Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[N:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([O:27][CH2:28][C:29](Cl)=O)[CH3:26].C(O)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]3[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:26]([CH2:25][O:27][CH2:28][CH3:29])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CC(C)CNc1c(N)cnc2cc(Br)cnc12
Reactant: CCOCC(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)C
Temperature: 25 °C
Yield: 51 %

Procedure:
A solution of 7-bromo-N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine (22.29 g, 75.51 mmol) in dichloromethane (300 mL) was cooled to 0° C., and triethylamine (13.15 mL, 94.39 mmol) was added to the reaction mixture. Ethoxyacetyl chloride (11.56 g, 94.39 mmol) was added dropwise to the reaction mixture, and the reaction was maintained at ambient temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, triethylamine (52.62 mL, 377.6 mmol) and ethanol (250 mL) was added, and the resulting mixture was heated at reflux for 16 hours. The solvent was removed under reduced pressure and the residue was triturated with n-heptanes. The resulting precipitate was collected by filtration, washed with water, and dried. The product was then recrystallized from acetonitrile to yield 14 g of 7-bromo-2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine as an off-white solid. The mother liquor was concentrated, and the residue was recrystallized from acetonitrile to yield an additional 2.37 g of 7-bromo-2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine. The n-heptanes fraction from the trituration was concentrated under reduced pressure, triturated with acetonitrile, and isolated by filtration to give an additional 0.88 g of 7-bromo-2-(ethoxymethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine, for a total yield of 17.25 g of an off-white solid, mp 115-116° C.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[C:29]([C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1ccccc1F)c1cccc2c1OCCO2

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2′-fluoro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.39 min; [M+H]+=473.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: [H][H]
Reactant: COc1cc(OCCN2CCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCCC2)ccc1N
Yield: 91.8 %

Procedure:
A mixture of 1-[2-(3-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine (2.2 g, 8.3 mmol) and 5% Pd—C (0.4 g) in ethyl acetate (70 mL) was shaken under 50 psi of hydrogen for 22 hours. The mixture was filtered through Celite and evaporated, providing 1.8 g of the product, in 89% yield; 1H NMR (DMSO-d6) δ 1.78-1.83 (m, 4H), 2.58-2.63 (m, 4H), 2.86 (t, J=6.0 Hz, 2H), 3.53 (by, 2H), 3.81 (s, 3H), 4.04 (t, J=6.0 Hz, 2H), 6.35 (dd, J=8.4 Hz, J=2.7 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1
Reactant: OCCO
Reactant: O=Cc1ccoc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: c1cc(C2OCCO2)co1
Yield: 64.2 %

Procedure:
To a solution of furan-3-carbaldehyde (SM1-A, 2 g, 20 mmol) and ethane-1,2-diol (3.72 g, 60 mmol) in toluene (100 ml) was added pyridinium p-toluenesulfonate (PPTS, 50 mg, 0.2 mmol), and the solution was heated at reflux utilizing a Dean-Stark trap. After the theoretical amount of water was collected, the solvent was evaporated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give product (2-A) (1.8 g, 80%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.54 (s, 1H), 7.41-7.40 (t, 1H), 6.47-6.46 (d, 1H), 5.85 (s, 1H), 4.09-4.06 (m, 2H), 4.00-3.98 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N=[N+]=[N-])C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C1COCC1>[C:23]([O:11][CH:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: OC(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: CCN=[N+]=[N-]
Solvent: C1CCOC1
Product: CC(=O)OC(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
To a solution of (1H-indazol-5-yl)(phenyl)methanol (1.1 g, 5.0 mmol) in 50 mL of dry THF was added EtN3 (2.8 mL, 20 mmol) and acetic anhydride (1.9 mL, 20 mmol). The reaction was heated at reflux for 12 h. The reaction was quenched with aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was taken up in toluene and concentrated in vacuo×2 to remove any excess acetic anhydride. Obtained a quantitative yield of (1H-indazol-5-yl)(phenyl)methyl acetate. MS found: (M+H)+=309.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]COCC.[N+](=C)=[N-]>COCCOC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([OH:21])[CH2:17][C:18]([O:20][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: O=C(O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Agent: C=[N+]=[N-]
Solvent: COCCOC
Product: COC(=O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Into 4 ml of 1,2-dimethoxyethane, was dissolved 450 mg (1.52 mmoles) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoic acid. To the solution, while being cooled in ice, was added dropwise 7 ml (4.56 mmoles) of an ether solution of diazomethane. The mixture was stirred for 30 minutes and then evaporated to dryness to yield 461 mg (98% yield) of methyl (S)-7-benzyloxycarbonylamino-3-hydroxyheptanoate. [α]D21 +1°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[CH:13].C([Mg]Br)C.Br[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O1CCCC1.CCOCC.[Cl-].[NH4+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[C:13][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C#CCC#CCOC1CCCCO1
Reactant: CCCCCCC#CCBr
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC#CCC#CCC#CCOC1CCCCO1
Reaction time: 2 h

Procedure:
To a stirred solution of 10.8 g (60 mmole) of hexa-2,5-diyn-1-ol tetrahydropyranyl ether [D. Van der Steen et al, Recueil 82, 1015 (1963)] in 100 ml of dry tetrahydrofuran there were added dropwise, under argon atmosphere, at 0°-5° C. 16.9 ml (0.60 mmol) of a 3.5N ethylmagnesium bromide solution in ether, maintaining the temperature at 0°-5° C. The mixture was stirred for 2 hours at 10°-15° C. and then 0.1 g of cuprous chloride were added. After 15 minutes a solution of 5.35 g (26 mmole) of 1-bromo-2-nonyne in 60 ml of dry tetrahydrofuran was added dropwise and the mixture stirred at room temperature for 3 hours. The reaction mixture was diluted with 70 ml of saturated ammonium chloride solution and extracted with methylene chloride. The organic extracts were dried and evaporated, and the residue purified by column chromatography on 450 g of silica gel, using hexane-ethyl acetate (99:1) as eluant, to provide pentadeca-2,5,8-triyn-1-ol tetrahydropyranyl ether.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11]>CO>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:10](=[O:11])[C:9]([F:16])([F:15])[F:8]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CNCCCCO
Solvent: CO
Product: CN(CCCCO)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a 250 mL round bottom flask, charged with 10.0 g (96.9 mmol) of the amine, 4-methylaminobutanol, in 100 mL of dry methanol, was added 17.5 mL (147 mmol) of ethyl trifluoroacetate. The mixture was stirred at room temperature for 24 hours and then concentrated to afford 18.55 g of the product as a near colorless oil (96%): 1H—NMR (200 MHz, D2O); 3.63 and 3.50 (2t's, 4H), 3.20 and 3.05 (d and s, 3H), and 1.82-1.47 (m, 4H) ppm.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:28]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:32]2C=CC=CC=2N=N1.Cl.CN.CCN(CC)CC>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([NH:28][CH3:32])=[O:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 47.7 %

Procedure:
To a mixture of 1-(3-iodophenyl)-3-isoquinolinecarboxylic acid (0.1186 g, 0.32 mmol), BOP (0.1402 g, 0.32 mmol), Methylamine hydrochloride (0.083 g, 1.23 mmol) in DMF (10 mL) was added Et3N (0.17 mL, 1.22 mmol). The resulting mixture was stirred under Ar at room temperature for 7 h and quenched by adding H2O (10 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was purified on column (SiO2, 35% ethyl acetate/hexane, 0.1% Et3N), thereby giving a white solid (59.2 mg, 48%). mp 172.1-173.6° C. 1H NMR (CDCl3) d 3.03, 3.04 (two s, 3 H, N-methyl), 7.24 (t, J=8.7 Hz, 1 H, aromatic), 7.55-7.65 (m, 2 H, aromatic), 7.71 (t, J=8.1 Hz, 1 H, aromatic), 7.82 (d, J=8.7 Hz, 1 H, aromatic), 7.95-8.05 (m, 3 H, aromatic), 8.19 (br s, 1 H, CONH), 8.57 (s, 1 H, aromatic). 13C NMR (CDCl3) d 26.16 (q, N-methyl), 94.24 (s, C--I), 119.86 (d, aromatic), 127.15 (d, aromatic), 128.70 (d, aromatic), 128.96 (d, aromatic), 129.13 (d, aromatic), 129.91 (d, aromatic), 130.77 (d, aromatic), 137.14 (s, aromatic), 137.85 (d, aromatic), 138.57 (d, aromatic), 140.99 (s, aromatic), 142.67 (s, aromatic), 157.62 (s, aromatic), 165.25 (s, CO). HRMS calcd. for C17H13IN2O: 388.0073. Found: 388.0071.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+].C1(B(O)O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][N:22]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: Clc1cc(NN=C(c2ccccc2)c2ccccc2)ncn1
Temperature: 90 °C

Procedure:
10.0 g (67.1 mmol) of 4,6-dichloropyrimidine, 14.5 g (73.8 mmol) of benzophenone hydrazone, 9.03 g (94.0 mmol) of sodium tert-butoxide, 409 mg (3.36 mmol) of phenylboronic acid, 301 mg (1.34 mmol) of palladium(II) acetate and 384 mg (1.34 mmol) of rac-2,2′-bis-(diphenylphosphino)-1,1′-binaphthalene are combined. The mixture is degassed and vented twice with argon, 400 ml of dry degassed toluene are added, the mixture is again degassed and vented twice with argon and heated at 90° C. overnight. After cooling, the reaction mixture is poured into water, the aqueous phase is extracted with ethyl acetate, the combined organic phases are concentrated and the residue is taken up in a mixture of dichloromethane and diethyl ether. The precipitate that remains is filtered off with suction (and discarded), the filtrate is concentrated and the residue is purified by column chromatography on silica gel 60 (mobile phase: toluene/ethyl acetate 8:2).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([Cl:26])=[CH:8][C:9]([F:25])=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:11]=1.C(N(CC)CC)C.[CH:34](O)=[O:35]>>[Cl:26][C:7]1[CH:8]=[C:9]([F:25])[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][NH:2][CH:34]=[O:35]
Reactant: O=CO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCN)c(Cl)cc2F)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCNC=O)c(Cl)cc2F)c1=O

Procedure:
A mixture of 2.0 g of 3-[5-(2-aminoethoxy)-4-chloro- 2-fluorophenyl]-1-methyl-6 -trifluoromethyl-2,4(1H.3H)pyrimidinedione hydrochloride in 20 ml of formic acid are heated to boiling temperature for 20 hours with 0.47 g of triethylamine. The reaction mixture is subsequently evaporated to dryness under reduced pressure, the residue is dissolved in ethyl acetate and extracted with water and thereafter with aqueous sodium bicarbonate solution, and the organic phase is dried over anhydrous sodium sulphate. The solution is thereafter evaporated to dryness under reduced pressure, and the resinous residue is dissolved in ethyl acetate and largely concentrated by evaporation. The residue, still in the liquid state, is treated with diethyl ether until slightly turbid and is seeded. The crystals are filtered off under suction, washed with diethyl ether and dried. There is obtained N-[2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenoxy}-ethyl]-formamide, m.p. 128°-131° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:13]([CH2:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:12]2=[O:32].C=O.[C:35]([BH3-])#N>C(#N)C.C(O)(=O)C.CO>[CH:29]([NH:28][C:26](=[O:27])[CH2:25][N:13]1[C:12](=[O:32])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([N:2]3[CH2:3][CH:4]4[CH:5]([CH2:6][N:7]([CH3:35])[CH2:8]4)[CH2:1]3)[CH:10]=2)[N:15]=[C:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:30])[CH3:31]
Reactant: CC(C)NC(=O)Cn1c(-c2ccccc2)nc2ccc(N3CC4CNCC4C3)cc2c1=O
Reactant: [BH3-]C#N
Agent: C=O
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC(=O)Cn1c(-c2ccccc2)nc2ccc(N3CC4CN(C)CC4C3)cc2c1=O
Temperature: 130 °C
Yield: 39.1 %

Procedure:
2-(6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxo-2-phenylquinazolin-3(4H)-yl-N-isopropylacetamide (EXAMPLE 4A) (100 mg, 0.23 mmol) was dissolved in acetonitrile (2 mL) before addition of formaldehyde (28 mg, 0.35 mmol) and MP-cyanoborohydride (140 mg, 0.36 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a microwave vial and heated at 130° C. for 20 minutes. Reaction mixture was then diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford N-isopropyl-2-(6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxo-2-phenylquinazolin-3(4H)-yl)acetamide (38 mg, 0.09 mmol).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.C(O)C.[CH2:19](O)[CH:20]=[CH2:21]>>[CH3:10][C:7]1[CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][CH2:21][CH:20]=[CH2:19])[CH2:5][CH:6]=1
Reactant: CC(=O)C1CC=C(C)CC1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C=CCCC(=O)C1CC=C(C)CC1
Temperature: 190 °C
Yield: 31.5 %

Procedure:
Execution: 4-acetyl-1-methyl-cyclohexene 1) was placed in the flask and mixed with the sulphuric acid/ethanol mixture 2) at room temperature for about 0.5 hours while being stirred and in conditions that exclude moisture. Component 3) was then added during the course of about 1 hour. The allyl alcohol (component 4) was added portion by portion. The mixture produced in this way was transferred to a steel autoclave insert and heated to 190° C. for 5 hours under 20 bar nitrogen. The GC control showed that the educt had been reduced down to 2% and that 31.5% main product had formed.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:46][CH2:45][C@H:44]([N:47]([CH3:49])[CH3:48])[CH2:43]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[CH3:48][N:47]([CH3:49])[C@H:44]1[CH2:45][CH2:46][N:42]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:30]=[CH:31][CH:32]=4)=[O:26])=[CH:20][C:19]=3[F:41])[NH:8][N:9]=2)[CH2:43]1
Reactant: COc1ccc(Cn2nc(N3CC[C@H](N(C)C)C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@H]1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)C1
Temperature: 50 °C

Procedure:
To a flask containing (S)—N-(4-(1-(4-methoxybenzyl)-3-(3-(dimethylamino)pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (14 mg, 0.02 mmol) at ambient temperature under a drying tube was added TFA (1 mL), and the reaction mixture was heated at 50° C. overnight. After cooling, the reaction was concentrated to dryness and then redissolved in 5 mL dichloromethane, to which 5 mL of 10% sodium carbonate was added. After stirring for a few minutes, the layers were separated and the organics were washed with 10% sodium carbonate. The organics were dried (MgSO4), filtered and concentrated to a crude oil. Biotage 12S with step gradient of dichloromethane (100 mL), 5/95 MeOH/dichloromethane (100 mL), and 9/1 dichloromethane/MeOH (200 mL) eluted the product. The product containing fractions were pooled and concentrated to a yellow solid (4.2 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 11.83 (br s, 1H), 8.41 (d, 1H), 8.23 (m, 1H), 7.96 (m, 1H), 7.60 (m, 2H), 7.40 (m, 1H), 7.24 (m, 2H), 6.16 (d, 1H), 3.82 (m, 1H), 3.72 (m, 2H), 3.56 (m, 1H), 2.87 (m, 1H), 2.30 (s, 6H), 2.20 (m, 1H), 1.94 (m, 1H). LCMS (APCI+): m/z 573 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[C:18](F)[CH:17]=[C:16](Cl)[CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].BrC1SC(C(OCC)=O)=[N:28][C:27]=1C1C=CC(F)=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:27]#[N:28])[CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Reactant: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Product: N#Cc1cccc(-c2sc(C(=O)O)nc2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 8A starting with the compound from Example 4A. 161 mg (76% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[O:9]C)(=[O:3])[CH3:2].CC(O)CC(O)C.CN1CCCC1=O>O.CCOC(C)=O>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[OH:9])(=[O:3])[CH3:2]
Reactant: COC1CCCN1C(C)=O
Agent: CC(O)CC(C)O
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCCC1O

Procedure:
One g of N-acetyl-2-methoxypyrrolidine (largely E plus lesser an amounts of B, C and D), 0.9 g of 2,4-pentandiol and 240 mg of N-methyl-2-pyrrolidone internal standard were heated at 50°-55° C. in 1 mL of H2O. A separate sample was heated in 1 mL of EtOAc. Results in both samples were similar: rapid initial formation of a small peak at 8.02 min (cyclic hemiamidal of the diol?), followed by growth of major product peaks at 8.35 and 8.73 min, the epimeric cyclic acetals. Small quantities of dehydrated product; G (r.t.=4.75 min), and, in the aqueous sample, N-acetyl-2-hydroxypyrrolidine, F (before A at ~5.6 min) were also produced. One of the diols appeared to react faster and to a greater extent than the other. Measurements at 3-4 hr were close to the overnight values: ~87% conversion of A, 60-70% of B and essentially quantitative conversion of C and D.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([OH:58])=O)=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1.CN1CCOCC1.[C:68]1([C:74]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)([C:76]([OH:78])=[O:77])[NH2:75])[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>CN(C=O)C.CO>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][CH:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[OH:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:75][C:74]([C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:76]([OH:78])=[O:77])=[O:58])=[O:53])=[CH:48][CH:47]=2)=[CH:28][CH:29]=1
Reactant: NC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)NC(C(=O)O)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
TBTU (0.016 g, 0.050 mmol) was added to a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.020 g, 0.037 mmol) and NMM (0.012 ml, 0.109 mmol) in DMF (2 ml) at 30° C. After 30 min, 2,2-diphenylglycine (0.009 g, 0.037 mmol, 98%) was added and the mixture was stirred at 30° C. for 2.5 h. The reaction was quenched with water (0.2 ml) and the mixture was diluted with MeOH (2 ml). NaBH4 (0.020 g, 0.529 mmol) was added and the mixture was stirred for 10 min. Ammonium acetate buffer (0.1M, 3 ml) was added and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC, using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, the title compound (0.012 g, 44% yield) was obtained as a white solid. M/z: 752.0. 1H NMR (DMSO, 400 MHz): δ 2.83-2.95 (m, 2H), 3.75 (d, 2H), 4.24-4.28 (m, 1H), 4.54 (s, 1H), 4.68-4.75 (m, 1H), 5.02-5.06 (m, 1H), 6.95-7.03 (m, 2H), 7.04-7.38 (m, 20H), 8.43-8.51 (m, 1H), 8.90 (s, 1H).