Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:25]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[CH2:2][C:1](=[O:3])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:9]=2)[N:16]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1cc(N2CCOCC2)ccc1NC(=O)c1ccccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CC(c2ccccc2OCc2ccccc2)=Nc2ccc(N3CCOCC3)cc21
Yield: 118.5 %

Procedure:
To a solution of 92 (1.2 g, 2.7 mmol) in 1,4 dioxane (150 ml) was added NaOH (0.9 g, 21.4 mmol). The mixture was refluxed for 5 h, concentrated and added 10% NH4Cl (100 ml). The precipitate was collected and washed with H2O and acetone. The crude product was purified by column chromatography (silica gel, CHCl3:MeOH=25:1) to give 113 as yellow solid (1.3 g, 3.2 mmol). Yield: 65.4%; mp 281-283° C.; MS (EI, 70 eV): m/z 412.4 (M+); 1H-NMR (DMSO-d6. 200 MHz): δ 3.15 (m, 4H), 3.77 (m, 4H), 5.12 (s, 2H), 6.30 (s, 1H), 7.36-7.50 (m, 11H), 7.66 (d, J=9.2 Hz, 1H), 11.57 (s, 1H); Anal. Calcd for C26H24N2O3; C, 75.71; H, 5.86; N, 6.79.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.Cl[C:41]([O:43][CH3:44])=[O:42]>>[CH3:44][O:43][C:41]([C:7]1[N:8]([CH3:11])[N:9]=[C:10]2[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]2[Br:1])=[O:42]
Reactant: COC(=O)Cl
Reactant: Cn1cc2cccc(Br)c2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: COC(=O)c1c2cccc(Br)c2nn1C
Temperature: 2.5 °C
Yield: 79.3 %

Procedure:
To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me, 1.50 g, 7.12 mmol) in 50 mL of THE at −78° C. was added a 2 M solution of lithium diisopropylamide in THF/heptane/ethylbenzene (4.3 mL, 8.6 mmol). The solution was stirred at 0-5° C. for 15 m, then rechilled to −78° C. To the solution was added methyl chloroformate (0.66 mL, 8.5 mmol) all at once, and the mixture was stirred while slowly warmed to room temperature over 19 h. The reaction was quenched with silica gel and concentrated. Column chromatography (0→20% EtOAc/hexanes) afforded of 7-bromo-2-methyl-2H-indazole-3-carboxylic acid methyl ester (35a: 1.52 g; 79%; m.p. 131-132) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)[C:5]=1[CH3:21])([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)[C:5]=1[CH3:21]
Reactant: COc1ccnc(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccnc(-c2cc(N)cc(N)c2C)c1
Yield: 98.4 %

Procedure:
A suspension of 2,4-dinitro-6-(4-methoxypyridin-2-yl)toluene (132 mg) in tetrahydrofuran (2 ml) and ethanol (2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 50 mg) under a hydrogen atmosphere for 4 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 2,4-diamino-6-(4-methoxypyridin-2-yl)toluene (103 mg).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]#[N:12])=[CH:6][C:4]=1[OH:5])#[N:2].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.CN(C=O)C>[CH2:13]([O:10][C:8]1[C:7]([C:11]#[N:12])=[CH:6][C:4]([OH:5])=[C:3]([C:1]#[N:2])[CH:9]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCBr
Reactant: N#Cc1cc(O)c(C#N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(C#N)c(O)cc1C#N
Temperature: 120 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
In a 300 ml-reaction vessel, 35.0 g (2.19×10-1M) of 2,5-dicyanohydroquinone, 23.8 g (1.44×10-1M) of n-hexylbromide, 20.0 g (1.45×10-1M) of potassium carbonate and 180 ml of DMF were placed, followed by stirring for 3 hours at 120° C. After the reaction, the reaction mixture was cooled and poured into 500 ml of 4N-hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent. The resultant residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to obtain 17.6 g of a crude product. The crude product was dissolved in ethanol and treated with activated carbon, followed by recrystallization from ethanol to obtain 8.2 g of 4-hexyloxy-2,5-dicyanophenol (Yield: 22.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:14]([NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)(=[O:16])[CH3:15]
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.875 g.) was acetylated with acetic anhydride (7 ml.) and acetic acid (7 ml.) and the acetylation product was recrystallized from ethanol. By the above procedure there was obtained 5-acetylaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as yellow prisms melting at 211°-212° C.
Reaction SMILES: CN1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH2:4][C:3]1=[O:19].[CH2:20]([O:22]C(=O)OCC)[CH3:21]>>[CH2:20]([O:22][C:3]([C:4]1[NH:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:19])[CH3:21]
Reactant: CCOC(=O)OCC
Reactant: CN1C(=O)CN=C(c2ccccc2)c2ccccc21
Product: CCOC(=O)c1[nH]c(-c2ccccc2)c2ccccc12

Procedure:
The starting material can be prepared from 1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and diethylcarbonate in a manner analogous to that described in Example 1. After recrystallization from ethanol, there is obtained 3-phenylisoindole-1-carboxylic acid ethyl ester; m.p. 144°-147° C (decomposition).
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH2:18][C:19]2[N:23]([CH3:24])[N:22]=[CH:21][N:20]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1.[S:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][C:14]1[O:13][N:12]=[C:11]([C:6]2[N:5]3[N:4]=[C:3]([O:17][CH2:18][C:19]4[N:23]([CH3:24])[N:22]=[CH:21][N:20]=4)[C:2]([C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)=[C:10]3[CH:9]=[N:8][N:7]=2)[CH:15]=1
Reactant: OB(O)c1ccsc1
Reactant: Cc1cc(-c2nncc3c(Br)c(OCc4ncnn4C)nn23)no1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(-c2nncc3c(-c4ccsc4)c(OCc4ncnn4C)nn23)no1
Temperature: 90 °C
Reaction time: 24 h
Yield: 34.1 %

Procedure:
A stirred mixture of the bromide (Example 7) (100 mg, 0.26 mmol), thiophene-3-boronic acid (49 mg, 0.38 mmol) and cesium carbonate (167 mg, 0.51 mmol) in dioxan (20 mL) was degassed by evaporating under high vacuum until cold then refilled with N2 and allowed to thaw. This freeze/thaw procedure was repeated 3 times. Pd2(dba)3 (23 mg, 0.026 mmol) and tri-tert-butylphosphine (0.1M solution in dioxane) (0.6 mL, 0.06 mmol) were added and the degassing procedure repeated twice. The mixture was heated at 90° C. under a flow of nitrogen overnight. Further quantities of reagents were added at room temperature: thiophene-3-boronic acid (49 mg, 0.38 mmol), cesium carbonate (167 mg, 0.51 mmol), Pd2(dba)3 (23 mg, 0.026 mmol) and tri-tert-butylphosphine (0.6 mL, 0.06 mmol) followed by the degassing procedure 3 times. Heating was continued at 90° C. for a further 24 h. After cooling the mixture was filtered and the solid washed with EtOAc. The combined organic filtrates were washed with brine, dried (MgSO4) and evaporated. The residue was purified using silica plug chromatography eluting with 1% MeOH/DCM to give the title compound (35 mg, 37%) as a yellow solid. MS (ES+) 395 (M+1). 1H NMR (400 MHz, d6-DMSO) δ2.61 (3H, s), 3.96 (3H, s), 5.74, (2H, s), 7.15 (1H, s), 7.69-7.71 (1H, m), 7.74-7.78 (1H, m), 7.96 (1H, s), 8.03-8.05 (1H, m), 9.85 (1H, s).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:4].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.Br.C(N(CC)CC)C.[ClH:44]>O1CCCC1.C(OCC)C>[ClH:44].[ClH:44].[OH:15][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH3:16])[CH2:24][CH2:25]2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1O
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)CN2CCN(c3ccccc3C)CC2)ccc1O

Procedure:
A solution of 10.9 g (0.04 mol) of methyl 5-(2-bromoacetyl)-2-hydroxybenzoate in 100 ml of dry tetrahydrofuran is added dropwise over 4 hours to a stirred solution of 7.1 g (0.04 mol) of 1-(2-methylphenyl)piperazine and 4.0 g (0.04 mol) of triethylamine in 75 ml of tetrahydrofuran at room temperature. Stirring is continued for 2-12 hours or until the theoretical amount (7.3 g) of triethylamine hydrobromide precipitates. The precipitates is removed by filtration and the filtrate is evaporated to dryness. Addition of 2 equivalents of methanolic HCl and precipitation by addition of ethyl ether at room temperature affords the crude methyl 2-hydroxy-5-[2-[4-(2-methylphenyl)-1-piperazinyl]acetyl]benzoate dihydrochloride (9.4 g). Attempts to purify this product by recrystallization frequently led to decomposition and were subsequently avoided.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([F:16])[CH2:15][C@@:9]1([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:22])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[Pd].ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@@:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([F:16])[CH2:15][C@@:9]1([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:10](=[O:22])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@]1(F)C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (1R*,5S*,6S*)-8-benzyl-6-ethoxycarbonyl-6-fluoro-1-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one (Description 36; 795 mg, 66 mmol), 10% palladium on charcoal (250 mg), ethyl acetate (5 ml) and ethanol(10 mi) was stirred under hydrogen atmosphere (1 atm) at room temperature for 1 hour. The reaction mixture was treated with dichloromethane (500 ml), filtered through a pad of Celite™. The filtrate was concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:4]1[NH:3][CH:2]([CH3:1])[N:7]=[C:6]2[N:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:9]([CH3:11])=[CH:10][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-n2c(C)cc3c(=O)[nH]c(C)nc32)c(C)c1
Product: Cc1cc(C)c(-n2c(C)cc3c2=NC(C)NC=3Cl)c(C)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of compound (5) (18.3 g, 65.0 mmol) in POCl3 (30 mL) was refluxed for 3 hours, cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The combined organic extracts were washed with aqueous sodium bicarbonate, dried, and concentrated under vacuum. The residue was chromatographed (elution with 10% ethyl acetate in hexanes) to afford 16.3 g (84%) of compound (6) as a tan powder.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:14]O>>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH3:14])=[O:5]
Reactant: CC(C)(CO)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)CO
Yield: 57.2 %

Procedure:
3-Hydroxy-2,2-dimethylpropanoic acid (15.00 g, 127.0 mmol) was dissolved in a solution of MeOH (200 mL) and conc. H2SO4 (13.5 g, 254 mmol) and stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with water (2×50 mL), sat. NaHCO3 (aq) (50 mL), water (50 mL), brine (1×50 mL), and dried (Na2SO4). Organic solvent was removed in vacuo to afford methyl 3-hydroxy-2,2-dimethylpropanoate (6.4 g, 57.2%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 3.71 (s, 3H), 3.56 (s, 2H), 2.05-2.04 (m, 1H), 1.19 (s, 6H).
Reaction SMILES: C[Mg]I.[CH2:4](OCC)C.[F:9][C:10]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:11]=1[O:12][C:13]1[C:21]2[N:20]=[CH:19][N:18]([CH3:22])[C:17]=2[C:16]([CH:23]=[O:24])=[CH:15][C:14]=1[C:25]1[C:26]2[CH:35]=[N:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:27]=2[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1>O1CCCC1>[F:9][C:10]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:11]=1[O:12][C:13]1[C:21]2[N:20]=[CH:19][N:18]([CH3:22])[C:17]=2[C:16]([CH:23]([OH:24])[CH3:4])=[CH:15][C:14]=1[C:25]1[C:26]2[CH:35]=[N:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:27]=2[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1
Reactant: CCOCC
Reactant: Cn1cc(-c2cc(C=O)c3c(ncn3C)c2Oc2ccc(F)cc2F)c2cnn(COCC[Si](C)(C)C)c2c1=O
Agent: C[Mg]I
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c2ncn(C)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A 3.0 M solution of methylmagnesium iodide in diethyl ether (21.1 μL, 0.0634 mmol) was added to a solution of 4-(2,4-difluorophenoxy)-1-methyl-5-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-1H-benzimidazole-7-carbaldehyde (0.0478 g, 0.0845 mmol) in tetrahydrofuran (0.734 mL) at 0° C. The resultant reaction mixture was stirred at 0° C. for 1 h, after which time an additional amount of 3.0 M solution of methylmagnesium iodide in diethyl ether (42.2 μL, 0.127 mmol) was added to the reaction mixture and stirring was continued at 0° C. for 30 min. The reaction mixture was quenched at 0° C. with methanol, diluted with methanol, and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (25.2 mg, 51%). LCMS calculated for C29H34F2N5O4Si (M+H)+: m/z=582.2. found: 582.2.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:22]=[CH:21][N:20]=[C:19]3[C:15]=1[N:16]=[CH:17][NH:18]3)[CH2:9][CH2:8]2)=[O:4].[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>O>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:21]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][NH:18]3)=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3](=[O:4])[CH3:2])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:22]=2)[CH2:26][CH2:25]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(CCl)c1ccc2c(c1)CCN2c1ncnc2[nH]cnc12
Solvent: O
Product: CC(=O)c1ccc2c(c1)CCN2c1nc(N[C@H]2CC[C@H](N)CC2)nc2[nH]cnc12
Temperature: 140 °C
Reaction time: 48 h

Procedure:
1.88 g of product obtained in stage 1 above are mixed with 4.8 g of trans-1,4-diaminocyclohexane, and the mixture is then heated at 140° C. for approximately 72 hours. The mixture is allowed to return to ambient temperature for 48 hours. A paste is formed in water, and drying is carried out under vacuum at 50° C. 2.7 g of expected product are obtained, in the form of a beige powder.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]2[C:9](=[C:10]([N+:16]([O-:18])=[O:17])[C:11]([Cl:15])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1>CO>[Cl:15][C:11]1[C:10]([N+:16]([O-:18])=[O:17])=[C:9]2[C:14]([C:5]([O:2][CH3:1])=[CH:6][CH:7]=[N:8]2)=[CH:13][CH:12]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(Cl)ccc2c(Cl)ccnc12
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2c([N+](=O)[O-])c(Cl)ccc12
Yield: 86.5 %

Procedure:
Sodium methoxide (2.0 g, 37.0 mmol) was added to a solution of 4,7-dichloro-8-nitro-quinoline (Intermediate 68) (3.0 g, 12.3 mmol) in MeOH (20 ml) and the reaction was heated under reflux for 24 h. The solvent was removed in vacuo. The residue was dissolved in EtOAc (150 ml) and washed with water, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by column chromatography with EtOAc/heptane (4:1) to give the title compound (2.54 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].Cl[CH2:15][O:16][CH2:17][CH3:18].O>CN(C=O)C.CCN(C(C)C)C(C)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([O:13][CH2:15][O:16][CH2:17][CH3:18])([CH3:11])[CH3:12]
Reactant: CCOCCl
Reactant: Cc1cc(C(C)(C)O)c(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOCOC(C)(C)c1cc(C)c(F)cc1Br
Temperature: 100 °C
Yield: 89 %

Procedure:
To a solution of 2-(2-bromo-4-fluoro-5-methylphenyl)propan-2-ol (2.0 g, 8.1 mmol) in DMF:DIPEA (2:1, 9 mL) was added (chloromethoxy)ethane (1.53 g, 16.2 mmol). The reaction mixture was heated at 100° C. in microware equipment for 1.5 h. Water (200 mL) was added and the mixture was extracted with DCM (200 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE-EA (30:1) to give 1-bromo-2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylbenzene (2.2 g, 89%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.208-7.234 (m, 2H), 4.572 (s, 2H), 3.594 (q, J=7.0 Hz, 2H), 2.149 (s, 3H), 1.665 (s, 6H), 1.115 (t, J=7.0 Hz, 3H) ppm.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][CH3:11])[CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O.[NH3:19]>CO>[C:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][C@H:9]([O:10][CH3:11])[C@H:5]1[C:3](=[O:2])[NH2:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1[C@@H](OC)CCN1C(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(N)=O
Yield: 31 %

Procedure:
(2S,3S)-3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (518 mg, 2.0 mmol) was stirred in 7M ammonia in methanol (5 mL) for 4 days. The reaction mixture was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, gradient 0 to 6% methanol in DCM) to give (2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (153 mg, 31%). 1H NMR 400 MHz (DMSO-d6) δ: 7.54 (1H, br, s), 7.09 (1H, br, s), 4.09-4.00 (1H, m), 3.78 (1H, m), 3.47 (1H, m), 3.26 (3H, s), 1.93 (3H, m), 1.37 (9H, s)
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[CH3:3].[F:8][C:9]([P:15]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])(=[O:17])[O-:16])([F:14])[C:10]([F:13])([F:12])[F:11].[CH3:25][N:26]([C+:28]([N:30]([CH3:32])[CH3:31])Cl)[CH3:27]>C(Cl)(Cl)Cl>[F:14][C:9]([P:15]([C:18]([F:23])([F:24])[C:19]([F:22])([F:21])[F:20])(=[O:16])[O-:17])([F:8])[C:10]([F:13])([F:12])[F:11].[CH3:1][N:2]([CH3:3])[C:28](=[N+:26]([CH3:27])[CH3:25])[N:30]([CH3:32])[CH3:31]
Reactant: CN(C)[C+](Cl)N(C)C
Reactant: CN(C)[Si](C)(C)C
Agent: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of dry chloroform and 1.85 g (15.78 mmol) of N,N-dimethyltrimethylsilylamine are added to 6.23 g (14.27 mmol) of bis(dimethylamino)chlorocarbenium bis(pentafluoroethyl)phosphinate. The reaction mixture is stirred for 1 hour at room temperature, and all volatile products are removed under reduced pressure. The residue is subsequently dried at 7.0 Pa and an oil-bath temperature of 50° C. for 1 hour, giving 6.29 g of hexamethylguanidinium bis(pentafluoroethyl)phosphinate, corresponding to a yield of 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2)([O-])=O.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2cccnc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc2c(ccn2Cc2cccnc2)c1
Yield: 71.7 %

Procedure:
To a stirred suspension of nitroindole (D46) (0.63 g, 2.5 mmol), and iron powder (0.41 g, 7.2 mmol) in methanol (20 ml) was added a solution of ammonium chloride (0.66 g, 12.4 mmol) in water (13 ml). The mixture was then heated under reflux for 12 h, then filtered while hot and evaporated. The residue was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried and evaporated to give the title compound (0.40 g, 72%) as a gum.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH3:10])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:12][OH:13].CO.O.O.O.C([O-])(=O)C.[Na+]>O.[Cl-].[Na+].O>[CH3:10][C:6]1[CH:5]=[C:4]([C:1](=[N:12][OH:13])[CH3:2])[CH:9]=[CH:8][N:7]=1
Reactant: NO
Reactant: CC(=O)c1ccnc(C)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(=NO)c1ccnc(C)c1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 67 %

Procedure:
To a stirred suspension of 4-acetyl-2-methyl-pyridine [CAS No. 2732-28-7] (9.7 g, 71.8 mmol) in water (115 ml) was added at room temperature hydroxylamine hydrochloride (8.48 g, 122 mmol) and the mixture was heated to 70° C. At this temperature methanol (145 ml) was added dropwise over a period of 15 min and afterwards a solution of sodium acetate trihydrate (25.4 g, 187 mmol) in water (115 ml) was added dropwise over a period of 15 min. The reaction mixture was stirred at 80° C. for 3.5 h, brine (150 ml) was added and the solution was extracted with ethyl acetate (2×250 ml). The combined organic layers were washed with brine (150 ml), dried (MgSO4) and evaporated. The crude product was purified by crystallization from ethyl acetate/hexane to give 1-(2-methyl-pyridin-4-yl)-ethanone oxime (7.25 g, 67%) as an off-white solid; mp 154° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[C:12]2[O:17][CH2:16][O:15][NH:14][C:13]=2[CH:18]=[CH:19][C:20]=1[F:21]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:18]=[C:19]3[O:15][CH2:16][O:17][C:12]=2[C:11]([F:10])=[C:20]3[F:21])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1ccc2c(c1F)OCON2
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1cc2c(F)c(F)c1OCO2

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoromethylenedioxyaniline gave 2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.09 (d, 1H, J=3 Hz), 7.70 (d, 1H, J=2.4 Hz), 7.10 (dd, 1H, J=2.4 and 8.7 Hz), 7.06 (t, 1H, J=8.1 Hz), 6.97 (bs, 1H); 19F NMR (CDCl3): −14175 and −44562; LCMS: purity: 95%; MS (m/e): 304 (MH+).