2:24]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC#N
Reactant: O=C(NC[C@@H]1CO1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CCN)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC[C@H](O)CNC(=O)OCc2ccccc2)C1
Yield: 63 %

Procedure:
The title compound was prepared in analogy to Example 17, step 17.1, starting from [(2R)-oxiranylmethyl]-carbamic acid benzyl ester (5.17 g; prepared according to WO 2004/002973) and (S)-3-aminoethylpyrrolidine-1-carboxylic acid tert-butyl ester (5.00 g; commercial) in MeCN (120 mL), affording a colourless oil (6.4 g; 63% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15].C(=O)([O-])O.[Na+]>P(=O)(O)(O)O>[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([OH:15])[C:8]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[N:7]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Product: COc1ccc2nc(C(F)(F)F)cc(O)c2c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 4.6 %

Procedure:
4-Methoxyaniline (5.00 g) was dissolved in 75% phosphoric acid (20 mL) and ethyl trifluoroacetoacetate (7.48 g) was dropwise added thereto at 110° C. The mixture was stirred at 110° C. for 4 hr with heating. After allowing to cool, the reaction mixture was added to saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 2-trifluoromethyl-4-hydroxy-6-methoxyquinoline (0.450 g).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[NH:13][C:12](=[S:24])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:25]([S:24][C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=2)[N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: C#CCOc1ccc2[nH]c(=S)nc(-c3ccc(C(C)C)cc3)c2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc2nc(SCc3ccccc3)nc(-c3ccc(C(C)C)cc3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100 mg (299 μmol) 4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione in 2 ml THF are added 35.5 μl (299 μmol) benzyl bromide and 76 μl (448 μmol) DIEA. After stirring for 18 h at r.t. the reaction mixture is extracted with dichloromethane and water. After evaporation of the organic layers the crude product is purified by flash chromatography using hexanes/ethyl acetate 20:1 as eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:5]=1[NH2:11].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)#[CH:14]>C1COCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:14]#[C:13][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:5]=1[NH2:11]
Reactant: COC(=O)c1cccc(I)c1N
Reactant: C#Cc1ccc(-c2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C#Cc2ccc(-c3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
To a solution of 2-amino-3-iodo-benzoic acid methyl ester (500 mg, 1.8 mmol), 4-ethynyl-biphenyl (416 mg, 2.3 mmol) in THF (20 mL), CuI (17 mg, 0.09 mmol), bis-(triphenylphosphine)-palladium (II)-chloride (64 mg, 0.09 mmol) and TEA (0.75 mL, 5.4 mmol) were added. This mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mass was filtered through celite, and the collected filtrate was diluted with ethyl acetate (30 mL), washed with water (2×20 mL) and the combined organic layer was separated and dried over sodium sulphate and concentrated under reduced pressure to obtain brown mass which was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain 450 mg of 2-amino-3-biphenyl-4-ylethynyl-benzoic acid methyl ester as a pale yellow coloured solid (76%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([CH3:32])[N:30]=[CH:31][C:24]=12.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([CH3:32])[N:30]=[CH:31][C:24]=23)[CH2:12][CH2:13]1
Reactant: Cn1ncc2c(Cl)ncnc21
Reactant: NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ncc2c(NCCCN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)ncnc21

Procedure:
The product from step (ii) (0.08 g), 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.054 g) and diisopropylethylamine (0.082 g) in 1-methyl-2-pyrrolidinone (2 ml) was heated at 50° C. for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried and the solvent removed under reduced pressure. Purification was by chromatography eluting with 9% methanol/dichloromethane. Yield 0.052 g
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[C:17]([Cu])#[N:18]>C1C=CC=CC=1>[C:17]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2)#[N:18]
Reactant: ClC1c2ccccc2COc2ccccc21
Reactant: N#C[Cu]
Solvent: c1ccccc1
Product: N#CC1c2ccccc2COc2ccccc21
Yield: 92 %

Procedure:
11-Chloro-6,11-dihydrodibenz[b,e]oxepin (32.69 g; 0.14 mole) is dissolved in dry benzene (300 ml) and placed under a dry nitrogen atmosphere. To this solution is added in one portion, CuCN (32.04 g; 0.35 mole). The reaction is heated to reflux for 31/2 hours and filtered while hot. After washing the salts with benzene, the filtrate is removed in vacuo to give a solid. This solid is triturated several times with isopropyl ether and finally hexane to give a solid (92%) of 11-cyano-6,11-dihydrodibenz[b,e]oxepin m.p. 65°-66.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:3]=1.[CH:15]1([C:18](=O)[CH2:19][C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH:15]1([C:18]2[CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]3[C:2]([CH3:1])=[N:3][N:4]([CH:8]4[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]4)[C:5]=3[N:7]=2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C2CCN(C)CC2)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCN(C)CC1
Temperature: 70 °C

Procedure:
3-Methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazol-5-amine (500 mg, 2.57 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (474 mg, 2.57 mmol) were suspended in Toluene (10 mL) and heated at 70° C. for 5 h. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: gradient of 0 to 10% MeOH:DCM). The final product was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=343.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.11 (m, 4H), 1.38 (t, J=7.07 Hz, 3H), 1.83 (d, J=6.06 Hz, 2H), 2.12-2.22 (m, 4H), 2.27 (s, 3H), 2.35 (m, J=7.83, 7.83, 5.05, 4.80 Hz, 1H), 2.54 (s, 3H), 2.94 (d, J=6.57 Hz, 2H), 4.42 (q, J=7.16 Hz, 2H), 4.57-4.73 (m, 1H), 7.46 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1.Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1.CCN(CC)CC>COCCOC>[O-:26][N+:15]1[C:16]2[CH:25]=[C:24]3[C:20](=[CH:19][C:17]=2[N:18]=[C:13]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]2)[N:14]=1)[CH2:21][CH2:22][CH2:23]3
Reactant: N#CC1CCN(CCCN)C1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: N#CC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Yield: 78.1 %

Procedure:
1-(3-Aminopropyl)-3-pyrrolidinecarbonitrile (302) (0.36 g, 2.4 mmol) was added to a stirred solution of chloride 21 (402 mg, 1.8 mmol) and Et3N (0.76 mL, 5.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 56 (476 mg, 78%) as a yellow solid: mp (EtOAc/pet. ether) 111-112° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.72 (br t, J=5.3 Hz, 1H, NH), 3.58 (q, J=6.4 Hz, 2H, CH2N), 2.95-3.07 (m, 6H, H-6, H-8, CH2N), 2.73-2.80 (m, 1H, CHCN), 2.55-2.68 (m, 4H, 2×CH2), 2.23-2.32 (m, 1H, CH2), 2.10-2.18 (m, 3H, CH2, H-7), 1.85 (p, J=6.7 Hz, 2H, CH2); 13C NMR δ 158.7, 154.6, 148.7, 143.3, 129.8, 122.1, 120.6, 114.6, 57.4, 53.3, 52.9, 40.2, 33.1, 32.3, 29.2, 27.7, 26.3, 25.7. Anal. calcd for C18H22N6O: C, 63.9; H, 6.6; N, 24.8. Found: C, 64.0; H, 6.4; N, 24.8%.
Reaction SMILES: C(O)(=O)C.O.[I:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1>[Fe].C(O)C>[I:6][C:7]1[CH:8]=[C:9]([NH2:15])[C:10]([NH:13][CH3:14])=[CH:11][CH:12]=1
Reactant: CNc1ccc(I)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CNc1ccc(I)cc1N
Temperature: 70 °C
Yield: 89.7 %

Procedure:
A mixture of an iron powder (1.7 g), acetic acid (2.2 ml), ethanol (80 ml), and water (25 ml) was stirred at 70° C. To the reaction mixture was added dropwise a mixture of (4-iodo-2-nitro-phenyl)-methyl-amine (2.0 g) and ethanol (20 ml). After that, the mixturee was stirred at 70° C. for 6 hours. Then, the reaction mixture was filtrated and thoroughly washed with THF. The resulting filtrate was concentrated under reduced pressure. To the resulting residue was poured saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4-iodo-N1-methyl-benzene-1,2-diamine (1.6 g)
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[CH:25]=[CH:26][O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([CH2:12][NH:13][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24](=[O:30])[CH:25]=[CH:26][O:27]4)=[CH:22][CH:21]=3)[O:8][C:7]=2[CH:14]=1
Reactant: NCC1COc2ccc(O)cc2O1
Reactant: O=c1ccoc2cc(OCCCBr)ccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccoc2cc(OCCCNCC3COc4ccc(O)cc4O3)ccc12
Temperature: 80 °C
Yield: 10.1 %

Procedure:
2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine hydrochloride (4.7 g, 22 mmole), 7-(3-bromopropoxy)chromen-4-one (6.1 g, 22 mmole) and diisopropylethylamine (18.8 ml, 108 mmole) were combined in 200 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. The residue was chromatographed on a silica gel column using first dichloromethane and then 5% methanol/dichloromethane as eluents. The fractions containing material with Rf=0.37 on silica gel tlc (chloroform/methanol/ammonia=95/5/1) were combined, concentrated, and the residual solid was recrystallized from ethanol with the addition of 4N isopropanolic HCl and ether to give 0.85 g of title compound as a light brown solid hydrochloride, quarter hydrate, m.p. 186°-189° C.