Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:37])[C@H:10]([CH:34]([CH3:36])[CH3:35])[N:11]([C:30]([O:32][CH3:33])=[O:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1.C(OC(=O)[C@H](C(C)C)N(C(OC)=O)CC1C=CC(C2C=CC=CC=2C#N)=CC=1)C1C=CC=CC=1.C([Sn](N=[N+]=[N-])(CCCC)CCCC)CCC>>[C:9]([C@@H:10]([N:11]([C:30]([O:32][CH3:33])=[O:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[NH:26][N:27]=[N:28][N:29]=2)=[CH:15][CH:14]=1)[CH:34]([CH3:35])[CH3:36])([OH:37])=[O:8]
Reactant: COC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: COC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Product: COC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C

Procedure:
N-Carbomethoxy-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine benzyl ester starting from 3.21 g of N-carbomethoxy-N-[(2 '-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 3.50 g of tributyltin azide and subsequent flash chromatography using the system N6. Amorphous product, TLC (system N6) Rf : 0.26.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH2:16])[N:12]=[CH:11][C:10]=3[N:9]3[CH:17]=[N:18][N:19]=[C:8]3[C@H:7]2[CH2:20][CH3:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].ClC(OC)=O.[Cl-].[NH4+:30]>CN(C=O)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:2]4[CH:3]=[N:30][CH:4]=[CH:5][CH:1]=4)[N:12]=[CH:11][C:10]=3[N:9]3[CH:17]=[N:18][N:19]=[C:8]3[C@H:7]2[CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: CC[C@@H]1c2nncn2-c2cnc(N)nc2N1C1CCCC1
Agent: COC(=O)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC[C@@H]1c2nncn2-c2cnc(Nc3cccnc3)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To (R)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine (50 mg, 0.175 mmol) in DMF (1 ml) at 0° C. was added sodium hydride (60% in mineral oil, 7.7 mg, 0.193 mmol). The reaction mixture was stirred for 10 minutes, then methyl chloroformate (13.6 μL, 0.175 mmol) was added. The reaction was allowed to warm up to room temperature and was stirred for 18 hours. Ammonium chloride (5 ml, sat. aq. soln.) was added and extracted with EtOAc (3×10 ml). The combined organics were washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed under vacuum. The crude product was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 M, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound as an off-white powder (25 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][C@@H:18]([N:20]1[C:29](=[O:30])[CH2:28][C:23]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][C:21]1=[O:31])[CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:19][C@@H:18]([N:20]2[C:29](=[O:30])[CH2:28][C:23]3([CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:22][C:21]2=[O:31])[CH3:17])[CH2:14][CH2:15]1
Reactant: Fc1cc(F)c(N2CCNCC2)cc1F
Reactant: C[C@@H](CCl)N1C(=O)CC2(CCCC2)CC1=O
Product: C[C@@H](CN1CCN(c2cc(F)c(F)cc2F)CC1)N1C(=O)CC2(CCCC2)CC1=O
Temperature: 160 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A mixture of 1-(2,4,5-trifluorophenyl)piperazine (20 mg, 0.093 mmol) and (S)-8-(2-chloro-1-methylethyl)-8-azaspiro[4.5]decane-7,9-dione (20 mg, 0.082 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (18.1 mg, 0.043 mmol, 52%): ESI-MS m/z 424 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:20][OH:21])[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2cccc(Cl)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(Cc2cccc(Cl)n2)=NO)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone (37.4 g, 142.9 mmol) in methanol (500 mL) was added hydroxylamine hydrochloride (49.7 g, 714.5 mmol) followed by the addition of a sodium hydroxide solution (28.6 g, 714.5 mmol in 50 mL of water). The resulting suspension was heated at reflux for 2 hours and then allowed to cool to room temperature. The mixture was concentrated and water was added to the resulting slurry. A white precipitate formed, which was collected by filtration, washed with water and dried to give 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (38.7 g, 97%) as a white solid. 1H NMR (CDCl3): δ 8.23 (b, 1H), 7.63 (d, 2H), 7.48 (d, 1H), 7.12 (m, 2H), 6.83 (dd, 2H), 4.33 (s, 2H), 3.76 (s, 3H); MS m/z 277 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Br[C:20]1[CH:21]=[CH:22][C:23]([C:26]#[C:27][CH2:28][O:29][CH3:30])=[N:24][CH:25]=1.O.C(OCC)(=O)C>C(=O)([O-])[O-].[K+].[K+].O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:29][CH2:28][C:27]#[C:26][C:23]1[N:24]=[CH:25][C:20]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: COCC#Cc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCC#Cc1ccc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 80 °C
Yield: 78.9 %

Procedure:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (37, 0.998 g, 4.09 mmol), 5-bromo-2-(3-methoxy-prop-1-ynyl)-pyridine (42, 0.616 g, 2.72 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.157 g, 0.136 mmol) were mixed in 8.2 mL of 1.00 M potassium carbonate in water (8.2 mmol) and 22 mL of tetrahydrofuran. The resulting mixture was heated at 80° C. Ethyl acetate and water were added, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (43, 565 mg). MS (ESI) [M+H+]+=264.3.
Reaction SMILES: C([N:9]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[S:30][N:29]=3)[CH2:24][CH2:23]2)[C:10]1=[O:37])(=O)C1C=CC=CC=1>O1CCOCC1.N>[S:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:28]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:11]3[CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]4[NH:9][C:10]3=[O:37])[CH2:27][CH2:26]2)=[N:29]1
Reactant: O=C(c1ccccc1)N1C(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C2CCCCC21
Agent: N
Solvent: C1COCCO1
Product: O=C1NC2CCCCC2N1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 120 °C

Procedure:
The compound (1.0 g, 1.9 mmoles) obtained in the above described paragraph (b) was dissolved in the mixed solution of 3 ml of dioxane and 3 ml of concentrated aqueous ammonia, and the resulting solution was heated in a sealed tube at 120° C. for 24 hours. The reaction was concentrated under reduced pressure, and the residue was then purified by chromatography on a silica gel column to give 0.56 g of the title compound.
Reaction SMILES: Br.[N:2]1([C:8](=[NH:10])[NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:10]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCCCC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(N2CCCCC2)ns1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of piperidine-1-carboximidamide hydrobromide (2.00 g, 9.61 mmol) and perchloromethyl mercaptan (1.04 ml, 9.61 mmol) in methylene chloride (10 ml) was added dropwise a solution of sodium hydroxide (1.54 g, 38.4 mmol) in water (4 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The reaction mixture was poured to water, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1) to give 500 mg (25.6%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH:9][N:10]=[CH:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH:11]=[N:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NN=CC=Cc1ccccc1)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: O=C(c1ccccc1)N1N=CCC1c1ccccc1
Temperature: 220 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Five grams of the cinnamaldehyde benzoylhydrazone was suspended in 20 ml of diphenyl ether, followed by stirring at 220° C. for 3 hours. After cooling, the reaction liquid was poured into 100 ml of hexane for the separation of insoluble matter. The insoluble matter was filtered off and recrystallized from a methanol-water solution. Thus there was obtained 3.8 g of 1-benzoyl-5-phenyl-2-pyrazoline (mp. 105°-106° C.) as the desired product. The yield was 76.0%.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=[C:9]([O:17][CH3:18])[C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.O.[OH-].[Na+]>O1CCCC1.ClCCl>[CH:1]1([C:4]2[NH:5][C:6]3[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[C:9]([O:17][CH3:18])[C:7]=3[N:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(OC)c2nc(C3CC3)[nH]c12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CO)c2[nH]c(C3CC3)nc12
Temperature: 25 °C

Procedure:
A stirred solution of methyl 2-cyclopropyl-7-methoxy-3 H-benzimidazole-4-carboxylate, in dry tetrahydrofuran (220 ml), at −78° C. and under nitrogen, was treated dropwise over 3 hours with a solution of diisobutylaluminium hydride in dichloromethane (270 ml, 1.0M). The reaction mixture was allowed to warm to room temperature over 30 minutes, then cooled to −78° C., then treated dropwise with water (27 ml), then allowed to warm to room temperature. The reaction mixture was diluted with ice-water (500 ml) and the pH of the mixture was adjusted to above 12 by the addition of aqueous sodium hydroxide (750 ml, 1M). The resulting white suspension was filtered to yield a clear filtrate which was extracted seven times with ethyl acetate (500 ml): The combined extracts were dried over magnesium sulphate and then evaporated to yield the title compound as a cream coloured powder (10.13 g).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][O:3][CH2:2]2.[NH4+].[Cl-].CCOC(C)=O.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:15]([NH:22][C@@H:5]1[CH2:4][O:3][CH2:2][C@H:1]1[OH:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1OCC2OC12
Reactant: NCc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: O[C@@H]1COC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ti(OiPr)4 (1.0 mL, 3.48 mmol) was added to a solution of 3,6-dioxabicyclo[3.1.0]hexane (1.5 g, 17.4 mmol) in benzylamine (2.0 mL). The mixture was irradiated in a microwave reactor at 130° C. for 2 hours. It was cooled to room temperature, and 50 mL of saturated aqueous NH4Cl solution and 20 mL of EtOAc were added to the reaction. The mixture was stirred for 10 minutes. The resulting gummy precipitate was filtered over a celite bed, and the filtrate was extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography on a C-18 column (0-100% CH3CN/water) to afford trans-4-(benzylamino) tetrahydrofuran-3-ol. MS APCl calc'd for C11H15NO2 [M+H]+ 194. found 194.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:21][CH2:22][CH:23]2[O:28][CH2:27][C:26](=O)[N:25]([CH:30]([CH3:32])[CH3:31])[CH2:24]2)[CH:14]=[CH:13]1.[OH-].[Na+]>C(OCC)(=O)C.O>[CH:30]([N:25]1[CH2:26][CH2:27][O:28][CH:23]([CH2:22][O:21][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:20]=2[CH2:12][CH:13]=[CH:14]3)[CH2:24]1)([CH3:32])[CH3:31]
Reactant: CC(C)N1CC(COc2cccc3c2CC=C3)OCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCOC(COc2cccc3c2CC=C3)C1
Reaction time: 10 h
Yield: 79 %

Procedure:
In 50 ml. of anhydrous tetrahydrofuran was suspended 0.5 g. of lithium aluminum hydride and after adding slowly to the suspension a solution of 2.0 g. of 2-(7-indenyloxymethyl)-4-isopropylmorpholin-5-one in 10 ml. of anhydrous tetrahydrofuran with stirring, the mixture was stirred for 10 hours at 40°-50° C. Then, to the reaction mixture thus formed were added 0.5 ml. of water, 0.5 ml. of an aqueous 15% sodium hydroxide solution, and then 1.5 ml. of water successively to decompose excess lithium aluminum hydride. After stirring the mixture for 30 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue formed was dissolved in a small amount of ethyl acetate and the solution was subjected to a silica gel column chromatography (column diameter 1.5 cm., height 10 cm., eluting solution 200 ml.) to provide 1.5 g. (yield 79%) of oily 4-isopropyl-2-(7-indenyloxymethyl)morpholine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 4-(3-bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (48 mg, 37%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].C([Li])(CC)C.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[OH:8][C:4]1[CH:3]=[C:2]([B:16]([OH:19])[OH:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: [H-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: OB(O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
3-Bromophenol (8.65 g, 50 mmol) in dry THF (150 mL) was treated with sodium hydride (60%, 2.4 g, 60 mmol) at r.t. After 1 h, sec-butyllithium (1.3 M, 50 mL, 65 mmoL) was added dropwise to the reaction solution at −78° C. The reaction mixture was then allowed to stir at the same temperature for 30 min prior to addition of trimethyl borate (15 mL). After warming up to r.t. for 2 hrs, the reaction mixture was quenched with water (50 mL), and extracted with dichloromethane (2×100 mL). The combined organic phases were dried over MgSO4 and evaporated to give the title compound as a white solid (4.0 g, 58%), which was used in the Suzuki coupling reactions without further purification.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25](=[O:28])[CH:26]=[CH2:27])=[CH:10][N:9]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25]([CH2:26][CH2:27][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:10][N:9]=1
Reactant: C=CC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Reactant: C1COCCN1
Solvent: CCO
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)CCN2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(acryloyl)pyrimidine (72 mg) in ethanol (2 ml) is added morpholine (78 μl) at room temperature, and the mixture is stirred at room temperature for 40 minutes. The reaction mixture is concentrated under reduced pressure, and the residue is poured into water, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-morpholinoethyl)carbonyl]-pyrimidine (91 mg).
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH3:25]>CN(C)C=O>[CH2:24]([N:3]1[CH2:2][CH2:1][N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4]1)[CH3:25]
Reactant: CCBr
Reactant: O=C1CC2CNCCN2c2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN2c3ccccc3NC(=O)CC2C1
Temperature: 60 °C

Procedure:
To a solution of Example 1D (30 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (57 mg, 0.41 mmol) and bromoethane (10.3 μl, 0.14 mmol). The reaction was warmed to 60° C. for 14 hours. Excess potassium carbonate was filtered off. The solution was passed through a PS-isocyanate cartridge (Silicycle, 2 g) to trap leftover starting material. The solution was concentrated and purified by preparative HPLC with a gradient of acetonitrile and 0.1% trifluoroacetic acid in water to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.19-7.24 (m, 1 H), 7.14-7.18 (m, 1 H), 7.09-7.13 (m, 1 H), 7.01 (dd, J=7.78, 1.37 Hz, 1 H), 3.52-3.64 (m, 3 H), 3.32-3.39 (m, 2 H), 3.19-3.27 (m, 2 H), 2.97-3.10 (m, 2 H), 2.66 (dd, J=13.73, 7.02 Hz, 1 H), 2.09 (d, J=13.12 Hz, 1 H), 1.27 (t, J=7.32 Hz, 3 H); MS (ESI) m/z 246.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][C:3]=1[CH:4]=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][C:27]#[N:28]>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:26]([CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH3:17])[C:27]([NH2:28])=[N:1]2)=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: COc1ccccc1CCC#N
Reactant: Nc1cc(F)c(N2CCOCC2)cc1C=O
Product: COc1ccccc1Cc1cc2cc(N3CCOCC3)c(F)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-fluoro-5-morpholin-4-ylbenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: O.[N:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:23])C(=O)C1.ClCCl>C(O)(C)C.C(OCC)(=O)C>[Cl:23][C:4]1[CH:3]=[N:2][C:15]2[C:6]([CH:5]=1)=[N:7][C:8]1[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc2nc3cccnc3cc2c1
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: Clc1cnc2cc3ccccc3nc2c1

Procedure:
A solution of the azaacridine hydrate 20 (100 mg, 0.33 mmol) and NCS (49 mg, 0.37 mmol) in isopropanol (5 mL) was refluxed for 15 minutes under nitrogen. The reaction was diluted with ethyl acetate (20 mL), washed with 1N HCl (3×10 mL) and saturated NaCl (5 mL), dried (MgSO4) and evaporated at reduced pressure giving a yellow powder. Trituration from dichloromethane and gave the 3-chloroazaacridine 21 as a creamy white crystalline powder, 102 mg (92%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]12[C:19](=O)[O:18][C:16](=[O:17])[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:16](=[O:17])[CH:11]3[CH:10]([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:19]2=[O:18])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1ccc(Br)cc1F
Reaction time: 2 h

Procedure:
11.4 Parts of 4-bromo-2-fluoroaniline were added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 100 parts of glacial acetic acid and the mixture was stirred for 2 hours. The mixture was refluxed for 20 hours and then poured into 200 parts of ice. The resulting purple crystals were filtered and recrystallized from 70 parts of methanol at -40° C to yield 7.6 parts of lavender crystals of 2-(4-bromo-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione melting at 90°-92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.C(Cl)(Cl)=O.ClC1C=C(C=CC=1Cl)[C:25]([NH:27][CH:28]1[C:34](=[O:35])[NH:33][C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[C:30]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:29]1)=[O:26]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:25]([NH:27][CH:28]1[C:34](=[O:35])[NH:33][C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[C:30]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:29]1)=[O:26]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccccc1N
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccccc1NC(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A solution of 2-methoxy-aniline (37 mg) in dry dichloromethane (3 ml) was treated with triethylamine (0.04 ml) followed by 20% phosgene in toluene (0.08 ml). The mixture was stirred at room temperature for 1 h, and then Intermediate 3 (37 mg) was then added, and the stirring continued for 18 h. The mixture was partitioned between water and ethyl acetate. The organic layer was passed through a hydrophobic frit and evaporated and the residue was purified on a silica gel SPE cartridge. Gradient elution with 0-5% methanol in dichloromethane gave the title compound as a colourless solid (24 mg).