Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH2:10]([O:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16])[CH3:11].C([O-])(=O)/C=C/C([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:18]([NH:17][C:15](=[O:16])[C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[O:12][CH2:10][CH3:11])=[O:19])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: CCOc1ccccc1C(=O)N=C=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CCOc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.63 g, 5 mmol) and crude 2-ethoxybenzoyl isocyanate (1.59 g, ca 7 mmol). The product (1.77 g) was converted to the 1:1 fumarate, mp 198°-199° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:24]=[CH:23][C:9]2[CH2:10][CH2:11][CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[N:13]3[CH2:14][C:8]=2[CH:7]=1)=[O:5].[CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[CH:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][C:4]([C:6]2[CH:24]=[CH:23][C:9]3[CH2:10][CH2:11][CH:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[N:13]4[CH2:14][C:8]=3[CH:7]=2)=[O:5])[CH2:29][CH2:28]1)=[O:26]
Reactant: O=CN1CCNCC1
Reactant: O=C(CCCl)c1ccc2c(c1)CN1C(=O)c3ccccc3C1CC2
Product: O=CN1CCN(CCC(=O)c2ccc3c(c2)CN2C(=O)c4ccccc4C2CC3)CC1
Yield: 84.9 %

Procedure:
Using 3.45 g of 3-(3-chloro-1-oxopropyl)-7,11b,12,13-tetrahydro-5H-isoindolo[2,1-b][2]benzazepin-7-one, corresponding to Reference Example 5 Compound No. 1, and 1.4 g of 1-formylpiperazine, the procedure of Example 1 was otherwise repeated to provide about 3.6 g of 3-[3-(4-formyl-1-piperazinyl)-1-oxopropyl]-7,11b,12,13-tetrahydro-5H-isoindolo[2,1-b][2]benzazepin-7-one as a crude oil. This oil was not further purified but directly dissolved in 50 ml of methanol and the solution was refluxed with 50 ml of concentrated hydrochloric acid for 4 hours. After the methanol was distilled off, the residual aqueous solution was adjusted to pH about 10 with 10% aqueous sodium hydroxide solution and the product was extracted into dichloromethane. The extract was washed with water and the solvent was distilled off under reduced pressure to provide 3.1 g of the title compound as a powder melting at 207°-210° C. Elemental analysis for C24H27N3O2
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC[O:10][CH2:11][CH3:12])C.P(Cl)(Cl)(Cl)=O.[CH3:18][C@H:19]1[C@@:36]2([CH3:37])[C:23]([CH2:24][C@@H:25](C)[C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][C@@H:29]([F:39])[C:30]2=[O:38])=[CH:22][C:21](=O)[CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:20][C@H:19]1[C@@:36]2([CH3:37])[C:23]([C:22](=[CH2:21])[C@@H:25]([CH3:24])[C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][C@@H:29]([F:39])[C:30]2=[O:38])=[CH:12][C:11](=[O:10])[CH2:18]1
Reactant: CCOCOCC
Reactant: C[C@@H]1CC2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C1C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1β,7α-dimethyl-16α-fluoroandrost-4-ene-3,17-dione (0.896 g, 2.7 mmol) is stirred at reflux for about 5 hrs, i.e. until the starting material has disappeared. The suspension is allowed to cool and under vigorous stirring a saturated sodium carbonate solution is added dropwise until the pH of the aqueous layer becomes alkaline. The organic layer is separated, washed to neutrality with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue is purified by chromatography on silica gel using hexane/ethyl acetate as eluant. Thus the pure 1β,7α-dimethyl-16α-fluoro-6-methylenandrost-4-ene-3,17-dione is obtained in 60% yield (0.56 g).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]=O)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:7][O:8][CH:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:9])([F:21])[F:22])=[CH:12][CH:13]=2)[O:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Reactant: CCCC(CO)CO
Solvent: Cc1ccccc1
Product: CCCC1COC(CCc2ccc(C(F)(F)F)cc2)OC1
Yield: 36.1 %

Procedure:
2-Propyl-1,3-propanediol 17.4 g (147 mol) and the above 3-(4-trifluoromethylphenyl)propanal 20.0 g (98.9 mmol) were dissolved in toluene 200 ml, and PTS 1 g was added, and the mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with a saturated sodium bicarbonate aqueous solution, and then with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene), and recrystallized twice from ethanol to obtain 5-propyl-2-(2-(4-trifluoromethylphenyl)ethyl)-1,3-dioxane 10.8 g (35.7 mmol). The yield was 36.1% from 3-(4-trifluoromethylphenyl) propanal.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:23]([O:21][C:3]1[C:2]([F:1])=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][C:4]=1[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
17D (2.500 g, 8.33 mmol) and (bromomethyl)benzene (1.483 mL, 12.49 mmol) were dissolved in acetone (40 mL). Cesium carbonate (5.43 g, 16.65 mmol) was added, and the reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was filtered, the filter cake was washed with acetone (3×25 mL). Organic fractions were combined, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (0-50% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 17E (2.789 g, 7.14 mmol, 86% yield) as a white solid. MS (ESI) m/z: 391.0 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.94 (1H, d, J=11.54 Hz), 7.77-7.90 (1H, m), 7.39 (5H, s), 5.31 (2H, br. s.), 4.25-4.50 (2H, m), 2.78 (3H, s), 1.35-1.55 (9H, m).
Reaction SMILES: Br[C:2]1[C:3]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[CH:9]1([CH:3]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:8]=2)[N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[CH2:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:17][CH2:16]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Cc1cccc(Br)c1C1CCCCC1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)C2CCCCC2)CC1

Procedure:
3.8 g (15.0 mmol) (bromocyclohexylphenyl)-methane, 4.3 g (15.0 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide, 3.1 g (22.5 mmol) potassium carbonate and 0.22 g (1.5 mmol) sodium iodide are stirred in 40 ml DMF for two hours at ca. 105° C. After cooling the mixture is poured into 100 ml water and extracted with 150 ml acetic acid ethyl ester. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified twice over silica gel with CHCl3/CH3OH (90/10 and 95/5) and crystallized from 10 ml acetonitrile after drawing off the solvent. Beige colored crystals with an MP of 109-110° C.; yield 1.4 g (200%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][N:18]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:17]2.[Cl-].[NH4+]>>[CH:20]12[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]1)[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=13)[CH2:19]2
Reactant: NCCCCN1CC2CCC(CC2)C1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nnc(NCCCCN2CC3CCC(CC3)C2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine, three equivalents of 4-(3-azabicyclo[3.2.2]non-3-yl)butylamine and one equivalent of ammonium chloride at 145° C. under nitrogen overnight gave the title compound as the free base after flash column chromatography (silica gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide). This was converted to the dihydrochloride salt and recrystallized from ethanol, mp 257°-258° C.
Reaction SMILES: [C@@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1(C)C=CC=CC=1>[C@@H:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1,2,3,4-tetrahydro-1-naphthylamine (26.9 g.) is dissolved in 200 ml. of toluene and 36 g. of acetic anhydride is added while the temperature from the reaction exotherm is moderated at 50° C. to 60° C. with an ice-bath. The solution is heated to reflux for 0.5 hr. and then stirred at room temperature overnight. The mixture is then evaporated to dryness and the residue is washed well with ether. On drying, 26.1 g. of the title compound, m.p. 153° C. to 155° C., is obtained.
Reaction SMILES: [F:1][C:2]1([F:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[O:4][C:3]1([F:15])[F:14].S(=O)(=O)(O)[OH:18]>O>[F:16][C:2]1([F:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]([NH2:13])=[O:18])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:15]
Reactant: N#Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To 2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile (200 mg) were added concentrated sulfuric acid (2 mL) and water (0.3 ml) at room temperature. The reaction mixture was stirred at 40° C. for 3 hr, water was added and the mixture was stirred for 40 min at room temperature. The resulting solid was collected by filtration, washed with purified water, and dried under reduced pressure to give the title compound (190.6 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH:21]1([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH:21]1([C:25]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:26])[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)C1CCC1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)C1CCC1)C2
Reaction time: 8 h
Yield: 65.5 %

Procedure:
200 mg of N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 80 mg of cyclobutan carboxylic acid, 111 mg HOBT, 276 mg EDC and 0.6 ml triethylamine are dissolved in 7 ml DMF and stirred overnight. The mixture is evaporated and the residue is purified by silica gel chromatography. 170 mg of a yellowish foam are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:19][CH2:18]1>>[CH2:24]([CH:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:18][CH2:19]1)[CH2:26][CH3:27])[CH3:25]
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCC(CC)N1CCC(N)CC1
Product: CCC(CC)N1CCC(Nc2ccc(-c3ccc(C#N)cc3)nn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-cyanophenyl)pyridazine and 4-amino-1-(1-ethylpropyl)piperidine.
Reaction SMILES: [C:1]([C:5]([NH:7][C@@H:8]([C@@H:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:29])[N:15]=1)[CH3:13])[C:9](O)=[O:10])=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH2:34])=[O:33].C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:1]([C:5]([NH:7][C@@H:8]([C@@H:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:29])[N:15]=1)[CH3:13])[C:9]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH2:34])=[O:33])=[O:10])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: C[C@H](c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)C(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)C(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the crude acid from Step D (0.15 g, 0.33 mmol) in 5 mL of dichloromethane was added L-prolineamide (0.057 g, 0.49 mmol), HOAt (0.090 g, 0.66 mmol), N,N-diisopropylethylamine (0.17 mL, 0.99 mmol) and HATU (0.25 g, 0.66 mmol). After stirring at room temperature for 12 h, the reaction was diluted with dichloromethane. The organic phase was washed sequentially with two portions of 0.5N aqueous sodium bicarbonate solution and saturated aqueous brine, dried over sodium sulfate, and evaporated in vacuo. Purification by HPLC (YMC Pro-C18 column, gradient elution, 10-90% acetonitrile/water with 0.1% TFA) afforded the title compound. LC/MS 556.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.I[C:42]1[CH:47]=[N:46][CH:45]=[CH:44][N:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:27]=[CH:28][C:29]([C:42]3[CH:47]=[N:46][CH:45]=[CH:44][N:43]=3)=[CH:30][CH:31]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(C#N)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Ic1cnccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile (prepared as described in example 28, 3.6 g, 6.54 mmol) in N,N-dimethylformamide (70 mL) is degassed with argon for 0.5 h. Then 2-iodopyrazine (2.0 g, 9.82 mmol), cesium carbonate (4.2 g, 13.09 mmol), Pd(dppf)2Cl2 (0.53 g, 0.654 mmol) is added and the resulted mixture is degassed with argon for 0.5 h The reaction mixture is then heated at 100° C. for 1.5 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford 3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrazin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile. 1H NMR (DMSO-d6, 400 MHz) δ 9.25 (s, 1H), 8.71 (m, 1H), 8.62 (m, 2H), 8.51 (m, 2H), 8.08 (d, 2H), 7.90 (m, 1H), 7.88 (m, 1H), 7.60 (d, 2H), 7.44 (m, 4H); LC-MS calculated for C28H16ClN7O (M+H+) 502.1, found 502.0.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]1[C:18](=[O:19])[NH:17][CH2:16][C:15](=[O:20])[NH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CN(C)C=O>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]1[C:18](=[O:19])[NH:17][CH2:16][C:15](=[O:20])[NH:14]1)[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)C(Cc2cccc(NCc3ccccc3)c2)N1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1cccc(CC2NC(=O)CNC2=O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
A suspension of 2-[3-(benzylamino)benzyl]-3,6-piperazinedione (0.45 g), 37% aqueous formaldehyde (81 mg), sodium triacetoxyborohydride (0.62 g) and acetic acid (175 mg) in a mixture of 1,2-dichloroethane (15 ml) and N,N-dimethylformamide (5 ml) was stirred for 5 hours at room temperature. Then additional 37% aqueous formaldehyde (0.1 ml), acetic acid (0.2 ml) and sodium triacetoxyborohydride (0.60 g) were added to the reaction mixture and the whole was stirred for further 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. The resulting precipitates were collected by filtration and washed with isopropyl alcohol to give 2-[3-(N-benzyl-N-methylamino)benzyl]-3,6-piperazinedione (0.46 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[CH:5]=[C:4]([CH2:13][O:14][CH3:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1)[NH2:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:8]([C:6]1[CH:5]=[C:4]([CH2:13][O:14][CH3:15])[N:3]=[C:2]([NH:21][C:20]2[CH:22]=[CH:23][C:24]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:18]([O:17][CH3:16])[CH:19]=2)[N:7]=1)=[CH2:9])[CH3:12]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: C=C(OCC)c1cc(COC)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(COC)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 52 %

Procedure:
2-Chloro-4-(1-ethoxyvinyl)-6-(methoxymethyl)pyrimidine (167 mg, 0.73 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (178 mg, 0.88 mmol), cesium carbonate (476 mg, 1.46 mmol), palladium acetate (25 mg, 0.11 mmol) and 2-(dicyclohexylphosphino)biphenyl (38 mg, 0.11 mmol) in dioxane (4 mL) was heated under argon at 120° C. for 90 minutes in a microwave reactor. The mixture was filtered through a short silica plug which was washed with 10% MeOH in EtOAc (75 mL). The solvent was evaporated and the residue was purified by preparative HPLC to give the title compound 150 mg (52%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[P:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)Cl>CCOCC>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[PH:15][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1P(Cl)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccccc1Pc1ccccc1
Temperature: 20 °C
Yield: 79.5 %

Procedure:
To a well stirred suspension of lithiumaluminium hydride (266.0 mg, 7.0 mmol) in 50 mL of ether was added dropwise a solution of 2-methoxyphenyl-phenylchlorophosphine (3.20 g, 12.8 mmol) in 10 mL ether. Reaction was heated under reflux for 12 hrs and then allowed to cool to room temperature (ca. 20° C.). The excess of hydride was destroyed by the careful addition (dropwise) of 30 mL of water. Organic phase was separated and the aqueous phase was extracted with ether (2×60 mL). The organic layers were combined, dried over MgSO4 and concentrated to give 2.2 g (82%) of 2-methoxyphenyl-phenylphosphine.
Reaction SMILES: [OH:1][C:2]1[C:3]([I:15])=[C:4]([C:7]([N+:12]([O-:14])=[O:13])=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].Br[CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:1][C:2]1[C:3]([I:15])=[C:4]([C:7]([N+:12]([O-:14])=[O:13])=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6])[CH3:18]
Reactant: CCBr
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc([N+](=O)[O-])c(C#N)c1I
Temperature: 60 °C
Yield: 38.9 %

Procedure:
To a solution of the product of step (a) (6.95 g, 21.7 mmol) and bromoethane (1.78 ml, 23.8 mmol) in DMF (70 ml) was added potassium carbonate (4.49 g, 32.5 mmol) and the reaction was heated to 60° C. for 18 h. After cooling, the reaction mixture was partitioned between 2N aqueous HCl and EtOAc, the organic layer was separated, washed with H2O, dried over MgSO4 and evaporated. The crude product was purified on silica gel, eluting with CH2Cl2/MeOH (97/3, v/v) to afford the subtitle compound as a colourless solid (2.94 g, 39%). Rf 0.68 (CH2Cl2/MeOH 95/5, v/v). MS m/z 366 (MNH4+).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:15](=[O:30])[NH:14]2)=O)=CC=1)([O-])=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35][NH2:36]>CCO>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35][NH:36][C:11]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15](=[O:30])[NH:14]1)=[O:10]
Reactant: O=C1NN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(c2ccccc2)C1c1ccccc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: O=C1NN(C(=O)NCc2ccc(Cl)c(Cl)c2)C(c2ccccc2)C1c1ccccc1
Yield: 23 %

Procedure:
A solution of 1-[(4-nitrophenyl)oxycarbonyl]-4,5-diphenyl-3-pyrazolidinone (1.00 g, 2.48 mmol) and 3,4-dichlorobenzylamine (5 mL) in 50 mL abs. EtOH was heated to reflux for 8 hours. Solvent was removed in vacuo, the residue taken up in CH2Cl2, washed twice with 1N HCl and once with pH 7 buffer, and dried over Na2SO4. After removal of solvent in vacuo, the product was purified by chromatography (0-35% EtOAc:hexane gradient) to give 250 mg (23%) solid: